Methods for predicting and treating immunotherapy toxicity based on immune cell populations

Abstract

The present disclosure generally relates to compositions and methods for predicting or diagnosing immune-related adverse events (irAEs) in subjects with cancer before, during, or after immune checkpoint inhibitor (ICI) treatment. The methods include evaluating transcripts, autoantibody levels, cytokine levels, and immune cells. The irAEs can be ICI-associated myositis, ICI-associated myocarditis, or ICI-associated myositis and myocarditis. The present disclosure relates to identifying biomarkers for predicting, diagnosing, or monitoring immune-related adverse events associated with immune checkpoint inhibitor therapy.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 382,972, entitled "METHODS OF PREDICTING AND TREATING IMMUNOTHERAPY TOXICITY BASED ON BIOMARKERS INCLUDING RNA," filed November 9, 2022, and U.S. Provisional Patent Application No. 63 / 503,946, entitled "METHODS OF PREDICTING AND TREATING IMMUNOTHERAPY TOXICITY BASED ON BIOMARKERS INCLUDING RNA," filed May 23, 2023, the contents of which are incorporated herein by reference in their entireties.

[0002] Acknowledgments for Government Support This invention was made with support under Grant Nos. AI156189 and CA201543 awarded by the National Institutes of Health (NIH). The Government has certain rights in this invention. [Background technology]

[0003] background 1. Field

[0004] The present disclosure relates to the identification of biomarkers for predicting, diagnosing, or monitoring immune-related adverse events associated with immune checkpoint inhibitor therapy.

[0005] 2.Background

[0006] Immune-related adverse events (irAEs) can affect nearly every organ system during and after treatment with immune checkpoint inhibitors (ICIs). ICI-associated myositis and myocarditis are rare but potentially fatal toxicities. Understanding the etiology of these cases and their pathophysiological differences from non-ICI-associated inflammatory myopathies and myocarditis is crucial for optimal monitoring and treatment of patients receiving ICIs. Summary of the Invention [Means for solving the problem]

[0007] overview In some aspects, the present disclosure provides a method for predicting risk of developing and / or diagnosing an immune-related adverse event (irAE) associated with immune checkpoint inhibitor (ICI) treatment in a subject, comprising the steps of providing a sample from the subject, assessing one or more transcript levels in the sample, and predicting / diagnosing risk of developing an irAE in the subject, wherein the subject has a transcript level of leukocyte immunoglobulin-like receptor B4 (LILRB4), cytokine-induced SH2-containing protein (CISH), poly(ADP- Ribose polymerase family member 9 (PARP9), ring finger protein 145 (RNF145), asialoglycoprotein receptor 2 (ASGR2), solute carrier family 16 member 13 (SLC16A13), lysophosphatidic acid receptor 6 (LPAR6), GTPase, IMAP family member 7 (GIMAP7), C-X-C motif chemokine receptor 6 (CXCR6), dehydrogenase / reductase 9 (DHRS9), Fc gamma receptor Ic, pseudogene (FCGR1CP), and / or ankyrin If transcript levels of one or more of the following are elevated before ICI treatment (baseline) compared to control samples, and / or if transcript levels of one or more of the following are elevated: amphiregulin (AREG), epiregulin (EREG), oncostatin M (OSM), cysteine- and serine-rich nuclear protein 1 (CSRNP1), DNA damage-induced transcript 4 (DDIT4), IL-10 (interleukin-10), prostaglandin-endoperoxide synthase (PTGS2), dual specificity phosphatase 1 (DUS), P1), CXC chemokine receptor type 4 (CXCR4), nuclear factor, interleukin 3-regulated (NFIL3), Fos proto-oncogene, AP-1 transcription factor subunit (FOS), NFKB inhibitor alpha (NFKBIA), PPP1R15A (protein phosphatase 1 regulatory subunit 15A), CD79A, JunB proto-oncogene, AP-1 transcription factor subunit (JUNB), CXC motif chemokine ligand 8 (CXCL8), early growth response 1 (EGR1), G0 / G1 switch 2 (G0S2), paired box 8 (PAX8),Activating transcription factor 6 beta (ATF6B), PAX8 antisense RNA1 (PAX8-AS1), RNA, variant U1 micronuclear 19 (RNVU1-19), vitelline membrane outer layer 1 homolog (VMO1), heparin-binding EGF-like growth factor (HBEGF), coiled-coil domain-containing 144A (CCDC144A), shisa family member 8 (SHISA8), nuclear receptor subfamily 4 group A member 2 (NR4A2), prostaglandin E synthase (PTGES), synapsin I (SYN1), C-X-C motif chemokine ligand 2 (CXCL2), peripheral myelin protein 22 (P MP22), CD83, early growth response 3 (EGR3), NUAK family kinase 1 (NUAK1), nocturnin (NOCT), atonal bHLH transcription factor 8 (ATOH8), polo-like kinase (PLK2), inhibitor of DNA binding 1 (ID1), adrenergic receptor beta 1 (ADRB1), snail family transcriptional repressor 1 (SNAI1), notch receptor 3 (NOTCH3), activating transcription factor 3 (ATF3), dual specificity phosphatase 2 (DUSP2), circadian rhythm regulator 1 (PER1), TNF superfamily member 9 (TNFSF9), MAF bzip transcription factor F (MAFF), microRNA 4420 (MIR4420), glutathione peroxidase (GPX3), TNF-alpha-inducible protein 3 (TNFAIP3), potassium voltage-gated channel modifier subfamily G member 1 (KCNG1), prostaglandin-endoperoxidase synthase 2 (PTGS2), A-kinase anchor protein 5 (AKAP5), dual specificity phosphatase 1 (DUSP1), diacylglycerol kinase kappa (DGKK), beta-1,4,-N-acetyl- Galactosaminyltransferase 3 (B4GALNT3), tribbles pseudokinase 1 (TRIB1), holobol-12-myristate-13-acetate-inducible protein 1 (PMAIP1), C-X-C motif chemokine receptor 4 (CXCR4), tumor protein p53-inducible nuclear protein 2 (TP53INP2), nuclear factor, interleukin-3-regulated (NFIL3), dual specificity phosphatase 4 (DUSP4), NFKB inhibitor alpha (NFKBIA),Arginine vasopressin-inducible 1 (AVPI1), CD79a, ADP-ribosylation factor-like GTPase 4D (ARL4D), polymeric IgA and IgM binding chain (JCHAIN), BTG anti-proliferative factor 2 (BTG2), TLE family member 1, transcriptional corepressor (TLE1), nuclear transport factor 2-like nuclear export factor 1 (NXT1), transduction factor of ERBB2 1 (TOB1), phosphodiesterase 4D (PDE4D), DNAJ heat shock protein family member B1 (DNAJB1), AT-rich interacting domain 5B (ARID5B), and predicting a subject to have a high risk of developing an irAE or being diagnosed with an irAE when the transcript level of one or more of G protein-coupled receptor 153 (GPR153), KLF transcription factor 9 (KLF9), SBDS ribosome maturation factor (SBDS), immediate early response 2 (IER2), TSC22 domain family member 3 (TSC22D3), A-type GABA receptor-associated protein-like 1 (GABARAPL1), JunD proto-oncogene, AP-1 transcription factor subunit (JUND), RUNX family transcription factor 3 (RUNX3), BABAM2 antisense RNA 1 (BRE-AS1), putative salt-inducible kinase (kinas) 1B (LOC102724428), FAM46C (FAM46C), and / or common receptor for phosphoinositides 1-associated scaffold protein (GRASP) is low in the subject compared to the transcript level in a control sample. ,

[0008] Further, a method of monitoring a subject's risk of developing an irAE associated with ICI treatment includes the steps of providing a sample from the subject, assessing the level of one or more transcripts in the sample, and monitoring the risk of developing an irAE in the subject, wherein the subject does not express one of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, ANKRD34B, and / or FCGR1CP. or multiple transcript levels are elevated before ICI treatment (baseline) compared to transcript levels in control samples, and / or AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PT GES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, GPX3, T NFAIP3, KCNG1, PTGS2, AKAP5, DUSP1, DGKK, B4GALNT3, TRIB1, PMAIP1, CXCR4, TP53INP2, NFIL3, DUSP4, NFKBIA, AVPI1, CD79a, ARL4D, JCHAIN, B predicting that the subject has a high risk of developing an irAE if the transcript level of one or more of TG2, TLE1, NXT1, TOB1, PDE4D, DNAJB1, ARID5B, GPR153, KLF9, SBDS, IER2, TSC22D3, JUND, GABARAPL1, RUNX3, BRE-AS1, LOC102724428, FAM46C, and / or GRASP is low in a sample derived from the subject compared to the transcript level in a control sample.

[0009] In some embodiments, the irAE comprises ICI-associated myositis, ICI-associated myocarditis, or ICI-associated myositis and myocarditis.

[0010] In some embodiments of the method, the assessment of transcript levels is performed prior to ICI treatment.

[0011] In some embodiments, a subject is predicted to have an elevated risk of developing an irAE if the transcript levels of one or more of LILRB4, CISH, and / or PARP9 are elevated prior to ICI treatment (baseline) compared to the transcript levels in a control sample.

[0012] In some embodiments, a subject is predicted to have an elevated risk of developing an irAE if the transcript levels of one or more of LILRB4, CISH, GIMAP7, CXCR6, DHRS9, ANKRD34B, and / or FCGR1CP are elevated before ICI treatment (baseline) compared to the transcript levels in a control sample.

[0013] In some embodiments, the subject is diagnosed with a tumor phenotype characterized by the following: AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD A high risk of developing an irAE is predicted when the transcript levels of one or more of 83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, BRE-AS1, LOC102724428, and / or GRASP are low compared to the transcript levels in a control sample before ICI treatment.

[0014] In some embodiments, a subject is predicted to have an elevated risk of developing an irAE if the transcript level of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, and / or JUNB is low compared to the transcript level in a control sample before ICI treatment.

[0015] In some embodiments, a subject is predicted to have an elevated risk of developing an irAE if the transcript levels of one or more of AREG, EREG, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, and / or SHISA8 are low compared to the transcript levels in a control sample before ICI treatment.

[0016] In some embodiments, a subject is predicted to have an elevated risk of developing an irAE if the transcript level of one or more of AREG, EREG, CXCL8, EGR1, PAX8, ATF6B, VMO1, HBEGF, BRE-AS1, NR4A2, OSM, NOCT, PLK2, LOC102724428, DUSP2, GRASP, PER1, TNFSF9, CSRNP1, MAFF, TNFAIP3, DUSP1, TRIB1, PMAIP1, FAM46C, NXT1, and / or KLF9 is low compared to the transcript level in a control sample before ICI treatment.

[0017] In some embodiments, a subject is predicted to have an increased risk of developing an irAE if the transcript level of PARP9 is elevated compared to the transcript level in a control sample before ICI treatment (baseline) and / or if the transcript level of one or more of CD79A, CD83, PLK2, PDE4D, TR1B1, EREG, CXCL8, EGR3, JUNB, DUSP1, NFKBIA, TNFSF9, TNFAIP3, IL-10, JUND, FOS, RUNX3, and / or TSC22D3 is low compared to the transcript level in a control sample before ICI treatment (baseline).

[0018] In some embodiments, the subject is diagnosed with a leukemia if the transcript levels of one or more of PARP9, CISH, CXCR6, LPAR6, and / or ASGR2 are elevated prior to ICI treatment (baseline) compared to the transcript levels in a control sample, and / or if the transcript levels of one or more of KLF9, CXCR4, ATF6B, CD79A, CD83, PLK2, GRASP, PPP1R15A, GPX3, PARP9, BTG2, PTGS2, NOTCH3, AKAP5, PDE4D, SBDS, TRIB1, SNAI1, PAX8, NFIL3, EREG, AREG, DGKK, PTGES, CS A high risk of irAE is predicted when the transcript levels of one or more of RNP1, DNAJB1, CXCL8, OSM, ARID5B, ID1, NR4A2, EGR3, JUNB, TLE1, CXCL2, DUSP1, GPR153, G0S2, ATF3, NFKBIA, TNFS9, NUAK1, ATOH8, TNFAIP3, ADRB1, HBEGF, IL-10, JUND, FOS, GABARAPL1, PMAIP1, DDIT4, and / or EGR1 are low compared to the transcript levels in control samples before ICI treatment (baseline).

[0019] In some embodiments, the sample is whole blood, serum, plasma, cerebrospinal fluid, pleural fluid, pericardial fluid, peritoneal fluid, bone marrow, or tissue, urine, cerebrospinal fluid (CSF), or other bodily fluid.

[0020] In some embodiments, the ICI treatment is administered as part of a cancer treatment.

[0021] In some embodiments, the ICI treatment comprises administration of an inhibitor of PD-1, PD-L1, TIM-3, LAG-3, CTLA-4, CSF-1R, or any combination thereof.

[0022] In some embodiments, the step of assessing transcript levels (step b) comprises RNA-seq, nanopore sequencing, nanostring, multiplex RT-PCR, singleplex RT-PCR, NASBA, fluorometry, or spectrophotometry.

[0023] In some embodiments, the method further comprises assessing the expression of one or more of Mi-2, GAD65, myosin, thyroglobulin, and / or TPO in a sample from the subject.

[0024] In some embodiments, the evaluating comprises determining whether expression of one or more autoantibodies is elevated in a sample from the subject relative to its abundance in a control sample.

[0025] In some aspects, the method further comprises assessing expression of one or more of CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, and / or CXCL10 in a sample from the subject.

[0026] In some embodiments, the evaluating comprises determining whether expression of one or more cytokines is elevated in a sample from the subject relative to expression in a control sample.

[0027] In some embodiments, the method further comprises assessing the abundance of one or more of PD-L+ naive B cells, switched memory B cells, and / or CTLA-4+ monocytes in a sample from the subject.

[0028] In some embodiments, assessing includes determining whether the sample from the subject has a decreased abundance of one or more PD-L+ naive B cells and / or switched memory B cells, and / or an increased abundance of CTLA-4+ monocytes, compared to abundance in a control sample.

[0029] In some embodiments, the method further comprises repeating steps (a)-(c) at a second time point, thereby allowing determination of a change in the subject's risk of developing an irAE and / or diagnosis of an irAE in a sample from the subject compared to a control sample.

[0030] In some embodiments, the method comprises detecting a subject for a pre-ICI treatment (baseline) transcript level of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, ANKRD34B, and / or FCGR1CP that is lower or similar to the transcript level in a control sample, and / or AREG, EREG, OSM, CSRNP, or EGFR. 1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-A S1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID 1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, GPX3, TNFAIP3, KCNG1, PTGS2, AKAP5, DUSP1, DGKK, B4G ALNT3, TRIB1, PMAIP1, CXCR4, TP53INP2, NFIL3, DUSP4, NFKBIA, AVPI1, CD79a, ARL4D, JCHAIN, BTG2, TLE1, NXT1, TOB1, PDE4 The method further comprises predicting that the subject has a low risk if the transcript levels of one or more of D, DNAJB1, ARID5B, GPR153, KLF9, SBDS, IER2, TSC22D3, JUND, GABARAPL1, RUNX3, BRE-AS1, LOC102724428, FAM46C, and / or GRASP are elevated or equivalent during ICI treatment compared to the transcript levels in the control sample.

[0031] In some embodiments, the method further comprises treating the subject with ICI therapy if the subject is predicted to have a low risk of developing an irAE.

[0032] In some embodiments, the method further comprises treating a subject predicted to have a high risk of developing an irAE with a non-ICI therapy, or treating the subject with an ICI therapy and an irAE-mitigating therapy, wherein the irAE-mitigating therapy is selected from a corticosteroid (e.g., prednisone, methylprednisolone, dexamethasone, budesonide), a TNF inhibitor (e.g., infliximab), or hormone replacement (e.g., hydrocortisone, levothyroxine), a CXCL8 inhibitor (e.g., repertaxin), or any combination thereof.

[0033] In some aspects, the disclosure provides a method of treating a subject having cancer, comprising the steps of: (a) providing a sample from the subject; (b) assessing one or more transcript levels in the sample; and (c) predicting the subject's risk of developing an irAE, wherein the subject has a transcript level of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, ANKRD34B, and / or FCGR1CP that is higher than or equal to a control sample. A diagnosis of low risk is made when the transcript levels are lower than or equal to those in the following: AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3 , NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, GPX3, TNFAIP3, KCNG1, PTGS2, AKAP5, DUSP1, DG KK, B4GALNT3, TRIB1, PMAIP1, CXCR4, TP53INP2, NFIL3, DUSP4, NFKBIA, AVPI1, CD79a, ARL4D, JCHAIN, BTG2, TLE1, NXT1, TOB1, PDE4D, DNAJB1, ARID5 A diagnosis of having a low risk is made when the transcript level of one or more of B, GPR153, KLF9, SBDS, IER2, TSC22D3, JUND, GABARAPL1, RUNX3, BRE-AS1, LOC102724428, FAM46C, and / or GRASP is elevated compared to or equal to the transcript level in a control sample, and LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, ANKRD34B,and / or FCGR1CP, and / or AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, GPX3, TNFAIP3, KCNG1, PTGS2, AKAP5, DUSP1, DGKK, B4GALNT3, TRIB1 , PMAIP1, CXCR4, TP53INP2, NFIL3, DUSP4, NFKBIA, AVPI1, CD79a, ARL4D, JCHAIN, BTG2, TLE1, NXT1, TOB1, PDE4D, DNAJB1, ARID5B, GPR153, KLF9, SBDS, IER2, TSC22D3, JUND, GABARAPL1, RUNX3, BRE-AS1, LOC102724428, FAM46C, and / or GRASP transcripts. the subject is diagnosed as having an elevated risk if the level is lower than the transcript level in the control sample; and (d) treating the subject with (i) ICI therapy if the subject is diagnosed as having a low risk of developing an irAE, (ii) non-ICI therapy if the subject is diagnosed as having an elevated risk of developing an irAE, or (iii) ICI therapy and irAE mitigation therapy if the subject is diagnosed as having an elevated risk of developing an irAE.

[0034] In some embodiments, the irAE comprises ICI-associated myositis, ICI-associated myocarditis, or ICI-associated myositis and myocarditis.

[0035] In some embodiments, a subject is predicted to have an elevated risk of developing an irAE if the transcript levels of one or more of LILRB4, CISH, and / or PARP9 are elevated prior to ICI treatment (baseline) compared to the transcript levels in a control sample.

[0036] In some embodiments, a subject is predicted to have an elevated risk of developing an irAE if the transcript levels of one or more of LILRB4, CISH, GIMAP7, CXCR6, DHRS9, ANKRD34B, and / or FCGR1CP are elevated before ICI treatment (baseline) compared to the transcript levels in a control sample.

[0037] In some embodiments, the subject is diagnosed with a tumor necrosis factor (TNF-α), ... A high risk of developing an irAE is predicted when the transcript levels of one or more of D83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, BRE-AS1, LOC102724428, and / or GRASP are low compared to the transcript levels in a control sample before ICI treatment.

[0038] In some embodiments, a subject is predicted to have an elevated risk of developing an irAE if the transcript level of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, and / or JUNB is low compared to the transcript level in a control sample before ICI treatment.

[0039] In some embodiments, a subject is predicted to have an elevated risk of developing an irAE if the transcript levels of one or more of AREG, EREG, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, and / or SHISA8 are low compared to the transcript levels in a control sample before ICI treatment.

[0040] In some embodiments, a subject is predicted to have an elevated risk of developing an irAE if the transcript level of one or more of AREG, EREG, CXCL8, EGR1, PAX8, ATF6B, VMO1, HBEGF, BRE-AS1, NR4A2, OSM, NOCT, PLK2, LOC102724428, DUSP2, GRASP, PER1, TNFSF9, CSRNP1, MAFF, TNFAIP3, DUSP1, TRIB1, PMAIP1, FAM46C, NXT1, and / or KLF9 is low compared to the transcript level in a control sample before ICI treatment.

[0041] In some embodiments, a subject is predicted to have an increased risk of an irAE if the transcript level of PARP9 is elevated compared to the transcript level in a control sample before ICI treatment (baseline) and / or if the transcript level of one or more of CD79A, CD83, PLK2, PDE4D, TR1B1, EREG, CXCL8, EGR3, JUNB, DUSP1, NFKBIA, TNFSF9, TNFAIP3, IL-10, JUND, FOS, RUNX3, and / or TSC22D3 is low compared to the transcript level in a control sample before ICI treatment (baseline).

[0042] In some embodiments, the subject is diagnosed with a leukemia if the transcript levels of one or more of PARP9, CISH, CXCR6, LPAR6, and / or ASGR2 are elevated prior to ICI treatment (baseline) compared to the transcript levels in a control sample, and / or if the transcript levels of one or more of KLF9, CXCR4, ATF6B, CD79A, CD83, PLK2, GRASP, PPP1R15A, GPX3, PARP9, BTG2, PTGS2, NOTCH3, AKAP5, PDE4D, SBDS, TRIB1, SNAI1, PAX8, NFIL3, EREG, AREG, DGKK, PTGES, CS A high risk of irAE is predicted when the transcript levels of one or more of RNP1, DNAJB1, CXCL8, OSM, ARID5B, ID1, NR4A2, EGR3, JUNB, TLE1, CXCL2, DUSP1, GPR153, G0S2, ATF3, NFKBIA, TNFS9, NUAK1, ATOH8, TNFAIP3, ADRB1, HBEGF, IL-10, JUND, FOS, GABARAPL1, PMAIP1, DDIT4, and / or EGR1 are low compared to the transcript levels in control samples before ICI treatment (baseline).

[0043] In some embodiments, the assessment further comprises detecting expression of one or more of CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, and / or CXCL10 in a sample from the subject.

[0044] In some embodiments, the evaluating comprises determining whether expression of one or more cytokines is elevated in a sample from the subject relative to expression in a control sample.

[0045] In some embodiments, the evaluation further comprises detecting expression of one or more of Mi-2, GAD65, myosin, thyroglobulin, and / or TPO in a sample from the subject.

[0046] In some embodiments, the evaluating comprises determining whether expression of one or more autoantibodies is elevated in a sample from the subject relative to expression in a control sample.

[0047] In some embodiments, the method further comprises assessing the abundance of one or more of PD-L+ naive B cells, switched memory B cells, and / or CTLA-4+ monocytes in a sample from the subject.

[0048] In some embodiments, assessing includes determining whether the sample from the subject has a decreased abundance of one or more PD-L+ naive B cells and / or switched memory B cells, and / or an increased abundance of CTLA-4+ monocytes, compared to abundance in a control sample.

[0049] In some embodiments, the ICI treatment comprises administration of an inhibitor of PD-1, PD-L1, TIM-3, LAG-3, CTLA-4, CSF-1R, or any combination thereof.

[0050] Further, there is provided a method for identifying the presence of at least one differentially expressed transcript associated with an irAE in a biological sample of a subject having cancer, comprising the steps of providing a sample from the subject and assessing transcript levels in the sample, wherein the assessment includes assessing one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, ANKRD34B, and / or FCGR1CP. Whether multiple transcript levels are elevated compared to transcript levels in control samples, including AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, C XCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, GPX3, TN FAIP3, KCNG1, PTGS2, AKAP5, DUSP1, DGKK, B4GALNT3, TRIB1, PMAIP1, CXCR4, TP53INP2, NFIL3, DUSP4, NFKBIA, AVPI1, CD79a, ARL4D, J detecting whether the transcript level of one or more of CHAIN, BTG2, TLE1, NXT1, TOB1, PDE4D, DNAJB1, ARID5B, GPR153, KLF9, SBDS, IER2, TSC22D3, JUND, GABARAPL1, RUNX3, BRE-AS1, LOC102724428, FAM46C, and / or GRASP is lower than the transcript level in the control sample.

[0051] In some embodiments, the subject is planning to undergo immune checkpoint inhibitor (ICI) treatment.

[0052] In some embodiments, the irAE comprises ICI-associated myositis, ICI-associated myocarditis, or ICI-associated myositis and myocarditis.

[0053] In some embodiments, the method further comprises detecting expression of one or more of CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, and / or CXCL10 in a sample from the subject.

[0054] In some embodiments, the evaluating comprises determining whether expression of one or more cytokines is elevated in a sample from the subject relative to expression in a control sample.

[0055] In some embodiments, the method further comprises detecting expression of one or more of Mi-2, GAD65, myosin, thyroglobulin, and / or TPO in a sample from the subject.

[0056] In some embodiments, the evaluating comprises determining whether expression of one or more autoantibodies is elevated in a sample from the subject relative to expression in a control sample.

[0057] In some embodiments, the method further comprises assessing the abundance of one or more of PD-L+ naive B cells, switched memory B cells, and / or CTLA-4+ monocytes in a sample from the subject.

[0058] In some embodiments, assessing includes determining whether the abundance of one or more of PD-L+ naive B cells and / or switched memory B cells is decreased, and / or whether the abundance of CTLA-4+ monocytes is increased, in the sample from the subject compared to the abundance in a control sample.

[0059] In some embodiments, the assessment includes determining a baseline or pre-treatment profile that correlates with future toxicity.

[0060] In some embodiments, the baseline or pre-treatment profile comprises elevated transcript levels of one or more of LILRB4, CISH, and / or PARP9 compared to the transcript levels in a control sample.

[0061] In some embodiments, the baseline or pre-treatment profile comprises elevated transcript levels of one or more of many of LILRB4, CISH, GIMAP7, CXCR6, DHRS9, ANKRD34B, and / or FCGR1CP compared to the transcript levels in a control sample.

[0062] In some embodiments, the baseline or pre-treatment profile includes any of the following: AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, and / or GRASP, wherein the transcript level of one or more of PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, BRE-AS1, LOC102724428, and / or GRASP is lower compared to the transcript level in a control sample.

[0063] In some embodiments, the baseline or pre-treatment profile comprises a lower transcript level of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, and / or JUNB compared to the transcript level in a control sample.

[0064] In some embodiments, the baseline or pre-treatment profile comprises lower transcript levels of one or more of AREG, EREG, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, and / or SHISA8 compared to the transcript levels in a control sample.

[0065] In some embodiments, the baseline or pre-treatment profile comprises a reduced transcript level of one or more of AREG, EREG, CXCL8, EGR1, PAX8, ATF6B, VMO1, HBEGF, BRE-AS1, NR4A2, OSM, NOCT, PLK2, LOC102724428, DUSP2, GRASP, PER1, TNFSF9, CSRNP1, MAFF, TNFAIP3, DUSP1, TRIB1, PMAIP1, FAM46C, NXT1, and / or KLF9 compared to the transcript level in the control sample.

[0066] In some embodiments, the baseline or pre-treatment profile comprises elevated transcript levels of PARP9 compared to the transcript levels in a control sample, and / or reduced transcript levels of one or more of CD79A, CD83, PLK2, PDE4D, TR1B1, EREG, CXCL8, EGR3, JUNB, DUSP1, NFKBIA, TNFSF9, TNFAIP3, IL-10, JUND, FOS, RUNX3, and / or TSC22D3 compared to the transcript levels in a control sample.

[0067] In some embodiments, the baseline or pre-treatment profile includes elevated transcript levels of one or more of PARP9, CISH, CXCR6, LPAR6, and / or ASGR2 compared to the transcript levels in the control sample, and / or elevated transcript levels of one or more of KLF9, CXCR4, ATF6B, CD79A, CD83, PLK2, GRASP, PPP1R15A, GPX3, PARP9, BTG2, PTGS2, NOTCH3, AKAP5, PDE4D, SBDS, TRIB1, SNAI1, PAX8, NFIL3, EREG, and / or EGR1, wherein the transcript level of one or more of AREG, DGKK, PTGES, CSRNP1, DNAJB1, CXCL8, OSM, ARID5B, ID1, NR4A2, EGR3, JUNB, TLE1, CXCL2, DUSP1, GPR153, G0S2, ATF3, NFKBIA, TNFS9, NUAK1, ATOH8, TNFAIP3, ADRB1, HBEGF, IL-10, JUND, FOS, GABARAPL1, PMAIP1, DDIT4, and / or EGR1 is lower compared to the transcript level in a control sample.

[0068] In some embodiments, the control sample is obtained from a subject who has a low risk of developing an irAE.

[0069] In some aspects, the transcript levels of the disclosed methods are relative transcript levels. [Brief explanation of the drawings]

[0070] [Figure 1] Figure 1 shows a contour plot showing definitive surface markers in clusters (immune cell subsets) for CyTOF analysis.

[0071] [Figure 2A]Figures 2A-2K show cytokine profiles in myositis / myocarditis cases and non-toxicity controls. Figure 2A shows baseline cytokines. Figures 2B-2H show baseline cytokines with significant differences depending on the occurrence and grade of myositis / myocarditis. Figure 2I shows changes in cytokines after ICI initiation with significant differences depending on the occurrence and grade of myositis / myocarditis. Figures 2J-2K show changes in cytokines after ICI initiation with significant differences depending on the occurrence and grade of myositis / myocarditis. ICI, immune checkpoint inhibitor; irAE, immune-related adverse event; NT, non-toxicity. [Figure 2BC] Same as above [Figure 2DE] Same as above [Figure 2FG] Same as above [Figure 2HI] Same as above [Figure 2JK] Same as above

[0072] [Figure 3A] Figures 3A-3F show autoantibody profiles in myositis / myocarditis cases and non-toxicity controls. Figure 3A shows baseline autoantibodies. Figures 3B-3F show baseline autoantibodies with significant differences depending on the occurrence and grade of myositis / myocarditis. [Figure 3BC] Same as above [Figure 3DE] Same as above [Figure 3F] Same as above

[0073] [Figure 4AB]Figures 4A-4C show immune cell profiles in myositis / myocarditis cases and non-toxicity controls. Figure 4A shows the identification of 28 clusters (immune cell subsets) using CyTOF. Four immune cell subsets showing significant differences between irAE cases and non-toxicity controls are shown. Figure 4B shows that in pretreatment baseline samples, irAE cases had reduced PD-L1+ naive B cells (P = 0.004), reduced switched memory B cells (P = 0.03), and increased CTLA4+ monocytes (P = 0.03) compared with non-toxicity controls (Mann-Whitney test). Figure 4C shows that after ICI initiation, irAE cases had a higher increase in PD-L1+ naive B cells (P = 0.03), switched memory B cells (P = 0.02), and CXCR3+ CD8+ T cells (P = 0.01) (two-way ANOVA). [Figure 4C] Same as above

[0074] [Figure 5A]Figures 5A-5D show transcriptional profiles in myositis / myocarditis cases (N = 4) and non-toxicity controls (N = 3) using bulk RNA sequencing analysis. Figure 5A shows that principal component analysis (PCA) reveals differences in pretreatment baseline transcriptional profiles according to irAE occurrence. Figure 5B shows a volcano plot depicting differentially expressed genes (DEGs) between irAE cases and non-toxicity controls in baseline samples. 94 of 14,174 genes had statistically significant differences (false discovery rate (FDR) < 0.05), including 12 up-regulated genes and 82 down-regulated genes. Of these, 7 up-regulated genes (red) and 75 down-regulated genes (blue) had a |Log2 fold change (FC)| > 1. Figure 5C shows a heat map of the transcriptional profiles of irAE cases and non-toxicity controls in baseline samples, with eight clusters indicating differences. The top enriched terms and FDRs for each cluster from the GO_Biological_Process_2021 gene set library from gene otology (GO) analysis are shown on the right. Figure 5D shows the relative differences in expression between irAE cases and non-toxicity controls for 18 (out of 94) genes associated with gene sets in eight functional biological processes. [Figure 5B] Same as above [Figure 5C] Same as above [Figure 5D] Same as above

[0075] [Figure 6] Figure 6 shows PCA plots of RNA-seq data from pre-treatment baseline and post-ICI initiation in irAE and non-toxicity cases. DETAILED DESCRIPTION OF THE INVENTION

[0076] The drawings do not limit the disclosure to the specific embodiments disclosed and described herein. The drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of certain embodiments of the present disclosure.

[0077] Detailed Description The following detailed description refers to the accompanying drawings, which illustrate various aspects of the present disclosure. The drawings and description are intended to explain aspects of the present disclosure in sufficient detail to enable those skilled in the art to practice the disclosure. Other components can be utilized, and changes can be made, without departing from the scope of the present disclosure. The following description, therefore, is not to be taken in a limiting sense.

[0078] Provided herein are methods for predicting, diagnosing, and / or monitoring immune-related adverse events (irAEs) in subjects undergoing or planning to undergo immune checkpoint inhibitor (ICI) treatment. The present disclosure is based on the surprising determination that subjects develop unique transcript, autoantibody, cytokine, and / or immune cell profiles at baseline or before treatment that correlate with irAEs during ICI treatment in subjects with cancer. These transcript, autoantibody, cytokine, and / or immune cell profiles can be used as biomarkers for predicting, diagnosing, and / or monitoring irAEs during ICI treatment, and can help guide more effective cancer treatment strategies, particularly with reduced toxic side effects associated with ICI treatment. I. Terminology

[0079] For the purposes of facilitating an understanding of the principles of the present disclosure, reference will now be made to preferred embodiments, and specific language will be used to describe the same. It will be understood that no limitation on the scope of the disclosure is intended in any way, and variations and further modifications of the disclosure exemplified herein that would normally occur to one skilled in the art to which the disclosure pertains are contemplated.

[0080] As used herein, the articles "a" and "an" are used herein to refer to one or to more than one (i.e., at least one) of the grammatical object of the article. By way of example, "an element" means at least one element and may include more than one element.

[0081] "About" is used to provide flexibility for the endpoints of a numerical range by providing that a given value may be "slightly more" or "slightly less" than that endpoint without affecting the desired result. The term "about" in connection with a numerical value means that the numerical value may vary by 5% or less above or below that numerical value.

[0082] Throughout this specification, unless otherwise required by context, the words "comprise" and "include", as well as variations thereof (e.g., "comprises", "comprising", "includes", "including") will be understood to imply the inclusion of a stated component, feature, element, or step, or group of components, features, elements, or steps, but not the exclusion of any other integer or step or group of integers or steps.

[0083] As used herein, "and / or" refers to and includes any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative ("or").

[0084] As used herein, the transitional phrase "consisting essentially of" (and grammatical variations) is to be interpreted as including the recited materials or steps and those that "do not materially affect the basic and novel characteristics" of the claimed invention. Thus, the term "consisting essentially of" as used herein is not to be interpreted as equivalent to "comprising."

[0085] Furthermore, the present disclosure also contemplates that in some embodiments, any feature or combination of features described herein may be excluded or omitted. To illustrate, if the specification indicates that a complex includes components A, B, and C, it is specifically contemplated that any of A, B, or C, or combinations thereof, alone or in any combination, may be omitted and waived.

[0086] Unless otherwise indicated herein, statements regarding ranges of values ​​are intended to serve simply as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated herein as if it were individually recited. For example, if a concentration range is stated as 1% to 50%, values ​​such as 2% to 40%, 10% to 30%, or 1% to 3%, etc., are intended to be expressly recited herein. These are merely examples of what is specifically intended, and all possible combinations of values ​​therebetween, including the recited lower and upper limits, shall be considered to be expressly recited in this disclosure.

[0087] As used herein, "treatment," "therapy," and / or "therapeutic regimen" refers to a clinical intervention undertaken in response to a disease, disorder, or physiological condition that manifests in or to which a patient may be susceptible. The goals of treatment include alleviating or preventing symptoms, slowing or halting the progression or worsening of the disease, disorder, or condition, and / or ameliorating the disease, disorder, or condition.

[0088] As used herein, "prevent" or "prevention" refers to eliminating or delaying the onset of a particular disease, disorder, or physiological condition, or reducing the degree of severity of a particular disease, disorder, or physiological condition, compared to the time and / or degree of onset or severity in the absence of intervention.

[0089] The term "effective amount" or "therapeutically effective amount" refers to an amount sufficient to effect beneficial or desired biological and / or clinical results.

[0090] As used herein, "individual," "subject," "host," and "patient" are used interchangeably herein and can refer to any mammalian subject for whom diagnosis, treatment, prevention, or therapy is desired, e.g., a human, a companion animal, livestock, a horse, or other animal. As used herein, the terms "subject" and "patient" are used interchangeably herein and refer to both human and non-human animals. The term "non-human animal" of the present disclosure includes all vertebrates, e.g., mammals and non-mammals, e.g., non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc. In some aspects, the subject can be a human. In other aspects, the subject can be a human in need of cancer treatment.

[0091] As used herein, "immune-related adverse events" or "irAEs" refer to various toxicities, side effects, or problems associated with cancer immunotherapy, including treatments using immunotoxins, T cell transfer, chimeric antigen receptors, antibodies, immune system modulators, and immune checkpoint inhibitors, and / or other immunotherapies known to those skilled in the art.

[0092] As used herein, an "immune checkpoint inhibitor" is a drug that blocks immune checkpoints. These checkpoints are a normal part of the immune system and prevent immune responses from becoming too strong. By blocking them, these drugs allow immune cells to respond more strongly to, for example, cancer. Immune checkpoint inhibitors work by preventing cancer cells from shutting down T cells (white blood cells that detect infections and abnormalities). Non-limiting examples of immune checkpoint inhibitors include inhibitors of PD-1, PD-L1, TIM-3, LAG-3, CTLA-4, and CSF-1R, as well as any combination thereof. Immune checkpoint receptors may be present on tumor cells or immune cells, such as T cells, monocytes, microglia, and macrophages, without limitation. Agents that exhibit immune checkpoint blockade may be small chemical entities or polymers, antibodies, antibody fragments, single-chain antibodies, or other antibody constructs, including, but not limited to, bispecific antibodies and diabodies. Immune checkpoint inhibitors that can be used according to the present disclosure include any that disrupt the inhibitory interaction between cytotoxic T cells and tumor cells. These include, but are not limited to, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA4 antibodies, anti-LAG-3 antibodies, and anti-TIM-3 antibodies. The inhibitor does not necessarily have to be an antibody, but can also be a small molecule or other polymer. If the inhibitor is an antibody, it can be polyclonal, monoclonal, fragment, single-chain, or other antibody variant construct. Inhibitors may target any immune checkpoint known in the art, including, but not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, CSF-1R, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, CD28, CD86, CD69, CD48, CD113, CEACAM-1, Galectin-1, TIGIT, GPR56, CD48, GARP, PD1H, LAIR1, TIM1, TIM4, and B-7 family of ligands.Inhibitors for a single target immune checkpoint or a combination of different inhibitors for different immune checkpoints may be used. Illustrative examples of immune checkpoint inhibitors include CTLA-4 blocking antibodies (ipilimumab (Yervoy), tremelimumab (Imjuno)), PD-1 inhibitors (pembrolizumab (Keytruda), nivolumab (Opdivo), cemiplimab (Libtayo), CT-011 (pidilizumab), AMP224), PD-L1 inhibitors (atezolizumab (tecentriq), avelumab (Bavencio), durvalumab (Imfin)), and the like. zi), BMS-936559), Lag3 inhibitors (relatolimab), combinations of Lag3 and PD1 inhibitors (PD-1 inhibitor nivolumab (Opdualag), OX40 inhibitors (MEDI6469), CD160 inhibitors (BY55). Non-limiting examples of inhibitors of CSF-IR include PLX3397, PLX486, RG7155, AMG820, ARRY-382, FPA008, IMC-CS4, JNJ-40346527, and MCS 110. The terms "ICI treatment," "ICI therapy," "ICI compound," and the like refer to one or more ICIs (or uses thereof) disclosed herein or known to those of skill in the art.

[0093] As used herein, a "transcript" or "RNA transcript" or "RNA" can be a messenger RNA (mRNA) molecule. In some embodiments, the RNA can be total RNA, mRNA, pre-mRNA, or any combination thereof.

[0094] As used herein, an "autoantigen" is a normal protein or protein complex (and sometimes DNA or RNA) that is recognized by the immune system of patients with a particular autoimmune disease. These antigens should not be targeted by the immune system under normal conditions, but their associated T cells are not eliminated and instead mount an attack.

[0095] As used herein, "cytokine" refers to a broad category of small proteins that are important in cell signaling. The release of cytokines has an effect on the behavior of surrounding cells. As immunomodulatory molecules, cytokines are involved in autocrine signaling, paracrine signaling, and endocrine signaling. Non-limiting examples of cytokines include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factors. Cytokines are produced by various cell types, including immune cells, such as macrophages, monocytes, dendritic cells, B lymphocytes, T lymphocytes, and mast cells, as well as endothelial cells, fibroblasts, and various stromal cells, and a given cytokine may be produced by more than one cell type.

[0096] As used herein, "immune cells" are cells that develop from stem cells in the bone marrow and become different types of white blood cells. Immune cells include neutrophils, eosinophils, basophils, mast cells, monocytes, macrophages, dendritic cells, natural killer cells, and lymphocytes (B cells and T cells).

[0097] As used herein, "abundance" refers to the amount of a particular analyte (e.g., immune cell subset) present in a sample. This amount can be the number, ratio, proportion, or percentage of the analyte compared to a control sample or determined using a standard curve. This amount can be an absolute amount or a relative amount (e.g., compared to an internal control, etc.).

[0098] As used herein, "expression" or "expression level" or "level of expression" refers to the amount of a particular analyte (e.g., an antibody or cytokine) present in a sample. The amount can be the concentration, number, ratio, proportion, or percentage of the analyte compared to a control sample or determined using a standard curve. The amount can be an absolute amount or a relative amount.

[0099] As used herein, "myositis" is inflammation of the muscles that serve physical activity.

[0100] As used herein, "myocarditis" is inflammation of the heart muscle.

[0101] As used herein, "cancer" can refer to one or more neoplasms or cancers. Neoplasms can be malignant or benign, cancers can be primary or metastatic, and neoplasms or cancers can be early or late stage. Non-limiting examples of neoplasms or cancers include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, appendix cancer, astrocytoma (pediatric cerebellar or cerebral), basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumors (cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, visual pathway and hypothalamic glioma), breast cancer, bronchial adenoma / carcinoid, and Burkitt's lymphoma. , carcinoid tumors (childhood, gastrointestinal), carcinoma of unknown primary, central nervous system lymphoma (primary), cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, cervical cancer, childhood cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorder, colon cancer, cutaneous T-cell lymphoma, desmoplastic small round cell tumor, endometrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma in the Ewing's tumor family, extracranial germ cell tumors (childhood), extragonadal germ cell tumors, extrahepatic bile duct cancer, eye cancer (intraocular melanoma, retinoblastoma) ), gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, germ cell tumor (pediatric extracranial, extragonadal, ovarian), gestational trophoblastic tumor, glioma (adult, pediatric brainstem, pediatric cerebral astrocytoma, pediatric visual pathway and hypothalamus), gastric carcinoid, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkin's lymphoma, hypopharyngeal cancer, hypothalamic and visual pathway glioma (pediatric), intraocular melanoma, pancreatic islet cell carcinoma, Kaposi's sarcoma, kidney cancer (renal cell carcinoma), Laryngeal cancer, leukemia (acute lymphoblastic, acute myeloid, chronic lymphocytic, chronic myeloid, hairy cell), lip and oral cavity cancer, liver cancer (primary), lung cancer (non-small cell, small cell), lymphoma (AIDS-related, Burkitt, cutaneous T-cell, Hodgkin, non-Hodgkin, primary central nervous system), macroglobulinemia (Waldenstrom), malignant fibrous histiocytoma / osteosarcoma of bone, medulloblastoma (childhood), melanoma, intraocular melanoma, Merkel cell carcinoma, mesothelioma (adult malignant, childhood), metastatic squamous cell carcinoma of the neck with unknown primary origin,Oral cavity cancer, multiple endocrine neoplasia (childhood), multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative disease, myeloid leukemia (chronic), myelocytic leukemia (acute adult, acute childhood), multiple myeloma, myeloproliferative disorder (chronic), nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, Osteosarcoma / malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer (surface epithelial-stromal tumor), ovarian germ cell tumor, ovarian tumor of low malignant potential, pancreatic cancer, pancreatic cancer (islet cell), paranasal sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal astrocytoma, pineal germinoma, pineoblastoma and supratentorial primitive neuroectodermal tumor (childhood), pituitary adenoma, plasma cell neoplasm, pleuropulmonary blastoma, primary central nervous system lymphoma , prostate cancer, rectal cancer, renal cell carcinoma (kidney cancer), transitional cell carcinoma of the renal pelvis and ureter, retinoblastoma, rhabdomyosarcoma (childhood), salivary gland cancer, sarcoma (Ewing's family of tumors, Kaposi's, soft tissue, uterine), Sézary syndrome, skin cancer (non-melanoma, melanoma), skin cancer (Merkel cell), small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous cell neck cancer of unknown primary (metastatic), gastric cancer, supratentorial primitive neuroectodermal tumor (childhood), T-cell lymphoma (skin), testicular cancer, throat cancer, thymoma (childhood), thymoma and thymic carcinoma, thyroid cancer, thyroid cancer (childhood), transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor (gestational), unknown primary site (adult, child), transitional cell carcinoma of the ureter and renal pelvis, urethral cancer, uterine cancer (endometrium), uterine sarcoma, vaginal cancer, visual pathway and hypothalamic glioma (childhood), vulvar cancer, and Wilms' tumor (childhood).

[0102] As used herein, cancer treatment can include increasing the inhibition of cancer progression and / or metastasis, inhibiting the increase in tumor volume, reducing tumor volume and / or growth, reducing tumor growth rate, eradicating tumors and / or cancer cells, or any combination thereof. In some embodiments, treatment can also prolong the subject's survival, improve the subject's prognosis, and / or improve the subject's quality of life.

[0103] As used herein, a biological sample can be any biological tissue, fluid, or cell derived from a subject. The sample can be solid or fluid. The sample can be a heterogeneous cell population. Non-limiting examples of suitable biological samples include sputum, serum, blood, blood cells (e.g., white blood cells), biopsy, urine, peritoneal fluid, pleural fluid, or cells derived therefrom. The biopsy can be a fine needle aspiration biopsy, core needle biopsy, suction biopsy, open surgical biopsy, shave biopsy, punch biopsy, incision biopsy, scraping biopsy, or deep shave biopsy. Biological samples can also include tissue sections taken for histological purposes, such as frozen sections or formalin-fixed sections. The sample can be tumor tissue, peritumoral tissue, or non-tumor tissue. Methods for collecting biological samples from subjects are well known in the art. In some embodiments, the biological sample is a peripheral blood sample. In some embodiments, the biological sample is peripheral blood mononuclear cells (PBMCs). In some embodiments, the biological sample is plasma.

[0104] Samples from subjects can be obtained one or more times before, during, and / or after diagnosis. In some embodiments, samples can be obtained from subjects before, during, and / or after cancer treatment, where the cancer treatment includes ICI treatment. In some embodiments, samples can be obtained from subjects before the initiation of ICI treatment. In some embodiments, samples can be obtained from subjects receiving ICI treatment before the onset of irAEs. In other embodiments, samples can be obtained after the onset of irAEs in subjects. In some embodiments, samples can be obtained before, during, and / or after the administration of ICI treatment in combination with non-ICI cancer treatment or steroid treatment to monitor the treatment of irAEs. In addition, samples can be obtained repeatedly at multiple stages after the initial sample acquisition to determine and / or monitor irAEs in subjects.

[0105] In some embodiments, the control sample may be obtained from a healthy subject and / or a subject receiving ICI treatment but with a low risk of developing irAEs or ICI toxicity. In some embodiments, the control sample may include non-cancerous cells. In some embodiments, the non-cancerous cells may be derived from the same tissue type as the cancer cells. For example, if the cancer cells are derived from breast cancer, the non-cancerous cells may be derived from healthy breast tissue. In some embodiments, the control may include the average level of a biomarker profile in samples from a subject before the onset of cancer. In some embodiments, the control sample may be a sample from a subject before diagnosis or treatment. In certain embodiments, the biomarker profile may be measured in a person(s) other than the subject with cancer. In some embodiments, the control may be a person(s) with similar characteristics to the subject with cancer. In some embodiments, the control may be the average of a combination of the disclosed biomarker levels from different healthy sources (e.g., more than one healthy control subject and / or more than one subject with a low risk of developing irAEs). In some embodiments, the control sample may be a pooled sample. In some embodiments, the control sample is obtained from a subject who has a low risk of developing an irAE.

[0106] As used herein, a subject with a low risk of developing an irAE may be a subject or population that does not develop an irAE due to ICI treatment. In some embodiments, a subject with a low risk of developing an irAE may be a subject or population that does not develop an irAE due to ICI treatment, determined through retrospective analysis, that does not develop an irAE due to ICI treatment. II. Biomarkers

[0107] This disclosure provides insight into the immunological characteristics of ICI-associated myositis and / or myocarditis irAEs, as well as the biological profiles of ICI-associated myositis and / or myocarditis, which can be used as biomarkers to provide evidence for promising cancer treatment options. Transcript profile

[0108] In some aspects, the present disclosure provides methods for predicting and / or diagnosing a risk of developing an immune-related adverse event (irAE) associated with immune checkpoint inhibitor (ICI) treatment in a subject. The method includes providing a sample from the subject, assessing the transcript levels of one or more transcripts in the sample, and predicting the risk of developing an irAE / diagnosing an irAE in the subject. In some aspects, assessing the transcripts includes comparing the transcript levels of one or more transcripts in the subject's sample with the levels of the same transcripts in a control sample. In some aspects, the transcript levels are relative transcript levels. In some aspects, the transcript profile associated with an ICI-associated irAE includes a transcript profile in which the transcript levels of one or more transcripts are elevated in the subject compared to the transcript levels in the control sample. In some aspects, the transcript profile associated with an ICI-associated irAE includes a transcript profile in which the transcript levels of one or more transcripts are decreased in the subject compared to the transcript levels in the control sample.

[0109] In some embodiments, the transcript is one or more of the transcripts disclosed in Table 5. In some embodiments, the transcript is one or more of the transcripts disclosed in Table 6. In some embodiments, the transcript is one or more of the transcripts disclosed in Table 8. In some embodiments, the transcript is one or more of the transcripts disclosed in Table 9. In some embodiments, the transcript is one or more of the transcripts disclosed in Table 10. In some embodiments, the transcript is one or more of the transcripts disclosed in Table 11. In some embodiments, the transcript profile associated with an ICI-associated irAE comprises an elevated transcript level for one or more transcripts in the subject compared to the transcript level in a control sample, and a decreased transcript level for one or more transcripts in the subject compared to the transcript level in a control sample. In some embodiments, the transcript profile comprises one or more of the transcripts disclosed in Table 5, Table 6, Table 8, Table 9, Table 10, Table 11, or any combination thereof.

[0110] In some embodiments, a subject is predicted or diagnosed as having a high risk of developing ICI-associated irAEs when the transcript level of one or more transcripts is elevated in the subject compared to the transcript level of the same transcript level in a sample. In some embodiments, a subject is predicted or diagnosed as having a high risk of developing ICI-associated irAEs when the transcript level of one or more transcripts is decreased in the subject compared to the transcript level of the same transcript in a control sample. In other embodiments, a subject is predicted or diagnosed as having a low risk of developing ICI-associated irAEs when the transcript level of one or more transcripts is elevated in the subject compared to the transcript level of the same transcript in a control sample. In another embodiment, a subject is predicted or diagnosed as having a low risk of developing ICI-associated irAEs when the transcript level of one or more transcripts is decreased in the subject compared to the transcript level of the same transcript in a control sample.

[0111] In some embodiments, the transcript profile comprises baseline or pre-treatment transcript profile that correlates with future toxicity.These transcripts are used as biomarkers for assessing the risk that the subject will develop irAE during ICI treatment.In some embodiments, the subject is planning to receive or has received ICI treatment as part of cancer therapy.

[0112] In some embodiments, a transcript having an elevated expression level has an elevated expression level that is at least about 0.01%, at least about 0.05%, at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100% higher compared to the expression level of the same transcript in a control sample.

[0113] In some embodiments, transcripts with elevated expression levels have elevated expression levels with a log 2 fold change value of about 0.1 to about 5. For example, the log 2 fold change value can be about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.

[0114] In some embodiments, a transcript having a decreased expression level has a decreased expression level that is at least about 0.01%, at least about 0.05%, at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least 100% lower compared to the expression level of the same transcript in a control sample.

[0115] In some embodiments, transcripts with decreased expression levels have decreased expression levels with a log 2 fold change value of about -0.1 to about -5. For example, the log 2 fold change values ​​are about -0.1, -0.2, -0.3, -0.4, -0.5, -0.6, -0.7, -0.8, -0.9, -1, -1.1, -1.2, -1.3, -1.4, -1.5, -1.6, -1.7, -1.8, -1.9, -2, -2.1, -2.2, -2.3, -2.4, -2. The offset can be -5, -2.6, -2.7, -2.8, -2.9, -3, -3.1, -3.2, -3.3, -3.4, -3.5, -3.6, -3.7, -3.8, -3.9, -4, -4.1, -4.2, -4.3, -4.4, -4.5, -4.6, -4.7, -4.8, -4.9, or -5.

[0116] In some embodiments, the subject is diagnosed with leukocyte immunoglobulin-like receptor B4 (LILRB4), cytokine-inducible SH2-containing protein (CISH), poly(ADP-ribose) polymerase family member 9 (PARP9), ring finger protein 145 (RNF145), asialoglycoprotein receptor 2 (ASGR2), solute carrier family 16 member 13 (SLC16A13), lysophosphatidic acid receptor 6 (LPAR6), GTPase, IMAP family member 7 (IGMA), IL-16A16, IL-16B16, IL-16C16, IL-16D16, IL-16E16, IL-16F16, IL-16F26, IL-16F36, IL-16F46, IL-16F56, IL-16F6, IL-16F76, IL-16F86, IL-16F96, IL-16F97, IL-16F98, IL-16F9 ... A patient is predicted to have a high risk of developing an irAE or is diagnosed with an irAE if the transcript levels of one or more of the following are elevated before ICI treatment (baseline) compared to the transcript levels in a control sample: C-X-C motif chemokine receptor 6 (CXCR6), dehydrogenase / reductase 9 (DHRS9), Fc gamma receptor Ic, pseudogene (FCGR1CP), and / or ankyrin repeat domain 34B (ANKRD34B).

[0117] In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE if the transcript levels of one or more of LILRB4, CISH, and / or PARP9 are elevated before ICI treatment (baseline) compared to a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE if the transcript levels of one or more of LILRB4, CISH, GIMAP7, CXCR6, DHRS9, ANKRD34B, and / or FCGR1CP are elevated before ICI treatment (baseline) compared to the transcript levels in a control sample.

[0118] In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of LILRB4 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of CISH is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of PARP9 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of RNF145 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE if the transcript level of ASGR2 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE if the transcript level of SLC16A13 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE if the transcript level of LPAR6 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE if the transcript level of GIMAP7 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have an elevated risk of developing an irAE or is diagnosed with an irAE if the transcript level of CXCR6 is elevated compared to the transcript level in a control sample before ICI treatment.In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of DHRS9 is elevated compared to the transcript level in a control sample before ICI treatment.In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of FCGR1CP is elevated compared to the transcript level in a control sample before ICI treatment.In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of ANKRD34B is elevated compared to the transcript level in a control sample before ICI treatment.

[0119] In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least LILRB4 is elevated in the subject compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least CISH is elevated in the subject compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least PARP9 is elevated in the subject compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least GIMAP7 is elevated in the subject compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least CXCR6 is elevated in the subject compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least DHRS9 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least FCGR1CP is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least ANKRD34B is elevated compared to the transcript level in a control sample before ICI treatment.

[0120] In some embodiments, the subject is diagnosed with a gene encoding amphiregulin (AREG), epiregulin (EREG), oncostatin M (OSM), cysteine- and serine-rich nuclear protein 1 (CSRNP1), DNA damage-induced transcript 4 (DDIT4), IL-10 (interleukin-10), prostaglandin-endoperoxide synthase (PTGS2), dual specificity phosphatase 1 (DUSP1), CXC chemokine receptor type 4 (CXCR4), nuclear factor, interleukin-3 regulated (NFIL3), Fos proto-oncogene, AP-1 transcription factor. Subunit (FOS), NFKB inhibitor alpha (NFKBIA), PPP1R15A (protein phosphatase 1 regulatory subunit 15A), CD79A, JunB proto-oncogene, AP-1 transcription factor subunit (JUNB), C-X-C motif chemokine ligand 8 (CXCL8), early growth response 1 (EGR1), G0 / G1 switch 2 (G0S2), paired box 8 (PAX8), activating transcription factor 6 beta (ATF6B), PAX8 antisense RNA 1 (PAX8-AS1), variant U1 micronuclear RNA 19 (RNVU1-19), vitelline membrane outer layer 1 homolog (VMO1), heparin-binding EGF-like growth factor (HBEGF), coiled-coil domain-containing 144A (CCDC144A), shisa family member 8 (SHISA8), nuclear receptor subfamily 4 group A member 2 (NR4A2), prostaglandin E synthase (PTGES), synapsin I (SYN1), C-X-C motif chemokine ligand 2 (CXCL2), peripheral myelin protein 22 (PMP22), CD83, early growth response 3 (EGR3), NUAK family kinase 1 (NUAK1), nocturnin (NOCT), atonal bHLH transcription factor 8 (ATOH8), polo-like kinase (PLK2), inhibitor of DNA binding 1 (ID1), adrenergic receptor beta 1 (ADRB1), snail family transcriptional repressor 1 (SNAI1), notch receptor 3 (NOTCH3), activating transcription factor 3 (ATF3), dual specificity phosphatase 2 (DUSP2), circadian rhythm regulator 1 (PER1), TNF superfamily member 9 (TNFSF9), MAF bzip transcription factor F (MAFF), microRNA4420 (MIR4420), glutathione peroxidase (GPX3), TNF-alpha-inducible protein 3 (TNFAIP3), potassium voltage-gated channel modifier subfamily G member 1 (KCNG1), prostaglandin-endoperoxidase synthase 2 (PTGS2), A-kinase anchor protein 5 (AKAP5), dual specificity phosphatase 1 (DUSP1), diacylglycerol kinase kappa (DGKK), beta-1,4,-N-acetyl-galactosaminyltransferase 3 (B4GA LNT3), tribbles pseudokinase 1 (TRIB1), holobol-12-myristate-13-acetate-inducible protein 1 (PMAIP1), C-X-C motif chemokine receptor 4 (CXCR4), tumor protein p53-inducible nuclear protein 2 (TP53INP2), nuclear factor, interleukin-3-regulated (NFIL3), dual specificity phosphatase 4 (DUSP4), NFKB inhibitor alpha (NFKBIA), arginine vasopressin-inducible 1 (AVPI1), CD79a, ADP-ribosylation factor-like GTPase 4D (ARL4D), binding chain of polymeric IgA and IgM (JCHAIN), BTG anti-proliferative factor 2 (BTG2), TLE family member 1, transcriptional corepressor (TLE1), nuclear transport factor 2-like nuclear export factor 1 (NXT1), transfer factor of ERBB2 1 (TOB1), phosphodiesterase 4D (PDE4D), DNAJ heat shock protein family member B1 (DNAJB1), AT-rich interacting domain 5B (ARID5B), G protein-coupled receptor 153 (GPR153), KLF transcription factor 9 (KLF9), SBDS ribosome maturation factor (SBDS), immediate early response 2 (IER2), TSC22 domain family member 3 (TSC22D3), A-type GABA receptor-associated protein-like 1 (GABARAPL1), JunD proto-oncogene, AP-1 transcription factor subunit (JUND), RUNX family transcription factor 3 (RUNX3), BABAM2 antisense RNAIf the transcript levels of one or more of BRE-AS1, putative salt-inducible kinase 1B (LOC102724428), FAM46C (FAM46C), and / or general receptor for phosphoinositides 1-related scaffold protein (GRASP) are low in a subject compared to the transcript levels in a control sample, the subject is predicted to have a high risk of developing an irAE or is diagnosed as having an irAE.

[0121] In some embodiments, the subject is a patient with any of the following: AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, N If the transcript level of one or more of UAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, BRE-AS1, LOC102724428, and / or GRASP is low in a subject compared to the transcript level in a control sample, the subject is predicted to have a high risk of developing an irAE or is diagnosed as having an irAE.

[0122] In some embodiments, a subject is predicted to have an elevated risk of developing an irAE or diagnosed with an irAE if the transcript levels of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, and / or JUNB are low compared to the transcript levels in a control sample before ICI treatment. In various embodiments, a subject is predicted to have an elevated risk of developing an irAE or diagnosed with an irAE if the transcript levels of one or more of AREG, EREG, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, and / or SHISA8 are low compared to the transcript levels in a control sample before ICI treatment. In some other embodiments, a subject is predicted to have an elevated risk of developing an irAE or diagnosed with an irAE if the transcript level of one or more of AREG, EREG, CXCL8, EGR1, PAX8, ATF6B, VMO1, HBEGF, BRE-AS1, NR4A2, OSM, NOCT, PLK2, LOC102724428, DUSP2, GRASP, PER1, TNFSF9, CSRNP1, MAFF, TNFAIP3, DUSP1, TRIB1, PMAIP1, FAM46C, NXT1, and / or KLF9 is low compared to the transcript level in a control sample before ICI treatment.

[0123] In some embodiments, a subject is predicted to have a high risk of developing irAEs or diagnosed with irAEs when the transcript level of at least AREG is low in the subject compared to the transcript level in a control sample.In some embodiments, a subject is predicted to have a high risk of developing irAEs or diagnosed with irAEs when the transcript level of at least EREG is low in the subject compared to the transcript level in a control sample.In some embodiments, a subject is predicted to have a high risk of developing irAEs or diagnosed with irAEs when the transcript level of at least OSM is low in the subject compared to the transcript level in a control sample.In some embodiments, a subject is predicted to have a high risk of developing irAEs or diagnosed with irAEs when the transcript level of at least CSRNP1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least DDIT4 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least IL-10 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least PTGS2 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least DUSP1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have an elevated risk of developing an irAE or diagnosed with an irAE when the transcript level of at least CXCR4 is low in the subject compared to the transcript level in a control sample.In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least NFIL3 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least FOS is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least NFKBIA is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least PPP1R15A is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least CD79A is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least JUNB is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least CXCL8 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least EGR1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have an elevated risk of developing an irAE or diagnosed with an irAE when the transcript level of at least G0S2 is low in the subject compared to the transcript level in a control sample.In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least PAX8 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least ATF6B is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least PAX8-AS1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least RNVU1-19 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least VMO1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least HBEGF is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least CCDC144A is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least SHISA8 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have an elevated risk of developing an irAE or diagnosed with an irAE when the transcript level of at least NR4A2 is low in the subject compared to the transcript level in a control sample.In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least PTGES is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least SYN1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least CXCL2 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least PMP22 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least CD83 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least EGR3 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least NUAK1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least NOCT is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have an elevated risk of developing an irAE or diagnosed with an irAE when the transcript level of at least ATOH8 is low in the subject compared to the transcript level in a control sample.In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least PLK2 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least ID1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least ADRB1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least SNAI1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least NOTCH3 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least ATF3 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least DUSP2 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least PER1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have an elevated risk of developing an irAE or diagnosed with an irAE when the transcript level of at least TNFSF9 is low in the subject compared to the transcript level in a control sample.In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed as having an irAE when the transcript level of at least MAFF is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed as having an irAE when the transcript level of at least MIR4420 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least BRE-AS1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least LOC102724428 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least GRASP is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least TNFAIP3 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least TRIB1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least PMAIP1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least FAM46C is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of at least NXT1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted to have an elevated risk of developing an irAE or diagnosed with an irAE when the transcript level of at least KLF9 is low in the subject compared to the transcript level in a control sample.

[0124] In some embodiments, a subject is predicted to have a high risk of developing irAEs or diagnosed with irAEs when the transcript level of AREG transcript is low compared to the transcript level in a control sample before ICI treatment.In some embodiments, a subject is predicted to have a high risk of developing irAEs or diagnosed with irAEs when the transcript level of EREG transcript is low compared to the transcript level in a control sample before ICI treatment.In some embodiments, a subject is predicted to have a high risk of developing irAEs or diagnosed with irAEs when the transcript level of OSM transcript is low compared to the transcript level in a control sample before ICI treatment.In some embodiments, a subject is predicted to have a high risk of developing irAEs or diagnosed with irAEs when the transcript level of CSRNP1 transcript is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of DDIT4 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of IL-10 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of PTGS2 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of DUSP1 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have an elevated risk of developing an irAE or is diagnosed with an irAE if the transcript level of CXCR4 is low compared to the transcript level in a control sample before ICI treatment.In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of NIFL3 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of FOS is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of NFKBIA is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a high risk of developing an irAE or diagnosed with an irAE when the transcript level of PPP1R15A is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have an elevated risk of developing an irAE or diagnosed with an irAE when the transcript level of CD79A is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have an elevated risk of developing an irAE or diagnosed with an irAE when the transcript level of JUNB is low compared to the transcript level in a control sample before ICI treatment.

[0125] In some embodiments, the subject is diagnosed with a leukemia if the transcript levels of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B are elevated prior to ICI treatment (baseline) compared to the transcript levels in a control sample, and if the transcript levels of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10 , PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNA I1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, GPX3, TNFAIP3, KCNG1, PTGS2, AKAP5, DUSP1, DGKK, B4GALNT3, TRIB 1, PMAIP1, CXCR4, TP53INP2, NFIL3, DUSP4, NFKBIA, AVPI1, CD79a, ARL4D, JCHAIN, BTG2, TLE1, NXT1, TOB1, PDE4D, DNAJB1, If the transcript level of one or more of ARID5B, GPR153, KLF9, SBDS, IER2, TSC22D3, JUND, GABARAPL1, RUNX3, BRE-AS1, LOC102724428, FAM46C, and / or GRASP is low in a subject compared to the level in the transcript level in a control sample, the subject is predicted to have a high risk of developing an irAE or is diagnosed as having an irAE.

[0126] In some embodiments, the subject is diagnosed with a leukemia if the transcript levels of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B are elevated prior to ICI treatment (baseline) compared to the transcript levels in a control sample, as well as if the subject has a leukemia, encephalopathy, or other leukemia-associated ... If the transcript level of one or more of X8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, BRE-AS1, and / or LOC102724428 is low in a subject compared to the transcript level in a control sample, the subject is predicted to have an elevated risk of developing an irAE or is diagnosed as having an irAE.

[0127] In some embodiments, a subject is predicted to have a high risk of developing an irAE or is diagnosed with an irAE if the transcript level of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B is elevated compared to the transcript level in a control sample before ICI treatment (baseline), and if the transcript level of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, and / or JUNB is low in the subject compared to the transcript level in a control sample.

[0128] In some embodiments, a subject is predicted to have a high risk of developing an irAE or is diagnosed with an irAE if the transcript level of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B is elevated compared to the transcript level in a control sample before ICI treatment (baseline), and if the transcript level of one or more of AREG, EREG, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, and / or SHISA8 is low in the subject compared to the transcript level in a control sample.

[0129] In some embodiments, the subject is diagnosed with elevated transcript levels of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B prior to ICI treatment (baseline) compared to the transcript levels in a control sample, as well as elevated transcript levels of AREG, EREG, CXCL8, EGR1, PAX8, ATF6B, VMO1, HBEGF, BRE-AS If the transcript level of one or more of 1, NR4A2, OSM, NOCT, PLK2, LOC102724428, DUSP2, GRASP, PER1, TNFSF9, CSRNP1, MAFF, TNFAIP3, DUSP1, TRIB1, PMAIP1, FAM46C, NXT1, and / or KLF9 is low in a subject compared to the transcript level in a control sample, the subject is predicted to have an elevated risk of developing an irAE or is diagnosed as having an irAE.

[0130] In some embodiments, a subject is predicted to have an elevated risk of developing an irAE or is diagnosed with an irAE if the transcript levels of one or more of LILRB4, CISH, and / or PARP9 are elevated compared to the transcript levels in a control sample before ICI treatment (baseline), and if the transcript levels of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, and / or JUNB are low in the subject compared to the transcript levels in a control sample.

[0131] In some embodiments, a subject is predicted to have a high risk of developing an irAE or is diagnosed with an irAE if the transcript levels of LILRB4, CISH, and PARP9 are elevated compared to the transcript levels in a control sample before ICI treatment (baseline), and if the transcript levels of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, and JUNB are low in the subject compared to the transcript levels in a control sample.

[0132] In some embodiments, the subject is diagnosed with a leukemia if the transcript levels of one or more of LILRB4, GIMAP7, CISH, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B are elevated prior to ICI treatment (baseline) compared to the transcript levels in a control sample, as well as any of the following: AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, V If the transcript level of one or more of MO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, BRE-AS1, and / or LOC102724428 is low in a subject compared to the transcript level in a control sample, the subject is predicted to have a high risk of developing an irAE or is diagnosed as having an irAE.

[0133] In some embodiments, a subject is predicted to have an elevated risk of developing an irAE or is diagnosed with an irAE if the transcript level of CISH is elevated compared to the transcript level in a control sample before ICI treatment, and if the transcript level of one or more of AREG, EREG, CXCL8, EGR1, PAX8, ATF6B, VMO1, HBEGF, BRE-AS1, NR4A2, OSM, NOCT, PLK2, LOC102724428, DUSP2, GRASP, PER1, TNFSF9, CSRNP1, MAFF, TNFAIP3, DUSP1, TRIB1, PMAIP1, FAM46C, NXT1, and / or KLF9 is low in the subject compared to the transcript level in a control sample.

[0134] In some embodiments, a subject is predicted to have a high risk of developing an irAE or is diagnosed with an irAE if the transcript levels of one or more of LILRB4, GIMAP7, CISH, and / or CXCR6 are elevated compared to the transcript levels in a control sample before ICI treatment (baseline), and if the transcript levels of one or more of AREG, EREG, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, and / or SHISA8 are low in the subject compared to the transcript levels in a control sample.

[0135] In some embodiments, a subject is predicted to have an elevated risk of developing an irAE or is diagnosed with an irAE if the transcript level of PARP9 is elevated compared to the transcript level in a control sample before ICI treatment (baseline) and if the transcript level of one or more of CD79A, CD83, PLK2, PDE4D, TR1B1, EREG, CXCL8, EGR3, JUNB, DUSP1, NFKBIA, TNFSF9, TNFAIP3, IL-10, JUND, FOS, RUNX3, and / or TSC22D3 is low in the subject compared to the transcript level in a control sample.

[0136] In some embodiments, the subject is diagnosed with a leukemia if the transcript levels of one or more of PARP9, CISH, CXCR6, LPAR6, and / or ASGR2 are elevated prior to ICI treatment (baseline) compared to the transcript levels in a control sample, as well as if the transcript levels of one or more of KLF9, CXCR4, ATF6B, CD79A, CD83, PLK2, GRASP, PPP1R15A, GPX3, PARP9, BTG2, PTGS2, NOTCH3, AKAP5, PDE4D, SBDS, TRIB1, SNAI1, PAX8, NFIL3, EREG, AREG, DGKK, PTGES, CSRNP1, DNAJ A subject is predicted to have an elevated risk of developing an irAE or is diagnosed as having an irAE if the transcript level of one or more of B1, CXCL8, OSM, ARID5B, ID1, NR4A2, EGR3, JUNB, TLE1, CXCL2, DUSP1, GPR153, G0S2, ATF3, NFKBIA, TNFS9, NUAK1, ATOH8, TNFAIP3, ADRB1, HBEGF, IL-10, JUND, FOS, GABARAPL1, PMAIP1, DDIT4, and / or EGR1 is low in the subject compared to the transcript level in a control sample.

[0137] In some embodiments, a subject is predicted to have a low risk of developing an irAE if the transcript levels of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B are low before ICI treatment (baseline) compared to the transcript levels in a control sample.

[0138] In some embodiments, a subject is predicted to have a low risk of developing an irAE if the transcript level of one or more of LILRB4, CISH, and / or PARP9 is elevated compared to the transcript level in a control sample before ICI treatment (baseline). In some embodiments, a subject is predicted to have a high risk of developing an irAE or is diagnosed with an irAE if the transcript level of one or more of LILRB4, CISH, GIMAP7, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B is low compared to the transcript level in a control sample before ICI treatment (baseline).

[0139] In some embodiments, a subject is predicted to have a low risk of developing an irAE if the transcript level of LILRB4 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a low risk of developing an irAE if the transcript level of CISH is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a low risk of developing an irAE if the transcript level of PARP9 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a low risk of developing an irAE if the transcript level of RNF145 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a low risk of developing an irAE if the transcript level of ASGR2 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a low risk of developing an irAE if the transcript level of SLC16A13 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a low risk of developing an irAE if the transcript level of LPAR6 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a low risk of developing an irAE if the transcript level of GIMAP7 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a low risk of developing an irAE if the transcript level of CXCR6 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a low risk of developing an irAE if the transcript level of DHRS9 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a low risk of developing an irAE if the transcript level of FCGR1CP is low compared to the transcript level in a control sample before ICI treatment.In some embodiments, a subject is predicted to have a low risk of developing an irAE if the transcript level of ANKRD34B is low compared to the transcript level in a control sample before ICI treatment.

[0140] In some embodiments, a subject is predicted to have a low risk of developing an irAE if the transcript level of at least LILRB4 is low in the subject compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a low risk of developing an irAE if the transcript level of at least CISH is low in the subject compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a low risk of developing an irAE if the transcript level of at least PARP9 is low in the subject compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a low risk of developing an irAE if the transcript level of at least GIMAP7 is low in the subject compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a low risk of developing an irAE if the transcript level of at least CXCR6 is low in the subject compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted to have a low risk of developing irAEs when the transcript level of at least DHRS9 is low compared to the transcript level in a control sample before ICI treatment.In some embodiments, a subject is predicted to have a low risk of developing irAEs when the transcript level of at least FCGR1CP is low compared to the transcript level in a control sample before ICI treatment.In some embodiments, a subject is predicted to have a low risk of developing irAEs when the transcript level of at least ANKRD34B is low compared to the transcript level in a control sample before ICI treatment.

[0141] In some embodiments, the subject is diagnosed with a tumor necrosis factor (TNF)-1 (TNFSF) gene expression level detected by the tumor necrosis factor (TNF) gene, including AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, GPX3, TNFAIP3, KCNG1, PTGS2, If the transcript level of one or more of AKAP5, DUSP1, DGKK, B4GALNT3, TRIB1, PMAIP1, CXCR4, TP53INP2, NFIL3, DUSP4, NFKBIA, AVPI1, CD79a, ARL4D, JCHAIN, BTG2, TLE1, NXT1, TOB1, PDE4D, DNAJB1, ARID5B, GPR153, KLF9, SBDS, IER2, TSC22D3, JUND, GABARAPL1, RUNX3, BRE-AS1, LOC102724428, FAM46C, and / or GRASP is elevated in a subject compared to the transcript level in a control sample, the subject is predicted or diagnosed as having a low risk of developing an irAE.

[0142] In some embodiments, the subject has a tumor phenotype of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, If the transcript level of one or more of EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, BRE-AS1, LOC102724428, and / or GRASP is elevated in a subject compared to the transcript level in a control sample, the subject is predicted or diagnosed as having a low risk of developing an irAE.

[0143] In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the transcript levels of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, and / or JUNB are elevated compared to the transcript levels in a control sample before ICI treatment. In various embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the transcript levels of one or more of AREG, EREG, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, and / or SHISA8 are elevated compared to the transcript levels in a control sample before ICI treatment. In some other embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the transcript levels of one or more of AREG, EREG, CXCL8, EGR1, PAX8, ATF6B, VMO1, HBEGF, BRE-AS1, NR4A2, OSM, NOCT, PLK2, LOC102724428, DUSP2, GRASP, PER1, TNFSF9, CSRNP1, MAFF, TNFAIP3, DUSP1, TRIB1, PMAIP1, FAM46C, NXT1, and / or KLF9 are elevated compared to the transcript levels in a control sample before ICI treatment.

[0144] In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least AREG is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least EREG is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least OSM is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least CSRNP1 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least DDIT4 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least IL-10 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least PTGS2 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least DUSP1 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least CXCR4 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least NFIL3 is elevated in the subject compared to the transcript level in a control sample.In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least FOS is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least NFKBIA is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least PPP1R15A is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least CD79A is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least JUNB is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least CXCL8 is elevated in the subject compared to the level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least EGR1 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least G0S2 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least PAX8 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least ATF6B is elevated in the subject compared to the transcript level in a control sample.In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least PAX8-AS1 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least RNVU1-19 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least VMO1 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least HBEGF is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least CCDC144A is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE, or diagnosed as having an irAE, when the transcript level of at least SHISA8 is elevated in the subject compared to the transcript level in a control sample.In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE, or diagnosed as having an irAE, when the transcript level of at least NR4A2 is elevated in the subject compared to the transcript level in a control sample.In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE, or diagnosed as having an irAE, when the transcript level of at least PTGES is elevated in the subject compared to the transcript level in a control sample.In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE, when the transcript level of at least SYN1 is elevated in the subject compared to the transcript level in a control sample.In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least CXCL2 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least PMP22 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least CD83 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least EGR3 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least NUAK1 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least NOCT is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least ATOH8 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least PLK2 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least ID1 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least ADRB1 is elevated in the subject compared to the transcript level in a control sample.In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least SNAI1 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least NOTCH3 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least ATF3 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least DUSP2 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least PER1 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least TNFSF9 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least MAFF is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least MIR4420 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least BRE-AS1 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least LOC102724428 is elevated in the subject compared to the transcript level in a control sample.In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least GRASP is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least TNFAIP3 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least TR is elevated in the subject. A subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of IB1 is elevated compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least PMAIP1 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least FAM46C is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least NXT1 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the transcript level of at least KLF9 is elevated in the subject compared to the transcript level in a control sample.

[0145] In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the transcript level of AREG is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the transcript level of EREG is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the transcript level of OSM is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the transcript level of CSRNP1 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the transcript level of DDIT4 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the transcript level of IL-10 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the transcript level of PTGS2 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the transcript level of DUSP1 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the transcript level of CXCR4 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the transcript level of NIFL3 is elevated compared to the transcript level in a control sample before ICI treatment.In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the transcript level of FOS is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the transcript level of NFKBIA is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the transcript level of PPP1R15A is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the transcript level of CD79A is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the transcript level of JUNB is elevated compared to the transcript level in a control sample before ICI treatment.

[0146] In some embodiments, the subject is diagnosed with ICI-related leukemia if the transcript levels of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B are low prior to ICI treatment (baseline) compared to the transcript levels in a control sample, and if the transcript levels of AREG, EREG, OSM, CSRNP1, DDIT4, IL-1 0, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1 -19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADR B1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, GPX3, TNFAIP3, KCNG1, PTGS2, AKAP5, DUSP1, DGKK, B4GA LNT3, TRIB1, PMAIP1, CXCR4, TP53INP2, NFIL3, DUSP4, NFKBIA, AVPI1, CD79a, ARL4D, JCHAIN, BTG2, TLE1, NXT1, TOB1, PD If the transcript level of one or more of E4D, DNAJB1, ARID5B, GPR153, KLF9, SBDS, IER2, TSC22D3, JUND, GABARAPL1, RUNX3, BRE-AS1, LOC102724428, FAM46C, and / or GRASP is elevated in a subject compared to the transcript level in a control sample, the subject is predicted or diagnosed as having a low risk of developing an irAE.

[0147] In some embodiments, the subject is diagnosed with a low transcript level of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B prior to ICI treatment (baseline) compared to the transcript level in a control sample, as well as a low transcript level of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B , PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, BRE-AS1, and / or LOC102724428 are elevated in a subject compared to the transcript levels in a control sample, the subject is predicted or diagnosed as having a low risk of developing an irAE.

[0148] In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the transcript level of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B is low compared to the transcript level in a control sample before ICI treatment, and if the transcript level of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, and / or JUNB is elevated in the subject compared to the transcript level in a control sample.

[0149] In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the transcript levels of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, and / or CXCR6 are lower compared to a control sample before ICI treatment (baseline), and if the transcript levels of one or more of AREG, EREG, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, and / or SHISA8 are elevated in the subject compared to the transcript levels in a control sample.

[0150] In some embodiments, the subject is diagnosed with a condition characterized by a low transcript level of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B prior to ICI treatment (baseline) compared to the transcript level in a control sample, as well as a low transcript level of one or more of AREG, EREG, CXCL8, EGR1, PAX8, ATF6B, VMO1, HBEGF, BRE1, BRE2, BRE3, BRE4, BRE5, BRE6, BRE7, BRE8, BRE9, BRE10, BRE11, BRE12, BRE13, BRE14, BRE25, BRE15, BRE16, BRE17, BRE18, BRE19, BRE26, BRE27, BRE28, BRE30, BRE31, BRE42, BRE51, BRE52, BRE53, BRE54, BRE55, BRE56, BRE57, BRE58, BRE59, BRE60, BRE61, BRE62, BRE63, BRE64, BRE65, BRE76, BRE77, BRE78, BRE79, BRE80, BRE91, BRE92, BRE93, BRE94, BRE95, BRE96, BRE97, BRE98, BRE99, BRE106, BRE117, BRE120, BRE130, BRE141, BRE152, BRE153, BRE160, BRE171, BRE182, BRE190, BRE191, BRE192, BRE193, BRE194, BRE195, -If the transcript level of one or more of AS1, NR4A2, OSM, NOCT, PLK2, LOC102724428, DUSP2, GRASP, PER1, TNFSF9, CSRNP1, MAFF, TNFAIP3, DUSP1, TRIB1, PMAIP1, FAM46C, NXT1, and / or KLF9 is elevated in a subject compared to the transcript level in a control sample, the subject is predicted or diagnosed as having a low risk of developing an irAE.

[0151] In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the transcript level of one or more of LILRB4, CISH, and / or PARP9 is low compared to the transcript level in a control sample before ICI treatment (baseline), and if the transcript level of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, and / or JUNB is elevated in the subject compared to the transcript level in a control sample.

[0152] In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the transcript levels of LILRB4, CISH, and PARP9 are low compared to the transcript levels in a control sample before ICI treatment (baseline), and if the transcript levels of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, and JUNB are elevated in the subject compared to the transcript levels in a control sample.

[0153] In some embodiments, the subject is diagnosed with a condition characterized by a low transcript level of one or more of LILRB4, GIMAP7, CISH, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B prior to ICI treatment compared to a control sample, as well as a low transcript level of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBE If the transcript levels of one or more of GF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, BRE-AS1, and / or LOC102724428 are elevated in a subject compared to the transcript levels in a control sample, the subject is predicted or diagnosed as having a low risk of developing an irAE.

[0154] In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the transcript level of CISH is low compared to the transcript level in a control sample before ICI treatment, and if the transcript level of one or more of AREG, EREG, CXCL8, EGR1, PAX8, ATF6B, VMO1, HBEGF, BRE-AS1, NR4A2, OSM, NOCT, PLK2, LOC102724428, DUSP2, GRASP, PER1, TNFSF9, CSRNP1, MAFF, TNFAIP3, DUSP1, TRIB1, PMAIP1, FAM46C, NXT1, and / or KLF9 is elevated in the subject compared to the transcript level in a control sample.

[0155] In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the transcript level of one or more of LILRB4, GIMAP7, CISH, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B is low compared to the transcript level in a control sample before ICI treatment (baseline), and if the transcript level of one or more of AREG, EREG, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, and / or SHISA8 is elevated in the subject compared to the transcript level in a control sample.

[0156] In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the transcript level of PARP9 is low compared to the transcript level in a control sample before ICI treatment (baseline), and if the transcript level of one or more of CD79A, CD83, PLK2, PDE4D, TR1B1, EREG, CXCL8, EGR3, JUNB, DUSP1, NFKBIA, TNFSF9, TNFAIP3, IL-10, JUND, FOS, RUNX3, and / or TSC22D3 is elevated in the subject compared to the transcript level in a control sample.

[0157] In some embodiments, the subject is diagnosed with a condition characterized by a low transcript level of one or more of PARP9, CISH, CXCR6, LPAR6, and / or ASGR2 prior to ICI treatment (baseline) compared to the transcript level in a control sample, as well as a low transcript level of one or more of KLF9, CXCR4, ATF6B, CD79A, CD83, PLK2, GRASP, PPP1R15A, GPX3, PARP9, BTG2, PTGS2, NOTCH3, AKAP5, PDE4D, SBDS, TRIB1, SNAI1, PAX8, NFIL3, EREG, AREG, DGKK, PTGES, CSRNP1, DNA If the transcript level of one or more of the following transcripts is elevated in a subject compared to the transcript level in a control sample, the subject is predicted or diagnosed as having a low risk of developing an irAE.

[0158] In some aspects, the present disclosure provides methods for monitoring a subject's risk of developing an immune-related adverse event (irAE) associated with immune checkpoint inhibitor (ICI) treatment. The method includes providing a sample from the subject, assessing transcript levels in the sample, and predicting the risk of developing an irAE / diagnosing an irAE in the subject being monitored. In some aspects, assessing the transcripts includes comparing the levels of one or more transcripts in the subject's sample with the levels of the same transcripts in a control sample. In some aspects, the transcript profile associated with an ICI-associated irAE includes a transcript profile in which the levels of one or more transcripts are elevated in the subject compared to the levels of the same transcripts in a control sample. In some aspects, the transcript profile associated with an ICI-associated irAE includes a transcript profile in which the levels of one or more transcripts are decreased in the subject compared to the levels of the same transcripts in a control sample.

[0159] In some embodiments, the transcript is one or more of the transcripts disclosed in Table 5. In some embodiments, the transcript is one or more of the transcripts disclosed in Table 6. In some embodiments, the transcript is one or more of the transcripts disclosed in Table 8. In some embodiments, the transcript is one or more of the transcripts disclosed in Table 9. In some embodiments, the transcript is one or more of the transcripts disclosed in Table 10. In some embodiments, the transcript is one or more of the transcripts disclosed in Table 11. In some embodiments, the transcript profile associated with an ICI-associated irAE comprises one or more transcripts at elevated levels in the subject compared to the level of the transcript in a control sample, and one or more transcripts at decreased levels in the subject compared to the level of the transcript in a control sample. In some embodiments, the transcript profile comprises one or more of the transcripts disclosed in Table 5, Table 6, Table 8, Table 9, Table 10, Table 11, or a combination thereof.

[0160] In some embodiments, a monitored subject may have a high risk of developing an ICI-associated irAE if the transcript level of one or more transcripts in the subject is elevated compared to the transcript level of the same transcripts in a control sample. In some embodiments, a monitored subject may have a high risk of developing an ICI-associated irAE if the transcript level of one or more transcripts in the subject is decreased compared to the transcript level of the same transcripts in a control sample. In other embodiments, a monitored subject may have a low risk of developing an ICI-associated irAE if the transcript level of one or more transcripts in the subject is elevated compared to the transcript level of the same transcripts in a control sample. In another embodiment, a monitored subject may have a low risk of developing an ICI-associated irAE if the transcript level of one or more transcripts in the subject is decreased compared to the transcript level of the same transcripts in a control sample.

[0161] In some embodiments, the transcript profile comprises baseline or pre-treatment transcript profile that correlates with future toxicity.These transcripts are used as biomarkers for assessing the risk of developing irAE in the subject being monitored during ICI treatment.In some embodiments, the subject is planning to receive or has received ICI treatment as part of cancer therapy.

[0162] In some embodiments, during monitoring, transcripts having elevated levels have elevated expression levels that are at least about 0.01%, at least about 0.05%, at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100% higher compared to the sample.

[0163] In some embodiments, during monitoring, transcripts having elevated levels have elevated expression levels with a log 2 fold change value of about 0.1 to about 5. For example, the log 2 fold change value can be about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.

[0164] In some embodiments, during monitoring, transcripts having decreased levels have a decreased expression level that is at least about 0.01%, at least about 0.05%, at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least 100% lower compared to the sample.

[0165] In some embodiments, during monitoring, transcripts having decreased levels have decreased expression levels with a log 2 fold change value of about -0.1 to about -5, e.g., log 2 fold change values ​​of about -0.1, -0.2, -0.3, -0.4, -0.5, -0.6, -0.7, -0.8, -0.9, -1, -1.1, -1.2, -1.3, -1.4, -1.5, -1.6, -1.7, -1.8, -1.9, -2, -2.1, -2.2, -2.3, -2.4, -2. The offset can be -5, -2.6, -2.7, -2.8, -2.9, -3, -3.1, -3.2, -3.3, -3.4, -3.5, -3.6, -3.7, -3.8, -3.9, -4, -4.1, -4.2, -4.3, -4.4, -4.5, -4.6, -4.7, -4.8, -4.9, or -5.

[0166] In some embodiments, a subject being monitored may have an elevated risk of developing an irAE or may be diagnosed with an irAE if transcript levels of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B are elevated prior to ICI treatment (baseline) compared to transcript levels in a control sample.

[0167] In some embodiments, a subject being monitored may have an elevated risk of developing an irAE or may be diagnosed with an irAE if the transcript levels of one or more of LILRB4, CISH, and / or PARP9 are elevated before ICI treatment (baseline) compared to the transcript levels in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE or may be diagnosed with an irAE if the transcript levels of one or more of LILRB4, CISH, GIMAP7, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B are elevated before ICI treatment (baseline) compared to the transcript levels in a control sample.

[0168] In some embodiments, a monitored subject may have a high risk of developing an irAE if the transcript level of LILRB4 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a high risk of developing an irAE if the transcript level of CISH is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a high risk of developing an irAE if the transcript level of PARP9 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a high risk of developing an irAE if the transcript level of RNF145 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a high risk of developing an irAE if the transcript level of ASGR2 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a high risk of developing an irAE if the transcript level of SLC16A13 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a high risk of developing an irAE if the transcript level of LPAR6 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a high risk of developing an irAE if the transcript level of GIMAP7 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a high risk of developing an irAE if the transcript level of CXCR6 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a high risk of developing an irAE if the transcript level of DHRS9 is elevated compared to the transcript level in a control sample before ICI treatment.In some embodiments, a subject being monitored may have a high risk of developing an irAE if the transcript level of FCGR1CP is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject being monitored may have a high risk of developing an irAE if the transcript level of ANKRD34B is elevated compared to the transcript level in a control sample before ICI treatment.

[0169] In some embodiments, a monitored subject may have a high risk of developing an irAE if the transcript level of at least LILRB4 is elevated in the subject compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a high risk of developing an irAE if the transcript level of at least CISH is elevated in the subject compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a high risk of developing an irAE if the transcript level of at least PARP9 is elevated in the subject compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a high risk of developing an irAE if the transcript level of at least GIMAP7 is elevated in the subject compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a high risk of developing an irAE if the transcript level of at least CXCR6 is elevated in the subject compared to the transcript level in a control sample before ICI treatment. In some embodiments, the subject being monitored may have a high risk of developing an irAE if the transcript level of at least DHRS9 is elevated compared to the transcript level in a control sample before ICI treatment.In some embodiments, the subject being monitored may have a high risk of developing an irAE if the transcript level of at least FCGR1CP is elevated compared to the transcript level in a control sample before ICI treatment.In some embodiments, the subject being monitored may have a high risk of developing an irAE if the transcript level of at least ANKRD34B is elevated compared to the transcript level in a control sample before ICI treatment.

[0170] In some embodiments, the subject being monitored is a patient with a tumor necrosis factor (TNF)-1 (TNFSF), ... A subject may be at increased risk of developing an irAE if the transcript level of one or more of KCNG1, PTGS2, AKAP5, DUSP1, DGKK, B4GALNT3, TRIB1, PMAIP1, CXCR4, TP53INP2, NFIL3, DUSP4, NFKBIA, AVPI1, CD79a, ARL4D, JCHAIN, BTG2, TLE1, NXT1, TOB1, PDE4D, DNAJB1, ARID5B, GPR153, KLF9, SBDS, IER2, TSC22D3, GABARAPL1, JUND, RUNX3, BRE-AS1, LOC102724428, FAM46C, and / or GRASP is low compared to the transcript level in a control sample.

[0171] In some embodiments, the subject being monitored is a patient with a tumor necrosis factor (TNF-α), ... A subject may be at increased risk of developing an irAE if the transcript levels of one or more of: PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, BRE-AS1, LOC102724428, and / or GRASP are low in the subject compared to the transcript levels in a control sample.

[0172] In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript levels of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, and / or JUNB are low compared to the transcript levels in a control sample before ICI treatment. In various embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript levels of one or more of AREG, EREG, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, and / or SHISA8 are low compared to the transcript levels in a control sample before ICI treatment. In some other embodiments, the subject being monitored may have an elevated risk of developing an irAE if the transcript levels of one or more of AREG, EREG, CXCL8, EGR1, PAX8, ATF6B, VMO1, HBEGF, BRE-AS1, NR4A2, OSM, NOCT, PLK2, LOC102724428, DUSP2, GRASP, PER1, TNFSF9, CSRNP1, MAFF, TNFAIP3, DUSP1, TRIB1, PMAIP1, FAM46C, NXT1, and / or KLF9 are low compared to the transcript levels in a control sample before ICI treatment.

[0173] In some embodiments, a monitored subject may have a high risk of developing an irAE when the transcript level of at least AREG is low in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have a high risk of developing an irAE when the transcript level of at least EREG is low in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have a high risk of developing an irAE when the transcript level of at least OSM is low in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have a high risk of developing an irAE when the transcript level of at least CSRNP1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have a high risk of developing an irAE when the transcript level of at least DDIT4 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least IL-10 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least PTGS2 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least DUSP1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least CXCR4 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least NFIL3 is low in the subject compared to the transcript level in a control sample.In some embodiments, a monitored subject may have an elevated risk of developing an irAE when the transcript level of at least FOS is low in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have an elevated risk of developing an irAE when the transcript level of at least NFKBIA is low in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have an elevated risk of developing an irAE when the transcript level of at least PPP1R15A is low in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have an elevated risk of developing an irAE when the transcript level of at least CD79A is low in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have an elevated risk of developing an irAE when the transcript level of at least JUNB is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least CXCL8 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least EGR1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least G0S2 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least PAX8 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least ATF6B is low in the subject compared to the transcript level in a control sample.In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least PAX8-AS1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least RNVU1-19 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least VMO1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least HBEGF is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least CCDC144A is low in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have a high risk of developing an irAE when the transcript level of at least SHISA8 is low in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have a high risk of developing an irAE when the transcript level of at least NR4A2 is low in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have a high risk of developing an irAE when the transcript level of at least PTGES is low in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have a high risk of developing an irAE when the transcript level of at least SYN1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have a high risk of developing an irAE when the transcript level of at least CXCL2 is low in the subject compared to the transcript level in a control sample.In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least PMP22 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least CD83 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least EGR3 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least NUAK1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least NOCT is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least ATOH8 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least PLK2 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least ID1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least ADRB1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least SNAI1 is low in the subject compared to the transcript level in a control sample.In some embodiments, a monitored subject may have a high risk of developing an irAE when the transcript level of at least NOTCH3 is low in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have a high risk of developing an irAE when the transcript level of at least ATF3 is low in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have a high risk of developing an irAE when the transcript level of at least DUSP2 is low in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have a high risk of developing an irAE when the transcript level of at least PER1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have a high risk of developing an irAE when the transcript level of at least TNFSF9 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least MAFF is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least MIR4420 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least BRE-AS1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least LOC102724428 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of at least GRASP is low in the subject compared to the transcript level in a control sample.In some embodiments, a subject being monitored may have a high risk of developing an irAE if the transcript level of at least TNFAIP3 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a high risk of developing an irAE if the transcript level of at least TRIB1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a high risk of developing an irAE if the transcript level of at least PMAIP1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a high risk of developing an irAE if the transcript level of at least PMAIP1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a high risk of developing an irAE if the transcript level of at least FAM46C is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a high risk of developing an irAE if the transcript level of at least NXT1 is low in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a high risk of developing an irAE if the transcript level of at least KLF9 is low in the subject compared to the transcript level in a control sample.

[0174] In some embodiments, a monitored subject may have a high risk of developing an irAE if the transcript level of AREG is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a high risk of developing an irAE if the transcript level of EREG is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a high risk of developing an irAE if the transcript level of OSM is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a high risk of developing an irAE if the transcript level of CSRNP1 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a high risk of developing an irAE if the transcript level of DDIT4 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of IL-10 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of PTGS2 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of DUSP1 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of CXCR4 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of NIFL3 is low compared to the transcript level in a control sample before ICI treatment.In some embodiments, a monitored subject may have a high risk of developing an irAE if the transcript level of FOS is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a high risk of developing an irAE if the transcript level of NFKBIA is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a high risk of developing an irAE if the transcript level of PPP1R15A is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a high risk of developing an irAE if the transcript level of CD79A is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a high risk of developing an irAE if the transcript level of JUNB is low compared to the transcript level in a control sample before ICI treatment.

[0175] In some embodiments, the subject being monitored is monitored for elevated transcript levels of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B prior to ICI treatment (baseline) compared to the transcript levels in a control sample, as well as elevated transcript levels of AREG, EREG, OSM, CS RNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B , PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATO H8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, GPX3, TNFAIP3, KCNG1, PTGS2, AKAP5, DUSP1, DGKK, B4GALNT3, TRIB1, PMAIP1, CXCR4, TP53INP2, NFIL3, DUSP4, NFKBIA, AVPI1, CD79a, ARL4D, JCHAIN, BTG2, TL A subject may be at increased risk of developing an irAE if the transcript levels of one or more of E1, NXT1, TOB1, PDE4D, DNAJB1, ARID5B, GPR153, KLF9, SBDS, IER2, TSC22D3, JUND, GABARAPL1, RUNX3, BRE-AS1, LOC102724428, FAM46C, and / or GRASP are low in comparison to the transcript levels in a control sample.

[0176] In some embodiments, the subject being monitored is monitored for elevated transcript levels of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B prior to ICI treatment (baseline) compared to the transcript levels in a control sample, as well as elevated transcript levels of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G A subject may be at increased risk of developing an irAE if the transcript levels of one or more of: OS2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, BRE-AS1, and / or LOC102724428 are low in the subject compared to the transcript levels in a control sample.

[0177] In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript levels of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B are elevated compared to the transcript levels in a control sample prior to ICI treatment (baseline), and if the transcript levels of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, and / or JUNB are low in the subject compared to the transcript levels in a control sample.

[0178] In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript levels of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B are elevated compared to the transcript levels in a control sample prior to ICI treatment (baseline), and if the transcript levels of one or more of AREG, EREG, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, and / or SHISA8 are low in the subject compared to the transcript levels in a control sample.

[0179] In some embodiments, the subject being monitored is monitored for elevated transcript levels of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B prior to ICI treatment (baseline) compared to the transcript levels in a control sample, as well as for AREG, EREG, CXCL8, EGR1, PAX8, ATF6B A subject may be at increased risk of developing an irAE if the transcript levels of one or more of: VMO1, HBEGF, BRE-AS1, NR4A2, OSM, NOCT, PLK2, LOC102724428, DUSP2, GRASP, PER1, TNFSF9, CSRNP1, MAFF, TNFAIP3, DUSP1, TRIB1, PMAIP1, FAM46C, NXT1, and / or KLF9 are low in the subject compared to the transcript levels in a control sample.

[0180] In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript levels of one or more of LILRB4, CISH, and / or PARP9 are elevated prior to ICI treatment (baseline) compared to the transcript levels in a control sample, and if the transcript levels of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, and / or JUNB are low in the subject compared to the transcript levels in a control sample.

[0181] In some embodiments, a subject being monitored may be at high risk of developing an irAE if transcript levels of LILRB4, CISH, and PARP9 are elevated compared to control samples prior to ICI treatment (baseline), and if transcript levels of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, and JUNB are low in the subject compared to transcript levels in control samples.

[0182] In some embodiments, the subject being monitored is monitored for elevated transcript levels of one or more of LILRB4, GIMAP7, CISH, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B prior to ICI treatment (baseline) compared to the transcript levels in a control sample, as well as for elevated transcript levels of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PA A subject may be at increased risk of developing an irAE if the transcript level of one or more of X8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, BRE-AS1, and / or LOC102724428 is low compared to the transcript level in a control sample.

[0183] In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of CISH is elevated compared to the transcript level in a control sample before ICI treatment, and if the transcript level of one or more of AREG, EREG, CXCL8, EGR1, PAX8, ATF6B, VMO1, HBEGF, BRE-AS1, NR4A2, OSM, NOCT, PLK2, LOC102724428, DUSP2, GRASP, PER1, TNFSF9, CSRNP1, MAFF, TNFAIP3, DUSP1, TRIB1, PMAIP1, FAM46C, NXT1, and / or KLF9 is low in the subject compared to the transcript level in a control sample.

[0184] In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript levels of one or more of LILRB4, GIMAP7, CISH, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B are elevated compared to the transcript levels in a control sample before ICI treatment (baseline), and if the transcript levels of one or more of AREG, EREG, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, and / or SHISA8 are low in the subject compared to the transcript levels in a control sample.

[0185] In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the transcript level of PARP9 is elevated prior to ICI treatment (baseline) compared to the transcript level in a control sample, and if the transcript level of one or more of CD79A, CD83, PLK2, PDE4D, TR1B1, EREG, CXCL8, EGR3, JUNB, DUSP1, NFKBIA, TNFSF9, TNFAIP3, IL-10, JUND, FOS, RUNX3, and / or TSC22D3 is low in the subject compared to the transcript level in a control sample.

[0186] In some embodiments, the subject being monitored is monitored for elevated transcript levels of one or more of PARP9, CISH, CXCR6, LPAR6, and / or ASGR2 prior to ICI treatment (baseline) compared to the transcript levels in a control sample, as well as for KLF9, CXCR4, ATF6B, CD79A, CD83, PLK2, GRASP, PPP1R15A, GPX3, PARP9, BTG2, PTGS2, NOTCH3, AKAP5, PDE4D, SBDS, TRIB1, SNAI1, PAX8, NFIL3, EREG, AREG, DGKK A subject may be at increased risk of developing an irAE if the transcript levels of one or more of: , PTGES, CSRNP1, DNAJB1, CXCL8, OSM, ARID5B, ID1, NR4A2, EGR3, JUNB, TLE1, CXCL2, DUSP1, GPR153, G0S2, ATF3, NFKBIA, TNFS9, NUAK1, ATOH8, TNFAIP3, ADRB1, HBEGF, IL-10, JUND, FOS, GABARAPL1, PMAIP1, DDIT4, and / or EGR1 are low in the subject compared to the transcript levels in a control sample.

[0187] In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript levels of one or more of the transcripts LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7), CXCR6 DHRS9, FCGR1CP, and / or ANKRD34B are low prior to ICI treatment (baseline) compared to the transcript levels in a control sample.

[0188] In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript levels of one or more of LILRB4, CISH, and / or PARP9 are elevated compared to the transcript levels in a control sample before ICI treatment (baseline). In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript levels of one or more of LILRB4, CISH, GIMAP7, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B are low compared to the transcript levels in a control sample before ICI treatment (baseline).

[0189] In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of LILRB4 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of CISH is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of PARP9 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of RNF145 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of ASGR2 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of SLC16A13 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of LPAR6 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of GIMAP7 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of CXCR6 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of DHRS9 is low compared to the transcript level in a control sample before ICI treatment.In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of FCGR1CP is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of ANKRD34B is low compared to the transcript level in a control sample before ICI treatment.

[0190] In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of at least LILRB4 is low in the subject compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of at least CISH is low in the subject compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of at least PARP9 is low in the subject compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of at least GIMAP7 is low in the subject compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of at least CXCR6 is low in the subject compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of at least DHRS9 is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of at least FCGR1CP is low compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of at least ANKRD34B is low compared to the transcript level in a control sample before ICI treatment.

[0191] In some embodiments, the subject being monitored is a patient with a gene encoding a gene encoding a marker for a particular gene, such as AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, GPX3, TNFAIP3, K A subject may have a low risk of developing an irAE if the transcript level of one or more of CNG1, PTGS2, AKAP5, DUSP1, DGKK, B4GALNT3, TRIB1, PMAIP1, CXCR4, TP53INP2, NFIL3, DUSP4, NFKBIA, AVPI1, CD79a, ARL4D, JCHAIN, BTG2, TLE1, NXT1, TOB1, PDE4D, DNAJB1, ARID5B, GPR153, KLF9, SBDS, IER2, TSC22D3, JUND, GABARAPL1, RUNX3, BRE-AS1, LOC102724428, FAM46C, and / or GRASP is elevated in the subject compared to the transcript level in a control sample.

[0192] In some embodiments, the subject being monitored is a patient with a gene encoding a gene encoding a gene encoding a marker of a particular gene, such as AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, P A subject may have a low risk of developing an irAE if the transcript levels of one or more of MP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, BRE-AS1, LOC102724428, and / or GRASP are elevated in the subject compared to the transcript levels in a control sample.

[0193] In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript levels of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, and / or JUNB are elevated compared to the transcript levels in a control sample before ICI treatment. In various embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript levels of one or more of AREG, EREG, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, and / or SHISA8 are elevated compared to the transcript levels in a control sample before ICI treatment. In some other embodiments, the subject being monitored may have a low risk of developing an irAE if the transcript levels of one or more of AREG, EREG, CXCL8, EGR1, PAX8, ATF6B, VMO1, HBEGF, BRE-AS1, NR4A2, OSM, NOCT, PLK2, LOC102724428, DUSP2, GRASP, PER1, TNFSF9, CSRNP1, MAFF, TNFAIP3, DUSP1, TRIB1, PMAIP1, FAM46C, NXT1, and / or KLF9 are elevated compared to the transcript levels in a control sample before ICI treatment.

[0194] In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of at least AREG is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of at least EREG is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of at least OSM is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of at least CSRNP1 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of at least DDIT4 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least IL-10 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least PTGS2 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least DUSP1 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least CXCR4 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least NFIL3 is elevated in the subject compared to the transcript level in a control sample.In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least FOS is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least NFKBIA is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least PPP1R15A is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least CD79A is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least JUNB is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least CXCL8 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least EGR1 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least G0S2 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least PAX8 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least ATF6B is elevated in the subject compared to the transcript level in a control sample.In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least PAX8-AS1 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least RNVU1-19 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least VMO1 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least HBEGF is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least CCDC144A is low in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of at least SHISA8 is low in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of at least NR4A2 is low in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of at least PTGES is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of at least SYN1 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of at least CXCL2 is elevated in the subject compared to the transcript level in a control sample.In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least PMP22 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least CD83 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least EGR3 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least NUAK1 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least NOCT is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least ATOH8 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least PLK2 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least ID1 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least ADRB1 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least SNAI1 is elevated in the subject compared to the transcript level in a control sample.In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of at least NOTCH3 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of at least ATF3 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of at least DUSP2 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of at least PER1 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of at least TNFSF9 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least MAFF is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least MIR4420 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least BRE-AS1 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least LOC102724428 is elevated in the subject compared to the transcript level in a control sample.In some embodiments, a subject being monitored may have a reduced risk of developing an irAE if the transcript level of at least GRASP is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a reduced risk of developing an irAE if the transcript level of at least TNFAIP3 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a reduced risk of developing an irAE if the transcript level of at least TNFAIP3 is elevated in the subject compared to the transcript level in a control sample. A subject may have a low risk of developing an irAE if the transcript level of at least TRIB1 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least PMAIP1 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least FAM46C is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least NXT1 is elevated in the subject compared to the transcript level in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of at least KLF9 is elevated in the subject compared to the transcript level in a control sample.

[0195] In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of AREG is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of EREG is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of OSM is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of CSRNP1 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of DDIT4 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of IL-10 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of PTGS2 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of DUSP1 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of CXCR4 is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of NIFL3 is elevated compared to the transcript level in a control sample before ICI treatment.In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of FOS is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of NFKBIA is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of PPP1R15A is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of CD79A is elevated compared to the transcript level in a control sample before ICI treatment. In some embodiments, a monitored subject may have a low risk of developing an irAE if the transcript level of JUNB is elevated compared to the transcript level in a control sample before ICI treatment.

[0196] In some embodiments, the subject being monitored is diagnosed if the transcript levels of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B are low prior to ICI treatment (baseline) compared to the transcript levels in a control sample, and if the transcript levels of one or more of AREG, EREG, OSM, CSRNP1 are low prior to ICI treatment (baseline) compared to the transcript levels in a control sample. , DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX 8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, P LK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, GPX3, TNFAIP3, KCNG1, PTGS2, AKAP5, DUSP 1, DGKK, B4GALNT3, TRIB1, PMAIP1, CXCR4, TP53INP2, NFIL3, DUSP4, NFKBIA, AVPI1, CD79a, ARL4D, JCHAIN, BTG2, TLE1, N A subject may have a low risk of developing an irAE if the transcript levels of one or more of XT1, TOB1, PDE4D, DNAJB1, ARID5B, GPR153, KLF9, SBDS, IER2, TSC22D3, JUND, GABARAPL1, RUNX3, BRE-AS1, LOC102724428, FAM46C, and / or GRASP are elevated in the subject compared to the transcript levels in a control sample.

[0197] In some embodiments, the subject being monitored is diagnosed if the transcript levels of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B are low prior to ICI treatment (baseline) compared to the transcript levels in a control sample, as well as if the transcript levels of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, A subject may have a low risk of developing an irAE if the transcript level of one or more of PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, BRE-AS1, and / or LOC102724428 is elevated in the subject compared to the transcript level in a control sample.

[0198] In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript levels of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B are low compared to the transcript levels in a control sample before ICI treatment, and if the transcript levels of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, and / or JUNB are elevated in the subject compared to the transcript levels in a control sample.

[0199] In some embodiments, a subject being monitored may have a low risk of developing an irAE if transcript levels of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B are low compared to a control sample before ICI treatment (baseline), and if transcript levels of one or more of AREG, EREG, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, and / or SHISA8 are elevated in the subject compared to the transcript levels in a control sample.

[0200] In some embodiments, the subject being monitored is diagnosed if the transcript levels of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B are low prior to ICI treatment (baseline) compared to the transcript levels in a control sample, as well as if the transcript levels of AREG, EREG, CXCL8, EGR1, PAX8, ATF6B, VMO A subject may have a low risk of developing an irAE if the transcript levels of one or more of: 1, HBEGF, BRE-AS1, NR4A2, OSM, NOCT, PLK2, LOC102724428, DUSP2, GRASP, PER1, TNFSF9, CSRNP1, MAFF, TNFAIP3, DUSP1, TRIB1, PMAIP1, FAM46C, NXT1, and / or KLF9 are elevated in the subject compared to the transcript levels in a control sample.

[0201] In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript levels of one or more of LILRB4, CISH, and / or PARP9 are low compared to the transcript levels in a control sample before ICI treatment (baseline), and if the transcript levels of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, and / or JUNB are elevated in the subject compared to the transcript levels in a control sample.

[0202] In some embodiments, a subject being monitored may have a low risk of developing an irAE if transcript levels of LILRB4, CISH, and PARP9 are low compared to the transcript levels in a control sample before ICI treatment (baseline), and if transcript levels of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, and JUNB are elevated in the subject compared to the transcript levels in a control sample.

[0203] In some embodiments, the subject being monitored is diagnosed if the transcript levels of one or more of LILRB4, GIMAP7, CISH, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B are low compared to the transcript levels in a control sample prior to ICI treatment, as well as if the transcript levels of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, R A subject may have a low risk of developing an irAE if the transcript levels of one or more of NVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, BRE-AS1, and / or LOC102724428 are elevated in the subject compared to the transcript levels in a control sample.

[0204] In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of the transcript CISH is low compared to the transcript level in a control sample before ICI treatment, and if the transcript level of one or more of AREG, EREG, CXCL8, EGR1, PAX8, ATF6B, VMO1, HBEGF, BRE-AS1, NR4A2, OSM, NOCT, PLK2, LOC102724428, DUSP2, GRASP, PER1, TNFSF9, CSRNP1, MAFF, TNFAIP3, DUSP1, TRIB1, PMAIP1, FAM46C, NXT1, and / or KLF9 is elevated in the subject compared to the transcript level in a control sample.

[0205] In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript levels of one or more of LILRB4, GIMAP7, CISH, CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B are low compared to the transcript levels in a control sample before ICI treatment (baseline), and if the transcript levels of one or more of AREG, EREG, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, and / or SHISA8 are elevated in the subject compared to the transcript levels in a control sample.

[0206] In some embodiments, a subject being monitored may have a low risk of developing an irAE if the transcript level of PARP9 is low compared to the transcript level in a control sample before ICI treatment (baseline), and if the transcript level of one or more of CD79A, CD83, PLK2, PDE4D, TR1B1, EREG, CXCL8, EGR3, JUNB, DUSP1, NFKBIA, TNFSF9, TNFAIP3, IL-10, JUND, FOS, RUNX3, and / or TSC22D3 is elevated in the subject compared to the transcript level in a control sample.

[0207] In some embodiments, the subject being monitored is diagnosed if the transcript levels of one or more of PARP9, CISH, CXCR6, LPAR6, and / or ASGR2 are low prior to ICI treatment (baseline) compared to the transcript levels in a control sample, as well as if the transcript levels of one or more of KLF9, CXCR4, ATF6B, CD79A, CD83, PLK2, GRASP, PPP1R15A, GPX3, PARP9, BTG2, PTGS2, NOTCH3, AKAP5, PDE4D, SBDS, TRIB1, SNAI1, PAX8, NFIL3, EREG, AREG, DGKK, PTG A subject may have a low risk of developing an irAE if the transcript level of one or more of ES, CSRNP1, DNAJB1, CXCL8, OSM, ARID5B, ID1, NR4A2, EGR3, JUNB, TLE1, CXCL2, DUSP1, GPR153, G0S2, ATF3, NFKBIA, TNFS9, NUAK1, ATOH8, TNFAIP3, ADRB1, HBEGF, IL-10, JUND, FOS, GABARAPL1, PMAIP1, DDIT4, and / or EGR1 is elevated in the subject compared to the transcript level in a control sample.

[0208] Any method known in the art can be used to measure and / or monitor transcript levels. As non-limiting examples, transcript levels can be measured using RNA-seq, nanopore sequencing, nanostring, multiplex RT-PCR, singleplex RT-PCR, NASBA, fluorometry, or spectrophotometry. The sample to be tested can include whole blood, serum, plasma, urine, CSF, or other suitable body fluids. Samples can be obtained from subjects before, during, and / or after ICI treatment, and transcript levels can be quantified to assess the risk of irAEs. In some embodiments, the transcriptional profile is an RNA peripheral blood transcriptional profile. Risk assessment includes predicting, diagnosing, or monitoring ICI-associated myositis, ICI-associated myocarditis, or ICI-associated myositis and myocarditis. Autoantibody profile

[0209] In some embodiments, the present disclosure provides an autoantibody profile associated with ICI-related irAEs. In some embodiments, the autoantibody profile comprises autoantibodies with elevated expression in subjects with irAEs compared to control samples before treatment or at baseline. In some embodiments, the autoantibody profile comprises autoantibodies with lower expression in subjects with irAEs compared to control samples before treatment or at baseline. In some embodiments, the autoantibody is one or more of autoantibodies Mi-2, GAD65, myosin, thyroglobulin, and / or TPO, or any combination thereof.

[0210] In some embodiments, the autoantibody profile comprises baseline or pre-treatment transcript profile that correlates with future toxicity.These autoantibodies are used as biomarkers for assessing the risk that the subject will develop irAE during ICI treatment.In some embodiments, the subject is planning to receive or has received ICI treatment as part of cancer therapy.

[0211] In some aspects, the autoantibodies may include one or more of the autoantibodies disclosed in U.S. Patent Application No. 16 / 487,335 (U.S. Patent Application Publication No. US 2020 / 0284803), the disclosure of which is incorporated by reference in its entirety.

[0212] In some aspects, the present disclosure provides a method for predicting or diagnosing a subject as having an elevated risk of developing an irAE if expression of one or more autoantibodies is elevated compared to expression of the same autoantibodies in a control sample. The method includes providing a sample from the subject at a pre-treatment or baseline time point, assessing one or more autoantibodies in the sample, and predicting the risk of developing an irAE or diagnosing the subject as having an irAE.

[0213] In some aspects, the method further includes predicting or diagnosing the subject as having an elevated risk of developing an irAE if expression of one or more autoantibodies differs in the subject compared to expression in a control sample, as described in U.S. Patent Application No. 16 / 487,335 (U.S. Patent Application Publication No. US 2020 / 0284803), the disclosure of which is incorporated by reference in its entirety.

[0214] In some embodiments, a method for predicting or diagnosing a subject as having an elevated risk of developing an irAE associated with ICI treatment comprises assessing the expression of one or more of the autoantibodies Mi-2, GAD65, myosin, thyroglobulin, and / or TPO, or any combination thereof. In some embodiments, a subject is predicted or diagnosed as having an elevated risk of developing an irAE if the expression of one or more of the autoantibodies Mi-2, GAD65, myosin, thyroglobulin, and / or TPO, or any combination thereof, is elevated compared to that in a control sample. In some embodiments, a subject is predicted or diagnosed as having an elevated risk of developing an irAE if the expression of the autoantibody Mi-2 is elevated compared to that in a control sample. In some embodiments, a subject is predicted or diagnosed as having an elevated risk of developing an irAE if the expression of the autoantibody GAD65 is elevated compared to that in a control sample. In some embodiments, a subject is predicted or diagnosed as having a high risk of developing an irAE when the expression of the autoantibody myosin is elevated compared to that in a control sample. In some embodiments, a subject is predicted or diagnosed as having a high risk of developing an irAE when the expression of the autoantibody thyroglobulin is elevated compared to that in a control sample. In some embodiments, a subject is predicted or diagnosed as having a high risk of developing an irAE when the expression of the autoantibody TPO is elevated compared to that in a control sample.

[0215] In some aspects, the present disclosure provides a method for predicting or diagnosing a subject as having a low risk of developing an irAE if expression of one or more autoantibodies is low compared to expression in a control sample. The method includes providing a sample from the subject at a pre-treatment or baseline time point, evaluating one or more autoantibodies in the sample, and predicting the risk of developing an irAE or diagnosing the subject as having an irAE.

[0216] In some aspects, the method further includes predicting or diagnosing the subject as having an elevated risk of developing an irAE if expression of one or more autoantibodies differs in the subject compared to expression in a control sample, as described in U.S. Patent Application No. 16 / 487,335 (U.S. Patent Application Publication No. US 2020 / 0284803), the disclosure of which is incorporated by reference in its entirety.

[0217] In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the expression of one or more of the autoantibodies Mi-2, GAD65, myosin, thyroglobulin, and / or TPO, or any combination thereof, is low compared to that in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the expression of the autoantibody Mi-2 is low compared to that in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the expression of the autoantibody GAD65 is low compared to that in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the expression of the autoantibody myosin is low compared to that in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the expression of the autoantibody thyroglobulin is low compared to that in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if expression of the autoantibody TPO is low compared to expression in a control sample.

[0218] In some embodiments, while predicting or diagnosing the risk of an irAE, one or more of the disclosed autoantibodies have elevated expression that is at least about 0.01%, at least about 0.05%, at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100% higher compared to a control sample. In some aspects, the disclosed autoantibodies can have elevated expression greater than 100% expression compared to expression in a control sample.

[0219] In some embodiments, while predicting or diagnosing risk of an irAE, the one or more autoantibodies are at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61 %, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100% lower. In some embodiments, one or more autoantibodies may be at least about 25% lower, at least 50% lower, or 100% lower compared to expression in a control sample.

[0220] In some embodiments, the present disclosure provides an autoantibody profile for monitoring a subject's risk of developing an irAE associated with ICI treatment. In some embodiments, the autoantibody profile comprises an autoantibody with elevated expression in a subject with an irAE before treatment or at baseline compared to expression in a control sample. In some embodiments, the autoantibody profile comprises an autoantibody with lower expression in a subject with an irAE before treatment or at baseline compared to expression in a control sample. In some embodiments, the autoantibody is one or more of autoantibodies Mi-2, GAD65, myosin, thyroglobulin, and / or TPO, or any combination thereof.

[0221] In some aspects, the subject being monitored may have an elevated risk of developing an irAE if the expression of one or more autoantibodies differs in the subject compared to expression in a control sample, as described in U.S. Patent Application No. 16 / 487,335 (U.S. Patent Application Publication No. US 2020 / 0284803), the disclosure of which is incorporated by reference in its entirety.

[0222] In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the expression of one or more autoantibodies Mi-2, GAD65, myosin, thyroglobulin, and / or TPO, or any combination thereof, is elevated compared to expression in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the expression of the autoantibody Mi-2 is elevated compared to expression in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the expression of the autoantibody GAD65 is elevated compared to expression in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the expression of the autoantibody myosin is elevated compared to expression in a control sample. In some embodiments, a subject being monitored may have an elevated risk of developing an irAE if the expression of the autoantibody thyroglobulin is elevated compared to expression in a control sample. In some embodiments, a subject being monitored may be at increased risk of developing an irAE if expression of the autoantibody TPO is elevated compared to expression in a control sample.

[0223] In some aspects, the subject being monitored may have a lower risk of developing an irAE if the expression of one or more autoantibodies differs in the subject compared to expression in a control sample, as described in U.S. Patent Application No. 16 / 487,335 (U.S. Patent Application Publication No. US 2020 / 0284803), the disclosure of which is incorporated by reference in its entirety.

[0224] In some embodiments, a subject being monitored may have a low risk of developing an irAE if the expression of one or more autoantibodies Mi-2, GAD65, myosin, thyroglobulin, and / or TPO, or any combination thereof, is low compared to that in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the expression of the autoantibody Mi-2 is low compared to that in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the expression of the autoantibody GAD65 is low compared to that in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the expression of the autoantibody myosin is low compared to that in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the expression of the autoantibody thyroglobulin is low compared to that in a control sample. In some embodiments, a subject being monitored may have a low risk of developing an irAE if the expression of the autoantibody TPO is low compared to that in a control sample.

[0225] In some embodiments, during monitoring for risk of irAE, one or more of the disclosed autoantibodies have elevated expression compared to a control sample that is at least about 0.01%, at least about 0.05%, at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100% greater. In some embodiments, the disclosed autoantibodies may have elevated expression compared to expression in a control sample that is greater than 100% greater.

[0226] In some embodiments, during monitoring for risk of irAEs, the one or more autoantibodies are at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, or at least about 9%, compared to a control sample. , at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100% lower. In some embodiments, one or more autoantibodies may be at least about 25% lower, at least 50% lower, or 100% lower compared to expression in a control sample.

[0227] Isolating, purifying, measuring, and / or monitoring the expression of autoantibodies can be performed using any method known in the art. As non-limiting examples, autoantibodies can be detected using enzyme-linked immunosorbent assays (ELISAs), radioimmunoassays (RIAs), immunoradiometric assays, fluorescent immunoassays, chemiluminescent assays, bioluminescent assays, and Western blots. In some embodiments, autoantibody profiling can be performed using a protein array panel containing various antigens. As a non-limiting example, the protein array panel can be a custom protein array panel of autoantigens, including nuclear antigens, cytoplasmic / matrix antigens, and tissue / organ-specific antigens. The sample to be tested can include whole blood, serum, plasma, urine, CSF, or other suitable body fluids. Samples can be obtained from subjects before, during, and / or after ICI treatment, and quantification of autoantibody expression can be performed to assess the risk of irAEs. In some embodiments, the autoantibody profile is a plasma autoantibody profile. Risk assessment includes predicting, diagnosing, or monitoring ICI-associated myositis, ICI-associated myocarditis, or ICI-associated myositis and myocarditis. Cytokine profile

[0228] In some embodiments, the present disclosure provides a cytokine profile associated with an ICI-associated irAE. In some embodiments, the cytokine profile comprises one or more cytokines at elevated levels in a subject with an irAE compared to a control sample. In some embodiments, the cytokine profile comprises one or more cytokines at reduced levels in a subject with an irAE compared to a control sample.

[0229] In some embodiments, the cytokine is one or more of CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, or any combination thereof. In some embodiments, the disclosed cytokines may include one or more of the cytokines disclosed in U.S. Patent Application No. 14 / 045,482 (U.S. Patent Application Publication No. US 2021 / 0263045), the disclosure of which is incorporated by reference in its entirety.

[0230] In some embodiments, the cytokine profile includes baseline or pre-treatment cytokines that correlate with future toxicity. In some embodiments, the cytokine profile includes cytokines whose expression persists during treatment. In some embodiments, these cytokines are used as biomarkers to assess a subject's risk of developing an irAE before, during, or after ICI treatment.

[0231] In some embodiments, a method for predicting or diagnosing a subject as having an elevated risk of developing an irAE associated with ICI treatment comprises assessing the expression of one or more of the cytokines CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, or any combination thereof. In some embodiments, a subject is predicted or diagnosed as having an elevated risk of developing an irAE if the expression of one or more cytokines CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, or any combination thereof, is elevated compared to expression in a control sample. In some embodiments, a subject is predicted or diagnosed as having an elevated risk of developing an irAE if the expression of the cytokine CXCL2 is elevated compared to expression in a control sample. In some embodiments, a subject is predicted or diagnosed as having an elevated risk of developing an irAE if the expression of the cytokine CXCL5 is elevated compared to expression in a control sample. In some embodiments, a subject is predicted or diagnosed as having an elevated risk of developing an irAE if the expression of the cytokine CXCL6 is elevated compared to that in a control sample. In some embodiments, a subject is predicted or diagnosed as having an elevated risk of developing an irAE if the expression of the cytokine CCL7 is elevated compared to that in a control sample. In some embodiments, a subject is predicted or diagnosed as having an elevated risk of developing an irAE if the expression of the cytokine CCL19 is elevated compared to that in a control sample. In some embodiments, a subject is predicted or diagnosed as having an elevated risk of developing an irAE if the expression of the cytokine IFNγ is elevated compared to that in a control sample. In some embodiments, a subject is predicted or diagnosed as having an elevated risk of developing an irAE if the expression of the cytokine IL-6 is elevated compared to that in a control sample. In some embodiments, a subject is predicted or diagnosed as having an elevated risk of developing an irAE if the expression of the cytokine CXCL9 is elevated compared to that in a control sample.In some embodiments, a subject is predicted or diagnosed as having an elevated risk of developing an irAE if expression of the cytokine CXCL10 is elevated compared to expression in a control sample.

[0232] In some embodiments, the cytokine profile includes cytokines whose elevated expression is sustained after the initiation of ICI treatment. In some embodiments, the cytokines whose elevated expression is sustained after the initiation of ICI treatment are one or more of CXCL5, IL-6, IFN-γ, CXCL9, CXCL10, or any combination thereof. In some embodiments, the cytokine whose elevated expression is sustained is CXCL5. In some embodiments, the cytokine whose elevated expression is sustained is IL-6. In some embodiments, the cytokine whose elevated expression is sustained is IFN-γ. In some embodiments, the cytokine whose elevated expression is sustained is CXCL9. In some embodiments, the cytokine whose elevated expression is sustained is CXCL10.

[0233] In some embodiments, a method for predicting or diagnosing a subject as having a low risk of developing an irAE associated with ICI treatment comprises assessing the expression of one or more of the cytokines CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, or any combination thereof. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the expression of one or more cytokines CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, or any combination thereof, is low compared to expression in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the expression of the cytokine CXCL2 is low compared to a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the expression of the cytokine CXCL5 is low compared to expression in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the expression of the cytokine CXCL6 is low compared to that in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the expression of the cytokine CCL7 is low compared to that in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the expression of the cytokine CCL19 is low compared to that in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the expression of the cytokine IFNγ is low compared to that in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the expression of the cytokine IL-6 is low compared to that in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE when the expression of the cytokine CXCL9 is low compared to that in a control sample.In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if expression of the cytokine CXCL10 is low compared to expression in a control sample.

[0234] In some embodiments, during prediction or diagnosis, one or more of the disclosed cytokines having elevated expression have an elevated expression level that is at least about 0.01%, at least about 0.05%, at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100% higher compared to expression in a control sample.

[0235] In some embodiments, during prediction or diagnosis, one or more of the disclosed cytokines having low expression have an expression level that is at least about 0.01%, at least about 0.05%, at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100% lower compared to expression in a control sample.

[0236] In some embodiments, during prediction or diagnosis, one or more of the disclosed cytokines has a concentration of about 10 pg / ml, about 20 pg / ml, about 30 pg / ml, about 40 pg / ml, about 50 pg / ml, about 60 pg / ml, about 70 pg / ml, about 80 pg / ml, about 90 pg / ml, about 100 pg / ml, about 120 pg / ml, about 140 pg / ml, about 150 pg / ml, about 160 pg / ml, about 180 pg / ml, about 200 pg / ml, about 300 pg / ml, about 400 pg / ml, about 500 pg / ml, about 600 pg / ml, about 700 pg / ml, or about 800 pg / ml.

[0237] In some embodiments, during prognosis or diagnosis, one or more of the disclosed cytokines have elevated expression, wherein expression has a fold change of at least about 1-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, at least about 10-fold, at least about 11-fold, at least about 12-fold, at least about 13-fold, at least about 14-fold, at least about 15-fold, at least about 16-fold, at least about 17-fold, at least about 18-fold, at least about 19-fold, or at least about 20-fold compared to expression in a control sample.

[0238] In some embodiments, the present disclosure provides a cytokine profile for monitoring a subject's risk of developing an irAE associated with ICI treatment. In some embodiments, the cytokine profile includes one or more cytokines that are elevated in a subject with an irAE compared to a control sample. In some embodiments, the cytokine profile includes one or more cytokines that are reduced in a subject with an irAE compared to their expression in a control sample.

[0239] In some embodiments, cytokines for monitoring the risk of developing an irAE associated with ICI treatment are one or more of CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, or any combination thereof. In some embodiments, the disclosed cytokines may include one or more of the cytokines disclosed in U.S. Patent Application No. 14 / 045,482 (U.S. Patent Application Publication No. US 2021 / 0263045), the disclosure of which is incorporated by reference in its entirety.

[0240] In some embodiments, the cytokine profile for monitoring the risk of developing an irAE associated with ICI treatment includes baseline or pre-treatment cytokines that correlate with future toxicity. In some embodiments, the cytokine profile for monitoring the risk of developing an irAE associated with ICI treatment includes cytokines whose expression persists during treatment. In some embodiments, these cytokines are used as biomarkers to assess a subject's risk of developing an irAE before, during, or after ICI treatment.

[0241] In some embodiments, a subject being monitored may have an increased risk of developing an irAE if the expression of one or more cytokines CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, or any combination thereof, is elevated compared to expression in a control sample. In some embodiments, a subject being monitored may have an increased risk of developing an irAE if the expression of the cytokine CXCL2 is elevated compared to expression in a control sample. In some embodiments, a subject being monitored may have an increased risk of developing an irAE if the expression of the cytokine CXCL5 is elevated compared to expression in a control sample. In some embodiments, a subject being monitored may have an increased risk of developing an irAE if the expression of the cytokine CXCL6 is elevated compared to expression in a control sample. In some embodiments, a subject being monitored may have an increased risk of developing an irAE if the expression of the cytokine CCL7 is elevated compared to expression in a control sample. In some embodiments, a subject being monitored may have an increased risk of developing an irAE if expression of the cytokine CCL19 is elevated compared to expression in a control sample. In some embodiments, a subject being monitored may have an increased risk of developing an irAE if expression of the cytokine IFNγ is elevated compared to expression in a control sample. In some embodiments, a subject being monitored may have an increased risk of developing an irAE if expression of the cytokine IL-6 is elevated compared to expression in a control sample. In some embodiments, a subject being monitored may have an increased risk of developing an irAE if expression of the cytokine CXCL9 is elevated compared to expression in a control sample. In some embodiments, a subject being monitored may have an increased risk of developing an irAE if expression of the cytokine CXCL10 is elevated compared to expression in a control sample.

[0242] In some embodiments, the cytokine profile for monitoring the risk of developing an irAE associated with ICI treatment includes cytokines whose elevated expression is sustained after the initiation of ICI treatment. In some embodiments, the cytokines whose elevated expression is sustained after the initiation of ICI treatment are one or more of CXCL5, IL-6, IFN-γ, CXCL9, CXCL10, or any combination thereof. In some embodiments, the cytokine whose elevated expression is sustained is CXCL5. In some embodiments, the cytokine whose elevated expression is sustained is IL-6. In some embodiments, the cytokine whose elevated expression is sustained is IFN-γ. In some embodiments, the cytokine whose elevated expression is sustained is CXCL9. In some embodiments, the cytokine whose elevated expression is sustained is CXCL10.

[0243] In some embodiments, a subject being monitored may have a low risk of developing an irAE if the expression of one or more of the cytokines CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, or any combination thereof, is low compared to expression in a control sample. In some embodiments, a subject being monitored may have a high risk of developing an irAE if the expression of the cytokine CXCL2 is low compared to expression in a control sample. In some embodiments, a subject being monitored may have a high risk of developing an irAE if the expression of the cytokine CXCL5 is low compared to expression in a control sample. In some embodiments, a subject being monitored may have a high risk of developing an irAE if the expression of the cytokine CXCL6 is low compared to expression in a control sample. In some embodiments, a subject being monitored may have a high risk of developing an irAE if the expression of the cytokine CCL7 is low compared to expression in a control sample. In some embodiments, a subject being monitored may have an increased risk of developing an irAE if expression of the cytokine CCL19 is low compared to expression in a control sample. In some embodiments, a subject being monitored may have an increased risk of developing an irAE if expression of the cytokine IFNγ is low compared to expression in a control sample. In some embodiments, a subject being monitored may have an increased risk of developing an irAE if expression of the cytokine IL-6 is low compared to expression in a control sample. In some embodiments, a subject being monitored may have an increased risk of developing an irAE if expression of the cytokine CXCL9 is low compared to expression in a control sample. In some embodiments, a subject being monitored may have an increased risk of developing an irAE if expression of the cytokine CXCL10 is low compared to expression in a control sample.

[0244] In some embodiments, during monitoring, one or more of the disclosed cytokines having elevated expression have an elevated expression level that is at least about 0.01%, at least about 0.05%, at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100% greater compared to expression in a control sample.

[0245] In some embodiments, during monitoring, one or more of the disclosed cytokines having low expression have an expression level that is at least about 0.01%, at least about 0.05%, at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100% lower compared to expression in the control sample.

[0246] In some embodiments, during monitoring, one or more of the disclosed cytokines have a concentration of about 10 pg / ml, about 20 pg / ml, about 30 pg / ml, about 40 pg / ml, about 50 pg / ml, about 60 pg / ml, about 70 pg / ml, about 80 pg / ml, about 90 pg / ml, about 100 pg / ml, about 120 pg / ml, about 140 pg / ml, about 150 pg / ml, about 160 pg / ml, about 180 pg / ml, about 200 pg / ml, about 300 pg / ml, about 400 pg / ml, about 500 pg / ml, about 600 pg / ml, about 700 pg / ml, or about 800 pg / ml.

[0247] In some embodiments, during monitoring, one or more of the disclosed cytokines have elevated expression, wherein expression has a fold change of at least about 1-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, at least about 10-fold, at least about 11-fold, at least about 12-fold, at least about 13-fold, at least about 14-fold, at least about 15-fold, at least about 16-fold, at least about 17-fold, at least about 18-fold, at least about 19-fold, or at least about 20-fold compared to expression in a control sample.

[0248] Cytokine detection, quantification, and / or monitoring can be performed using methods well known in the art, including enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoradiometric assay, fluorescent immunoassay, chemiluminescence assay, bioluminescence assay, and Western blot. In some embodiments, cytokine level monitoring is performed using a readily available cytokine panel (e.g., Bio-Plex Pro Human Chemokine 40-plex Panel, Bio-Rad Laboratories, Hercules, California). Cytokine concentrations can be determined based on standard curve fitting of the provided mean fluorescence intensity. Samples to be tested can include whole blood, serum, plasma, urine, CSF, or other suitable body fluids. Samples can be obtained from subjects before, during, and / or after ICI treatment, and cytokine concentration quantification can be performed to assess the risk of irAEs. In some embodiments, samples are obtained from subjects before the initiation of ICI treatment. Risk assessment includes predicting, diagnosing, or monitoring ICI-associated myositis, ICI-associated myocarditis, or ICI-associated myositis and myocarditis. Immune cell profile

[0249] In some embodiments, the present disclosure provides an immune cell profile associated with an ICI-related irAE. In some embodiments, the immune cell profile comprises the presence of different immune cell subsets in a subject with an irAE compared to immune cell subsets in a control sample. In some embodiments, the immune cell profile comprises one or more of the immune cells disclosed in Figure 4A, or any combination thereof.

[0250] In some embodiments, the immune cell profile includes baseline or pre-treatment immune cell subsets that correlate with future toxicity. In some embodiments, the immune cell subsets are used as biomarkers to assess a subject's risk of developing an irAE before or during ICI treatment. In some embodiments, the immune cell profile includes one or more immune cell subsets that are elevated in abundance in a sample from the subject at pre-treatment or baseline compared to the abundance of the same immune cell subset in a control sample. In some embodiments, the immune cell profile includes one or more immune cell subsets that are decreased in abundance in a sample from the subject at pre-treatment or baseline compared to the abundance of the same immune cell subset in a control sample. In some embodiments, the immune cell profile includes immune cell subsets that have an increased abundance in a sample from the subject after initiation of ICI treatment compared to the abundance of the same immune cell subset in a control sample. In some embodiments, the immune cell subsets include PD-L1+ naive B cells, switched memory B cells, CTLA4+ monocytes, and CXCR3+ CD8 T cells.

[0251] In some aspects, the present disclosure provides methods for predicting or diagnosing a subject as having an elevated risk of developing an irAE associated with ICI treatment, the methods comprising assessing the abundance of one or more of the immune cell subsets PD-L1+ naive B cells, switched memory B cells, and / or CTLA4+ monocytes. In some aspects, a subject is predicted or diagnosed as having an elevated risk of developing an irAE if the abundance of one or more of the immune cell subsets PD-L1+ naive B cells, switched memory B cells, or any combination thereof is low and / or the abundance of CTLA4+ monocytes is elevated compared to their abundance in a control sample. In some aspects, a subject is predicted or diagnosed as having an elevated risk of developing an irAE if the abundance of the immune cell subset PD-L1+ naive B cells is low compared to a control sample. In some aspects, a subject is predicted or diagnosed as having an elevated risk of developing an irAE if the abundance of the immune cell subset switched memory B cells is low compared to their abundance in a control sample. In some embodiments, a subject is predicted or diagnosed as having an elevated risk of developing an irAE if the abundance of the immune cell subset CTLA4+ monocytes is elevated compared to its abundance in a control sample.

[0252] In some aspects, the present disclosure provides methods for predicting or diagnosing a subject as having a low risk of developing an irAE associated with ICI treatment, the methods comprising assessing the abundance of one or more of the immune cell subsets PD-L1+ naive B cells, switched memory B cells, and / or CTLA4+ monocytes. In some aspects, a subject is predicted or diagnosed as having a low risk of developing an irAE if the abundance of one or more of the immune cell subsets PD-L1+ naive B cells, switched memory B cells, or any combination thereof is elevated and / or the abundance of CTLA4+ monocytes is reduced compared to their abundance in a control sample. In some aspects, a subject is predicted or diagnosed as having a low risk of developing an irAE if the abundance of the immune cell subset PD-L1+ naive B cells is elevated compared to their abundance in a control sample. In some aspects, a subject is predicted or diagnosed as having a low risk of developing an irAE if the abundance of the immune cell subset switched memory B cells is elevated compared to their abundance in a control sample. In some embodiments, a subject is predicted or diagnosed as having a low risk of developing an irAE if the abundance of the immune cell subset CTLA4+ monocytes is low compared to its abundance in a control sample.

[0253] In some embodiments, a subject is predicted or diagnosed as having an elevated risk of developing an irAE if a change in the abundance of one or more of the immune cell subsets PD-L1+ naive B cells, switched memory B cells, and / or CXCR3+ CD8 T cells is enhanced in a sample from the subject after initiation of ICI treatment compared to their abundance in a control sample. In some embodiments, a subject is predicted or diagnosed as having an elevated risk of developing an irAE if a change in the abundance of the immune cell subset PD-L1+ naive B cells is enhanced after initiation of ICI treatment compared to their abundance in a control sample. In some embodiments, a subject is predicted or diagnosed as having an elevated risk of developing an irAE if a change in the abundance of the immune cell subset switched memory B cells is enhanced after initiation of ICI treatment compared to their abundance in a control sample. In some embodiments, a subject is predicted or diagnosed as having an elevated risk of developing an irAE if the change in abundance of the immune cell subset CXCR3+ CD8 T cells is enhanced after initiation of ICI treatment compared to abundance in a control sample.

[0254] In some embodiments, during prediction or diagnosis, the abundance of immune cells in an immune cell subset can be determined from a sample by determining the percentage of immune cells in that subset in the sample. (For example, X% of immune cells in a sample are subset 1.) The percentage of immune cells in a given subset can then be compared to the percentage of immune cells in that subset in a control sample.In some embodiments, the abundance (e.g., percentage) of immune cells in one or more immune cell subsets is at least about 0.1 percentage points (e.g., 1.0% compared to 1.1%), at least about 0.2 percentage points, at least about 0.3 percentage points, at least about 0.4 percentage points, at least about 0.5 percentage points, at least about 0.6 percentage points, at least about 0.7 percentage points, at least about 0.8 percentage points, at least about 0.9 percentage points, at least about 1 percentage point, at least about 2 percentage points, at least about 3 percentage points, at least about 4 percentage points, at least about 5 percentage points, at least about 6 percentage points, at least about 7 percentage points, at least about 8 percentage points, at least about 9 percentage points, at least about 10 percentage points, at least about 12 percentage points, at least about 13 percentage points, at least about 14 percentage points, at least about 15 percentage points, at least about 16 percentage points, at least about 17 percentage points, at least about 18 percentage points, at least about 19 percentage points, at least about 20 percentage points, at least about 21 percentage points, at least about 22 percentage points, at least about 23 percentage points, at least about 24 percentage points, at least about 25 percentage points, at least about 26 percentage points, at least about 27 percentage points, at least about 28 percentage points, at least about 29 percentage points, at least about 30 percentage points, at least about 31 percentage points, at least about 32 percentage points, at least about 33 percentage points, at least about 34 percentage points, at least about 35 percentage points, at least about 36 percentage points, at least about 37 percentage points, at least about 38 percentage points, at least about 39 percentage points, at least about 40 percentage points, at least about 42 percentage points, at least about 43 percentage points, at least about 44 percentage points, at least about 45 percentage points percentage points, at least about 9 percentage points, at least about 10 percentage points, at least about 15 percentage points, at least about 20 percentage points, at least about 25 percentage points, at least about 30 percentage points, at least about 35 percentage points, at least about 40 percentage points, at least about 45 percentage points, at least about 50 percentage points, at least about 55 percentage points, at least about 60 percentage points, at least about 65 percentage points, at least about 70 percentage points, at least about 75 percentage points, at least about 80 percentage points, at least about 85 percentage points, at least about 90 percentage points, at least about 95 percentage points, at least about 99 percentage points, or at least about 100 percentage points lower.

[0255] In some embodiments, during prediction or diagnosis, the abundance of immune cells in an immune cell subset can be determined from a sample by determining the percentage of immune cells in that subset in the sample. (For example, X% of immune cells in a sample are subset 1.) The percentage of immune cells in a given subset can then be compared to the percentage of immune cells in that subset in a control sample.In some embodiments, the abundance (e.g., percentage) of immune cells in one or more immune cell subsets is at least about 0.1 percentage points (e.g., 1.0% compared to 1.1%), at least about 0.2 percentage points, at least about 0.3 percentage points, at least about 0.4 percentage points, at least about 0.5 percentage points, at least about 0.6 percentage points, at least about 0.7 percentage points, at least about 0.8 percentage points, at least about 0.9 percentage points, at least about 1 percentage point, at least about 2 percentage points, at least about 3 percentage points, at least about 4 percentage points, at least about 5 percentage points, at least about 6 percentage points, at least about 7 percentage points, at least about 8 percentage points, at least about 9 percentage points, at least about 10 percentage points, at least about 12 percentage points, at least about 13 percentage points, at least about 14 percentage points, at least about 15 percentage points, at least about 16 percentage points, at least about 17 percentage points, at least about 18 percentage points, at least about 19 percentage points, at least about 20 percentage points, at least about 21 percentage points, at least about 22 percentage points, at least about 23 percentage points, at least about 24 percentage points, at least about 25 percentage points, at least about 26 percentage points, at least about 27 percentage points, at least about 28 percentage points, at least about 29 percentage points, at least about 30 percentage points, at least about 31 percentage points, at least about 32 percentage points, at least about 33 percentage points, at least about 34 percentage points, at least about 35 percentage points, at least about 36 percentage points, at least about 37 percentage points, at least about 38 percentage points, at least about 39 percentage points, at least about 40 percentage points, at least about 42 percentage points, at least about 43 percentage points, at least about 44 percentage points, at least about 45 percentage points percentage points, at least about 9 percentage points, at least about 10 percentage points, at least about 15 percentage points, at least about 20 percentage points, at least about 25 percentage points, at least about 30 percentage points, at least about 35 percentage points, at least about 40 percentage points, at least about 45 percentage points, at least about 50 percentage points, at least about 55 percentage points, at least about 60 percentage points, at least about 65 percentage points, at least about 70 percentage points, at least about 75 percentage points, at least about 80 percentage points, at least about 85 percentage points, at least about 90 percentage points, at least about 95 percentage points, at least about 99 percentage points, or at least about 100 percentage points higher.

[0256] In some embodiments, the methods of the present disclosure provide an immune cell profile for monitoring a subject's risk of developing an irAE associated with ICI treatment. In some embodiments, the immune cell profile comprises the presence of different immune cell subsets in subjects with irAEs compared to control samples. In some embodiments, the immune cell profile comprises one or more of the immune cells disclosed in Figure 4A, or any combination thereof.

[0257] In some embodiments, the monitoring method includes providing a sample from a subject prior to ICI treatment, assessing an immune cell profile in the subject, and comparing the immune profile to a control sample. In some embodiments, the immune cell profile includes baseline or pre-treatment immune cell subsets that correlate with future toxicity. In some embodiments, the immune cell subsets are used as biomarkers to assess a subject's risk of developing an irAE before or during ICI treatment. In some embodiments, the immune cell profile includes one or more immune cell subsets that are elevated in abundance in a sample from the subject prior to treatment or at baseline compared to their abundance in a control sample. In some embodiments, the immune cell profile includes one or more immune cell subsets that are decreased in abundance in a sample from the subject prior to treatment or at baseline compared to their abundance in a control sample. In some embodiments, the immune cell profile includes immune cell subsets that have an increased abundance change in a sample from the subject after initiation of ICI treatment compared to a control sample. In some embodiments, the immune cell subsets include PD-L1+ naive B cells, switched memory B cells, CTLA4+ monocytes, and CXCR3+ CD8 T cells.

[0258] In some embodiments, a monitored subject has an increased risk of developing an irAE associated with ICI treatment if the abundance of one or more immune cell subsets PD-L1+ naive B cells, switched memory B cells, or any combination thereof is low, and / or the abundance of CTLA4+ monocytes is elevated, compared to their abundance in a control sample. In some embodiments, a monitored subject has an increased risk of developing an irAE if the abundance of the immune cell subset PD-L1+ naive B cells is low, compared to their abundance in a control sample. In some embodiments, a monitored subject has an increased risk of developing an irAE if the abundance of the immune cell subset switched memory B cells is low, compared to their abundance in a control sample. In some embodiments, a monitored subject has an increased risk of developing an irAE if the abundance of the immune cell subset CTLA4+ monocytes is elevated, compared to their abundance in a control sample.

[0259] In some embodiments, a subject being monitored has a low risk of developing an irAE if the abundance of one or more immune cell subsets PD-L1+ naive B cells, switched memory B cells, or any combination thereof is elevated, and / or the abundance of CTLA4+ monocytes is low, compared to their abundance in a control sample. In some embodiments, a subject being monitored has a low risk of developing an irAE if the abundance of the immune cell subset PD-L1+ naive B cells is elevated, compared to their abundance in a control sample. In some embodiments, a subject being monitored has a low risk of developing an irAE if the abundance of the immune cell subset switched memory B cells is elevated, compared to their abundance in a control sample. In some embodiments, a subject being monitored has a low risk of developing an irAE if the abundance of the immune cell subset CTLA4+ monocytes is low, compared to their abundance in a control sample.

[0260] In some embodiments, a subject being monitored has an elevated risk of developing an irAE if a change in the abundance of one or more of the immune cell subsets PD-L1+ naive B cells, switched memory B cells, and / or CXCR3+ CD8 T cells is enhanced in a sample from the subject after initiation of ICI treatment compared to their abundance in a control sample. In some embodiments, a subject being monitored has an elevated risk of developing an irAE if a change in the abundance of the immune cell subset PD-L1+ naive B cells is enhanced after initiation of ICI treatment compared to their abundance in a control sample. In some embodiments, a subject being monitored has an elevated risk of developing an irAE if a change in the abundance of the immune cell subset switched memory B cells is enhanced after initiation of ICI treatment compared to their abundance in a control sample. In some embodiments, a subject being monitored has an elevated risk of developing an irAE if a change in the abundance of the immune cell subset CXCR3+ CD8 T cells is enhanced after initiation of ICI treatment compared to their abundance in a control sample.

[0261] In some embodiments, during monitoring, the abundance of immune cells in an immune cell subset can be determined from the sample by determining the percentage of immune cells in that subset in the sample. (For example, X% of immune cells in a sample are subset 1.) The percentage of immune cells in a given subset can then be compared to the percentage of immune cells in that subset in a control sample.In some embodiments, the abundance (e.g., percentage) of immune cells in one or more immune cell subsets is at least about 0.1 percentage points (e.g., 1.0% compared to 1.1%), at least about 0.2 percentage points, at least about 0.3 percentage points, at least about 0.4 percentage points, at least about 0.5 percentage points, at least about 0.6 percentage points, at least about 0.7 percentage points, at least about 0.8 percentage points, at least about 0.9 percentage points, at least about 1 percentage point, at least about 2 percentage points, at least about 3 percentage points, at least about 4 percentage points, at least about 5 percentage points, at least about 6 percentage points, at least about 7 percentage points, at least about 8 percentage points, at least about 9 percentage points, at least about 10 percentage points, at least about 12 percentage points, at least about 13 percentage points, at least about 14 percentage points, at least about 15 percentage points, at least about 16 percentage points, at least about 17 percentage points, at least about 18 percentage points, at least about 19 percentage points, at least about 20 percentage points, at least about 21 percentage points, at least about 22 percentage points, at least about 23 percentage points, at least about 24 percentage points, at least about 25 percentage points, at least about 26 percentage points, at least about 27 percentage points, at least about 28 percentage points, at least about 29 percentage points, at least about 30 percentage points, at least about 31 percentage points, at least about 32 percentage points, at least about 33 percentage points, at least about 34 percentage points, at least about 35 percentage points, at least about 36 percentage points, at least about 37 percentage points, at least about 38 percentage points, at least about 39 percentage points, at least about 40 percentage points, at least about 42 percentage points, at least about 43 percentage points, at least about 44 percentage points, at least about 45 percentage points percentage points, at least about 9 percentage points, at least about 10 percentage points, at least about 15 percentage points, at least about 20 percentage points, at least about 25 percentage points, at least about 30 percentage points, at least about 35 percentage points, at least about 40 percentage points, at least about 45 percentage points, at least about 50 percentage points, at least about 55 percentage points, at least about 60 percentage points, at least about 65 percentage points, at least about 70 percentage points, at least about 75 percentage points, at least about 80 percentage points, at least about 85 percentage points, at least about 90 percentage points, at least about 95 percentage points, at least about 99 percentage points, or at least about 100 percentage points lower.

[0262] In some embodiments, during monitoring, the abundance of immune cells in an immune cell subset can be determined from the sample by determining the percentage of immune cells in that subset in the sample. (For example, X% of immune cells in a sample are subset 1.) The percentage of immune cells in a given subset can then be compared to the percentage of immune cells in that subset in a control sample.In some embodiments, the abundance (e.g., percentage) of immune cells in one or more immune cell subsets is at least about 0.1 percentage points (e.g., 1.0% compared to 1.1%), at least about 0.2 percentage points, at least about 0.3 percentage points, at least about 0.4 percentage points, at least about 0.5 percentage points, at least about 0.6 percentage points, at least about 0.7 percentage points, at least about 0.8 percentage points, at least about 0.9 percentage points, at least about 1 percentage point, at least about 2 percentage points, at least about 3 percentage points, at least about 4 percentage points, at least about 5 percentage points, at least about 6 percentage points, at least about 7 percentage points, at least about 8 percentage points, at least about 9 percentage points, at least about 10 percentage points, at least about 12 percentage points, at least about 13 percentage points, at least about 14 percentage points, at least about 15 percentage points, at least about 16 percentage points, at least about 17 percentage points, at least about 18 percentage points, at least about 19 percentage points, at least about 20 percentage points, at least about 21 percentage points, at least about 22 percentage points, at least about 23 percentage points, at least about 24 percentage points, at least about 25 percentage points, at least about 26 percentage points, at least about 27 percentage points, at least about 28 percentage points, at least about 29 percentage points, at least about 30 percentage points, at least about 31 percentage points, at least about 32 percentage points, at least about 33 percentage points, at least about 34 percentage points, at least about 35 percentage points, at least about 36 percentage points, at least about 37 percentage points, at least about 38 percentage points, at least about 39 percentage points, at least about 40 percentage points, at least about 42 percentage points, at least about 43 percentage points, at least about 44 percentage points, at least about 45 percentage points percentage points, at least about 9 percentage points, at least about 10 percentage points, at least about 15 percentage points, at least about 20 percentage points, at least about 25 percentage points, at least about 30 percentage points, at least about 35 percentage points, at least about 40 percentage points, at least about 45 percentage points, at least about 50 percentage points, at least about 55 percentage points, at least about 60 percentage points, at least about 65 percentage points, at least about 70 percentage points, at least about 75 percentage points, at least about 80 percentage points, at least about 85 percentage points, at least about 90 percentage points, at least about 95 percentage points, at least about 99 percentage points, or at least about 100 percentage points higher.

[0263] Immune cell signatures can be detected, quantified, and / or monitored using methods well known in the art, including immune profiling assays, mass cytometry (time-of-flight cytometry, CyTOF), flow cytometry, and cell sorting, including FACS and immunomagnetic separation. In some embodiments, immune cell signatures are detected using high-dimensional mass cytometry (time-of-flight cytometry (CyTOF)). Samples to be tested may include whole blood, serum, plasma, urine, CSF, or other suitable bodily fluids. Samples can be obtained from subjects before, during, and / or after ICI treatment, and immune cell signatures are identified to assess the risk of irAEs. Risk assessment includes predicting, diagnosing, or monitoring ICI-associated myositis, ICI-associated myocarditis, or ICI-associated myositis and myocarditis.

[0264] In some embodiments, the disclosed method for assessing a subject's risk of developing an irAE assesses the risk of ICI-associated myositis, ICI-associated myocarditis, or a combination of ICI-associated myositis and myocarditis. Myositis and myocarditis can occur as a sole toxicity or can occur in conjunction with one or more other ICI-associated irAEs, including ocular toxicity, rash, dermatitis, pruritus, colitis, hepatitis, nephritis, arthritis, myositis, myocarditis, pneumonia, thyroiditis, hypophysitis, adrenalitis, gastritis, pancreatitis, vasculitis, diabetes, myasthenia gravis, encephalitis, peripheral neuropathy, meningitis, hemolytic anemia, thrombocytopenia, hemophagocytic lymphohistiocytosis / macrophage activation syndrome (HLH / MAS), aplastic anemia, pure red cell aplasia, and / or neutropenia. Autoimmune inflammatory myopathies (eg, myositis or myocarditis) can develop spontaneously or as paraneoplastic phenomena. Combination Profile

[0265] In some embodiments, the present disclosure further provides a profile comprising one or more of a transcript profile, a cytokine profile, an autoantibody profile, an immune cell profile, or any combination thereof. The profile comprises one or more of the transcripts, autoantibodies, cytokines, and / or immune cells provided in Table 5, Table 6, Table 8, Table 9, Table 10, Table 11, Figures 2B-K, 3B-F, and 4A, respectively, or a combination thereof. In some embodiments, the profile comprises baseline or pre-treatment transcripts, cytokines, autoantibodies, immune cells, or any combination thereof that correlate with future toxicity. In some embodiments, one or more transcripts, autoantibodies, cytokines, immune cell subsets, or any combination thereof are used as biomarkers to assess a subject's risk of developing an irAE before, during, or after ICI treatment. In some embodiments, the irAE is ICI-associated myositis, ICI-associated myocarditis, or ICI-associated myositis and myocarditis.

[0266] In some embodiments, the method includes providing a sample from a subject, evaluating one or more transcripts, autoantibody expression, cytokine expression, immune cell subset abundance, or any combination thereof in the sample, and predicting the risk of developing an irAE / diagnosing an irAE in the subject. In some embodiments, a subject can be predicted to have a higher risk of developing an irAE associated with ICI treatment or diagnosed as having an irAE if the profile includes one or more transcripts, autoantibodies, cytokines, immune cells, or any combination thereof at a higher level, expression, or abundance than a control sample. In some embodiments, a subject can be predicted to have a lower risk of developing an irAE associated with ICI treatment or diagnosed as having an irAE if the profile includes one or more transcripts, autoantibodies, cytokines, immune cells, or any combination thereof at a lower level, expression, or abundance than a control sample.

[0267] In some embodiments, subjects predicted or diagnosed as having a higher risk of developing an irAE have elevated transcript levels, expression, or abundance of: LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, ANKRD34B, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CC, CC8, CC9, CC10, CC11, CC12, CC13, CC14, CC15, CC20, CC16, CC21, CC17, CC18, CC22, CC19, CC23, CC24, CC25, CC30, CC40, CC50, CC60, CC70, CC81, CC91, CC92, CC19, CC19, CC19, CC25, CC19, CC26, CC19, CC27, CC19, CC28, CC29, CC30, CC41, CC50, CC51, CC52, CC53, CC54, CC55, CC56, CC57, CC58, CC59, CC60, CC61, CC62, CC63, CC64, CC70, CC82, CC83, CC84, CC91, CC92, CC93, CC94, CC95, CC95, CC96, CC97, CC98, CC99, CC99, CC100, CC101, CC102, CC103, CC104, CC105, CC106, CC107, CC108, CC109, CC1109, CC1111, CC1122, CC113, CC114, CC115, CC116, CC117, CC118, CC119 High transcript levels, expression, or abundance of one or more of L19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes, and / or AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEG F, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PE R1, TNFSF9, MAFF, MIR4420, GPX3, TNFAIP3, KCNG1, PTGS2, AKAP5, DUSP1, DGKK, B4GALNT3, TRIB1, PMAIP1, CXCR4, TP53INP2, NFIL3, DUSP4, N It is associated with low levels, expression, or abundance of one or more of FKBIA, AVPI1, CD79a, ARL4D, JCHAIN, BTG2, TLE1, NXT1, TOB1, PDE4D, DNAJB1, ARID5B, GPR153, KLF9, SBDS, IER2, TSC22D3, JUND, GABARAPL1, RUNX3, BRE-AS1, LOC102724428, FAM46C, GRASP, PD-L1+ naive B cells, and / or switched memory B cells.

[0268] In some embodiments, subjects predicted or diagnosed as having a higher risk of developing an irAE may have, at baseline or prior to the start of ICI treatment, a higher transcript level, expression, or abundance of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, ANKRD34B, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes, and / or one or more of AREG, EREG, OSM, CSRN, IFNγ, IL-6 ... P1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, BRE-AS1, LOC102724428, and PD-L1 are associated with low levels, expression, or abundance of naive and / or switched memory B cells.

[0269] In some embodiments, subjects predicted or diagnosed as having a higher risk of developing an irAE have elevated transcript levels, expression, or abundance of: LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, It is associated with high transcript levels, expression, or abundance of one or more of CXCL10, and / or CTLA4+ monocytes, and / or low levels, expression, or abundance of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, PD-L1+ naive B cells, and / or switched memory B cells.

[0270] In some embodiments, subjects predicted or diagnosed as having a higher risk of developing an irAE have elevated transcript levels, expression, or abundance of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, ANKRD34B, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, I ... It is associated with high transcript levels, expression, or abundance of one or more of FNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes, and / or low levels, expression, or abundance of one or more of AREG, EREG, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, PD-L1+ naive B cells, and / or switched memory B cells.

[0271] In some embodiments, subjects predicted or diagnosed as having a higher risk of developing an irAE have a transcript level, expression, or abundance of any of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, ANKRD34B, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes at baseline or prior to the start of ICI treatment, compared to a control sample. and / or with low levels, expression, or abundance of one or more of AREG, EREG, CXCL8, EGR1, PAX8, ATF6B, VMO1, HBEGF, BRE-AS1, NR4A2, OSM, NOCT, PLK2, LOC102724428, DUSP2, GRASP, PER1, TNFSF9, CSRNP1, MAFF, TNFAIP3, DUSP1, TRIB1, PMAIP1, FAM46C, NXT1, KLF9, PD-L1+ naive B cells, and / or switched memory B cells.

[0272] In some embodiments, subjects predicted or diagnosed as having a higher risk of developing an irAE are associated with a higher transcript level, expression, or abundance of one or more of LILRB4, CISH, PARP9, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes, and / or a lower level, expression, or abundance of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, PD-L1+ naive B cells, and / or switched memory B cells compared to the transcript level, expression, or abundance in a control sample at baseline or prior to the start of ICI treatment.

[0273] In some embodiments, subjects predicted or diagnosed as having a higher risk of developing an irAE are associated with a higher transcript level, expression, or abundance of one or more of LILRB4, CISH, PARP9, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes, and a lower level, expression, or abundance of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, PD-L1+ naive B cells, and / or switched memory B cells compared to the transcript level, expression, or abundance in a control sample at baseline or prior to the start of ICI treatment.

[0274] In some embodiments, subjects predicted or diagnosed as having a higher risk of developing an irAE may have, at baseline or prior to the start of ICI treatment, a higher transcript level, expression, or abundance of one or more of LILRB4, GIMAP7, CISH, CXCR6, DHRS9, FCGR1CP, ANKRD34B, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes, and / or one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PT, IFNγ, IL-10, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-2, IL-10, IL-2, IL-3, IL-4, IL-5, IL-10, IL-2 ...10, IL-2, IL-10, IL-2, IL-10, IL-10, IL-2, IL-10, IL-10, IL-2, IL-10, IL-10, IL-2, IL-10, IL-10, IL-10, IL-10, IL-10, GS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, BRE-AS1, LOC102724428, and PD-L1 are associated with low levels, expression, or abundance of naive and / or switched memory B cells.

[0275] In some embodiments, subjects predicted or diagnosed as having a higher risk of developing an irAE have, at baseline or prior to the start of ICI treatment, a higher transcript level, expression, or abundance of one or more of CISH, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes compared to the transcript level, expression, or abundance in a control sample; or is associated with low level, expression, or abundance of one or more of AREG, EREG, CXCL8, EGR1, PAX8, ATF6B, VMO1, HBEGF, BRE-AS1, NR4A2, OSM, NOCT, PLK2, LOC102724428, DUSP2, GRASP, PER1, TNFSF9, CSRNP1, MAFF, TNFAIP3, DUSP1, TRIB1, PMAIP1, FAM46C, NXT1, KLF9, PD-L1+ naive B cells, and / or switched memory B cells.

[0276] In some embodiments, subjects predicted or diagnosed as having a higher risk of developing an irAE have a higher transcript level, expression, or abundance of LILRB4, GIMAP7, CISH, CXCR6, DHRS9, FCGR1CP, ANKRD34B, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL1 ... It is associated with high transcript levels, expression, or abundance of one or more of CL10, and / or CTLA4+ monocytes, and / or low levels, expression, or abundance of one or more of AREG, EREG, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, PD-L1+ naive B cells, and / or switched memory B cells.

[0277] In some embodiments, subjects predicted or diagnosed as having a higher risk of developing an irAE are associated with a higher transcript level, expression, or abundance of one or more of PARP9, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes, and / or a lower level, expression, or abundance of one or more of CD79A, CD83, PLK2, PDE4D, TR1B1, EREG, CXCL8, EGR3, JUNB, DUSP1, NFKBIA, TNFSF9, TNFAIP3, IL-10, JUND, FOS, RUNX3, TSC22D3, PD-L1+ naive B cells, and / or switched memory B cells compared to the transcript level, expression, or abundance in a control sample at baseline or prior to the start of ICI treatment.

[0278] In some embodiments, subjects predicted or diagnosed as having a higher risk of developing an irAE may have, at baseline or prior to the start of ICI treatment, a higher transcript level, expression, or abundance of one or more of PARP9, CISH, CXCR6, LPAR6, ASGR2 Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes, and / or one or more of KLF9, CXCR4, ATF6B, CD79A, CD83, PLK2, GRASP, PPP1R15A, GPX3, PARP9, BTG2, PTGS2, NOTCH3, AK, AK+ ... AP5, PDE4D, SBDS, TRIB1, SNAI1, PAX8, NFIL3, EREG, AREG, DGKK, PTGES, CSRNP1, DNAJB1, CXCL8, OSM, ARID5B, ID1, NR4A2, EGR3, JUNB, TLE1, CXCL2, DUSP1, GPR153, G0S2, ATF3, NFKBIA, TNFS9, NUAK1, ATOH8, TNFAIP3, ADRB1, HBEGF, IL-10, JUND, FOS, GABARAPL1, PMAIP1, DDIT4, EGR1 are associated with low levels, expression, or abundance of PD-L1+ naive and / or switched memory B cells.

[0279] In some embodiments, the lower risk of developing an irAE is associated with one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, ANKRD34B, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes. Lower transcript levels, expression, or abundance of a number of transcripts or AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PM P22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, GPX3, TNFAIP3, KCNG1, PTGS2, AKAP5, DUSP1, DGKK, B4GALNT3, TRIB1, PMAIP1, CXCR4, TP53INP2, NFIL3, DUSP4, NFKBIA, AVPI1, CD79a, ARL4D, JCHAI It is associated with elevated transcript levels, expression, or abundance of one or more of N, BTG2, TLE1, NXT1, TOB1, PDE4D, DNAJB1, ARID5B, GPR153, KLF9, SBDS, IER2, TSC22D3, JUND, GABARAPL1, RUNX3, BRE-AS1, LOC102724428, FAM46C, GRASP, and / or PD-L1+ naive B cells and / or switched memory B cells.

[0280] In some embodiments, subjects who are predicted or diagnosed as having a lower risk of developing an irAE have a transcript level, expression, or abundance of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, or ... low transcript levels, expression, or abundance of one or more of Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes, and / or one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, P AX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, BRE-AS1, LOC102724428, correlate with transcript levels, expression, or abundance in PD-L1+ naive and / or switched memory B cells.

[0281] In some embodiments, subjects predicted or diagnosed as having a lower risk of developing an irAE have a lower transcript level, expression, or abundance of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, ANKRD34B, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, I ... L-6, CXCL9, CXCL10, and / or CTLA4+ monocytes, and / or higher transcript levels, expression, or abundance of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, PD-L1+ naive B cells, and / or switched memory B cells.

[0282] In some embodiments, subjects predicted or diagnosed as having a lower risk of developing an irAE have a transcript level, expression, or abundance of: LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, ANKRD34B, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, I ... It is associated with high transcript levels, expression, or abundance of one or more of FNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes, and / or high transcript levels, expression, or abundance of one or more of AREG, EREG, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, PD-L1+ naive B cells, and / or switched memory B cells.

[0283] In some embodiments, subjects predicted or diagnosed as having a lower risk of developing an irAE have a transcript level, expression, or abundance of one of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, ANKRD34B, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes at baseline or prior to the start of ICI treatment, compared to a control sample. and / or elevated transcript levels, expression, or abundance of one or more of AREG, EREG, CXCL8, EGR1, PAX8, ATF6B, VMO1, HBEGF, BRE-AS1, NR4A2, OSM, NOCT, PLK2, LOC102724428, DUSP2, GRASP, PER1, TNFSF9, CSRNP1, MAFF, TNFAIP3, DUSP1, TRIB1, PMAIP1, FAM46C, NXT1, KLF9, PD-L1+ naive B cells, and / or switched memory B cells.

[0284] In some embodiments, subjects predicted or diagnosed as having a lower risk of developing an irAE are associated with higher transcript levels, expression, or abundance of one or more of LILRB4, CISH, PARP9, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes, and / or transcript levels, expression, or abundance of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, PD-L1+ naive B cells, and / or switched memory B cells, compared to the transcript levels, expression, or abundance in a control sample at baseline or prior to the start of ICI treatment.

[0285] In some embodiments, subjects predicted or diagnosed as having a lower risk of developing an irAE are associated with a lower transcript level, expression, or abundance of one or more of LILRB4, CISH, PARP9, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes, and a higher transcript level, expression, or abundance of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, PD-L1+ naive B cells, and / or switched memory B cells compared to the transcript level, expression, or abundance in a control sample at baseline or prior to the start of ICI treatment.

[0286] In some embodiments, subjects predicted or diagnosed as having a lower risk of developing an irAE have, at baseline or prior to the start of ICI treatment, a lower transcript level, expression, or abundance of one or more of LILRB4, GIMAP7, CISH, CXCR6, DHRS9, FCGR1CP, ANKRD34B, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes, and / or one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS, compared to the transcript level, expression, or abundance in a control sample. 2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, BRE-AS1, LOC102724428, have been associated with higher transcript levels, expression, or abundance in PD-L1+ naive and / or switched memory B cells.

[0287] In some embodiments, subjects predicted or diagnosed as having a lower risk of developing an irAE have, at baseline or prior to the start of ICI treatment, a lower transcript level, expression, or abundance of one or more of CISH, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes compared to the transcript level, expression, or abundance in a control sample; and / or is associated with elevated transcript levels, expression, or abundance of one or more of AREG, EREG, CXCL8, EGR1, PAX8, ATF6B, VMO1, HBEGF, BRE-AS1, NR4A2, OSM, NOCT, PLK2, LOC102724428, DUSP2, GRASP, PER1, TNFSF9, CSRNP1, MAFF, TNFAIP3, DUSP1, TRIB1, PMAIP1, FAM46C, NXT1, KLF9, PD-L1+ naive B cells, and / or switched memory B cells.

[0288] In some embodiments, subjects predicted or diagnosed as having a lower risk of developing an irAE have a transcript level, expression, or abundance of: LILRB4, GIMAP7, CISH, CXCR6, DHRS9, FCGR1CP, ANKRD34B, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL1, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL1, CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6 ... 10, and / or CTLA4+ monocytes, and / or higher transcript levels, expression, or abundance of one or more of AREG, EREG, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, PD-L1+ naive B cells, and / or switched memory B cells.

[0289] In some embodiments, subjects predicted or diagnosed as having a lower risk of developing an irAE have a transcript level, expression, or abundance of one or more of PARP9, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes at baseline or prior to the start of ICI treatment, compared to a control sample. The present invention is associated with low transcript levels, expression, or abundance and / or high transcript levels, expression, or abundance of one or more of CD79A, CD83, PLK2, PDE4D, TR1B1, EREG, CXCL8, EGR3, JUNB, DUSP1, NFKBIA, TNFSF9, TNFAIP3, IL-10, JUND, FOS, RUNX3, TSC22D3, PD-L1+ naive B cells, and / or switched memory B cells.

[0290] In some embodiments, a subject who is predicted or diagnosed as having a lower risk of developing an irAE has, at baseline or prior to the start of ICI treatment, a lower transcript level, expression, or abundance of one or more of PARP9, CISH, CXCR6, LPAR6, ASGR2 Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes, and / or one or more of KLF9, CXCR4, ATF6B, CD79A, CD83, PLK2, GRASP, PPP1R15A, GPX3, PARP9, BTG2, PTGS2, NOTCH3, AKAP5, PDE4D, SBDS, TRIB1, SNAI1, PAX8, NF IL3, EREG, AREG, DGKK, PTGES, CSRNP1, DNAJB1, CXCL8, OSM, ARID5B, ID1, NR4A2, EGR3, JUNB, TLE1, CXCL2, DUSP1, GPR153, G0S2, ATF3, NFKBIA, TNFS9, NUAK1, ATOH8, TNFAIP3, ADRB1, HBEGF, IL-10, JUND, FOS, GABARAPL1, PMAIP1, DDIT4, EGR1, and PD-L1 are associated with higher transcript levels, expression, or abundance in naive and / or switched memory B cells.

[0291] In some embodiments, the present disclosure further provides a profile for monitoring the risk of developing an irAE, the profile including one or more of a transcript profile, a cytokine profile, an autoantibody profile, an immune cell profile, or any combination thereof. The profile includes one or more of the transcripts, autoantibodies, cytokines, and / or immune cells provided in Table 5, Table 6, Table 8, Table 9, Table 10, Table 11, Figures 2B-K, 3B-F, and 4A, respectively, or a combination thereof. In some embodiments, the profile includes baseline or pre-treatment transcripts, cytokines, autoantibodies, immune cells, or any combination thereof that correlate with future toxicity. In some embodiments, one or more transcripts, autoantibodies, cytokines, immune cell subsets, or any combination thereof are used as biomarkers to assess a subject's risk of developing an irAE before, during, or after ICI treatment. In some embodiments, the irAE is ICI-associated myositis, ICI-associated myocarditis, or ICI-associated myositis and myocarditis.

[0292] In some embodiments, a method for monitoring the risk of an irAE includes providing a sample from a subject, assessing one or more transcripts, autoantibody expression, cytokine expression, immune cell subset abundance, or any combination thereof in the sample, and predicting the risk of developing an irAE / diagnosing an irAE in the subject. In some embodiments, the subject being monitored may have a higher risk of an irAE associated with ICI treatment if the profile includes one or more transcripts, autoantibodies, cytokines, immune cells, or any combination thereof at a higher level, expression, or abundance than a control sample. In some embodiments, the subject being monitored may have a lower risk of an irAE associated with ICI treatment if the profile includes one or more transcripts, autoantibodies, cytokines, immune cells, or any combination thereof at a lower level, expression, or abundance than a control sample.

[0293] In some embodiments, the subject being monitored has a transcript level, expression, or abundance of: LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, ANKRD34B, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, High transcript levels, expression, or abundance of one or more of CXCL10, and / or CTLA4+ monocytes, and / or AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR 4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR44 20, GPX3, TNFAIP3, KCNG1, PTGS2, AKAP5, DUSP1, DGKK, B4GALNT3, TRIB1, PMAIP1, CXCR4, TP53INP2, NFIL3, DUSP4, NFKBIA, AVPI1, CD79a, AR Low transcript levels, expression, or abundance of one or more of L4D, JCHAIN, BTG2, TLE1, NXT1, TOB1, PDE4D, DNAJB1, ARID5B, GPR153, KLF9, SBDS, IER2, TSC22D3, JUND, GABARAPL1, RUNX3, BRE-AS1, LOC102724428, FAM46C, GRASP, PD-L1+ naive B cells, and / or switched memory B cells may be at higher risk of developing an irAE.

[0294] In some embodiments, the subject being monitored is diagnosed if, at baseline or prior to the start of ICI treatment, the subject has a higher transcript level, expression, or abundance of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, ANKRD34B, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes, and / or one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, IFNγ, IL-10, IL-20, IL-11, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, IL-39, IL-40, IL-41, IL-42, IL-43, IL-44, IL-45, IL-46, IL-47, IL-48, IL-49, IL-50, IL-51, IL-52, IL-53, IL-54, IL-55, IL-56, IL-57, IL-58, IL-59, IL-59, IL-59, IL-59, IL-59, IL-59, IL-5 , DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, BRE-AS1, LOC102724428, PD-L1+ naive B cells and / or switched memory B cells may be at higher risk of developing irAEs if they have low transcript levels, expression, or abundance.

[0295] In some embodiments, the subject being monitored has elevated transcript levels, expression, or abundance of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, ANKRD34B, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and IFNγ at baseline or prior to the start of ICI treatment, compared to a control sample. A person may be at higher risk of developing an irAE if they have high transcript levels, expression, or abundance of one or more of CTLA4+ monocytes and / or CTLA4+ monocytes, and / or low transcript levels, expression, or abundance of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, PD-L1+ naive B cells, and / or switched memory B cells.

[0296] In some embodiments, the subject being monitored has a transcript level, expression, or abundance of: LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, ANKRD34B, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL1 Patients may be at higher risk of developing an irAE if they have high transcript levels, expression, or abundance of one or more of PD-L1+ monocytes, CTLA4+ monocytes, and / or CTLA4+ monocytes, and / or low transcript levels, expression, or abundance of one or more of AREG, EREG, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, PD-L1+ naive B cells, and / or switched memory B cells.

[0297] In some embodiments, the subject being monitored has an elevated transcript level, expression, or abundance of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, ANKRD34B, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes compared to the transcript level, expression, or abundance in a control sample at baseline or prior to the start of ICI treatment. or high abundance and / or low transcript levels, expression, or abundance of one or more of AREG, EREG, CXCL8, EGR1, PAX8, ATF6B, VMO1, HBEGF, BRE-AS1, NR4A2, OSM, NOCT, PLK2, LOC102724428, DUSP2, GRASP, PER1, TNFSF9, CSRNP1, MAFF, TNFAIP3, DUSP1, TRIB1, PMAIP1, FAM46C, NXT1, KLF9, PD-L1+ naive B cells, and / or switched memory B cells.

[0298] In some embodiments, a subject being monitored may have a higher risk of developing an irAE if the transcript level, expression, or abundance of one or more of LILRB4, CISH, PARP9, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes is high, and / or the transcript level, expression, or abundance of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, PD-L1+ naive B cells, and / or switched memory B cells is low compared to the transcript level, expression, or abundance in a control sample at baseline or before the start of ICI treatment.

[0299] In some embodiments, a subject being monitored may have a higher risk of developing an irAE if the transcript level, expression, or abundance of one or more of LILRB4, CISH, PARP9, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes is high, and the transcript level, expression, or abundance of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, PD-L1+ naive B cells, and / or switched memory B cells is low compared to the transcript level, expression, or abundance in a control sample at baseline or before the start of ICI treatment.

[0300] In some embodiments, the subject being monitored is diagnosed if, at baseline or prior to the start of ICI treatment, the subject has a higher transcript level, expression, or abundance of one or more of LILRB4, GIMAP7, CISH, CXCR6, DHRS9, FCGR1CP, ANKRD34B, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes, and / or one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL-10, IFNγ, IL-10, PTGS2, DUSP1, IFNγ, IL-10 ... 3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, BRE-AS1, LOC102724428, PD-L1+ naive B cells and / or switched memory B cells may be at higher risk of developing irAEs if they have low transcript levels, expression, or abundance.

[0301] In some embodiments, the subject being monitored is diagnosed if, at baseline or prior to the start of ICI treatment, the subject has a higher transcript level, expression, or abundance of one or more of CISH, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes, and / or one or more of AREG, ERE, IFNγ, IL-6, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, IL-39, IL-40, IL-41, IL-42, IL-43, IL-44, IL-45, IL-46, IL-47, IL-48, IL-49, IL-49, IL-49, IL-49, IL-49, IL-49, IL-49, IL-49, IL-40, IL-41, IL-42, IL-43, IL-44, IL-45, IL-46, IL-47, IL-48, IL-49, IL-49, IL-49, G, CXCL8, EGR1, PAX8, ATF6B, VMO1, HBEGF, BRE-AS1, NR4A2, OSM, NOCT, PLK2, LOC102724428, DUSP2, GRASP, PER1, TNFSF9, CSRNP1, MAFF, TNFAIP3, DUSP1, TRIB1, PMAIP1, FAM46C, NXT1, KLF9, PD-L1+ naive B cells and / or switched memory B cells may be at higher risk of developing irAEs if they have low transcript levels, expression, or abundance.

[0302] In some embodiments, the subject being monitored has a transcript level, expression, or abundance of LILRB4, GIMAP7, CISH, CXCR6, DHRS9, FCGR1CP, ANKRD34B, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monoclonal antibody compared to a control sample at baseline or prior to the start of ICI treatment. Patients may be at higher risk of developing an irAE if they have high transcript levels, expression, or abundance in one or more of the spheres and / or low transcript levels, expression, or abundance in one or more of AREG, EREG, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, PD-L1+ naive B cells, and / or switched memory B cells.

[0303] In some embodiments, a subject being monitored may have a higher risk of developing an irAE if the transcript level, expression, or abundance of one or more of PARP9, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes is higher, and / or the transcript level, expression, or abundance of one or more of CD79A, CD83, PLK2, PDE4D, TR1B1, EREG, CXCL8, EGR3, JUNB, DUSP1, NFKBIA, TNFSF9, TNFAIP3, IL-10, JUND, FOS, RUNX3, TSC22D3, PD-L1+ naive B cells, and / or switched memory B cells is lower compared to the transcript level, expression, or abundance in a control sample at baseline or before the start of ICI treatment.

[0304] In some embodiments, the subject being monitored is diagnosed if, at baseline or prior to the start of ICI treatment, the subject has a higher transcript level, expression, or abundance of one or more of PARP9, CISH, CXCR6, LPAR6, ASGR2 Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes, and / or one or more of KLF9, CXCR4, ATF6B, CD79A, CD83, PLK2, GRASP, PPP1R15A, GPX3, PARP9, BTG2, PTGS2, NOTCH3, AK, AK+ ... AP5, PDE4D, SBDS, TRIB1, SNAI1, PAX8, NFIL3, EREG, AREG, DGKK, PTGES, CSRNP1, DNAJB1, CXCL8, OSM, ARID5B, ID1, NR4A2, EGR3, JUNB, TLE1, CXCL2, DUSP1, GPR153, G0S2, ATF3, NFKBIA, TNFS9, NUAK1, ATOH8, TNFAIP3, ADRB1, HBEGF, IL-10, JUND, FOS, GABARAPL1, PMAIP1, DDIT4, EGR1 PD-L1+ naive B cells and / or switched memory B cells may be at higher risk of developing irAEs if they have low transcript levels, expression, or abundance.

[0305] In some embodiments, the subject being monitored has a transcript level, expression, or abundance of: LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, ANKRD34B, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL 9, CXCL10, and / or CTLA4+ monocytes, or if the transcript levels, expression, or abundance of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A 2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR442 0, GPX3, TNFAIP3, KCNG1, PTGS2, AKAP5, DUSP1, DGKK, B4GALNT3, TRIB1, PMAIP1, CXCR4, TP53INP2, NFIL3, DUSP4, NFKBIA, AVPI1, CD79a, ARL Patients may have a lower risk of developing an irAE if they have high transcript levels, expression, or abundance of one or more of: 4D, JCHAIN, BTG2, TLE1, NXT1, TOB1, PDE4D, DNAJB1, ARID5B, GPR153, KLF9, SBDS, IER2, TSC22D3, JUND, GABARAPL1, RUNX3, BRE-AS1, LOC102724428, FAM46C, GRASP, PD-L1+ naive B cells, and / or switched memory B cells.

[0306] In some embodiments, the subject being monitored is diagnosed if, at baseline or prior to the start of ICI treatment, the subject has a lower transcript level, expression, or abundance of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, ANKRD34B, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and / or CTLA4+ monocytes, and / or one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, IFNγ, IL-10, IL-20, IL-11, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, IL-39, IL-40, IL-41, IL-42, IL-43, IL-44, IL-45, IL-46, IL-47, IL-48, IL-49, IL-50, IL-51, IL-52, IL-53, IL-54, IL-55, IL-56, IL-57, IL-58, IL-59, IL-59, IL-59, IL-59, IL-59, IL-59, IL-5 , DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, BRE-AS1, LOC102724428, PD-L1+ naive B cells and / or switched memory B cells may have a lower risk of developing an irAE if they have high transcript levels, expression, or abundance.

[0307] In some embodiments, the subject being monitored has elevated transcript levels, expression, or abundance of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, ANKRD34B, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL10, and IFNγ at baseline or prior to the start of ICI treatment, compared to a control sample. A patient may have a lower risk of developing an irAE if they have low transcript levels, expression, or abundance of one or more of CTLA4+ monocytes and / or CTLA4+ monocytes, and / or high transcript levels, expression, or abundance of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, PD-L1+ naive B cells, and / or switched memory B cells.

[0308] In some embodiments, the subject being monitored has a transcript level, expression, or abundance of: LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, CXCR6, DHRS9, FCGR1CP, ANKRD34B, Mi-2, GAD65, myosin, thyroglobulin, TPO, CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, CXCL1 0, and / or CTL...

Claims

1. 1. A method for predicting the risk of developing and / or diagnosing an immune-related adverse event (irAE) associated with immune checkpoint inhibitor (ICI) treatment in a subject, comprising: a. providing a sample from said subject; b. assessing the level of one or more transcripts in said sample; c. predicting / diagnosing the risk of developing an irAE in said subject, wherein said subject: i. the transcript levels of one or more of leukocyte immunoglobulin-like receptor B4 (LILRB4), cytokine-induced SH2-containing protein (CISH), poly(ADP-ribose) polymerase family member 9 (PARP9), ring finger protein 145 (RNF145), asialoglycoprotein receptor 2 (ASGR2), solute carrier family 16 member 13 (SLC16A13), lysophosphatidic acid receptor 6 (LPAR6), GTPase, IMAP family member 7 (GIMAP7), and / or C-X-C motif chemokine receptor 6 (CXCR6) are elevated compared to the transcript levels in a control sample prior to ICI treatment (baseline); and / or ii. Amphiregulin (AREG), epiregulin (EREG), oncostatin M (OSM), cysteine- and serine-rich nuclear protein 1 (CSRNP1), DNA damage-induced transcript 4 (DDIT4), IL-10 (interleukin-10), prostaglandin-endoperoxide synthase (PTGS2), dual specificity phosphatase 1 (DUSP1), C-X-C chemokine receptor type 4 (CXCR4), nuclear factor, interleukin-3 regulated (NFIL3), Fos proto-oncogene, AP-1 transcription factor subunit (AP-1), FOS), NFKB inhibitor alpha (NFKBIA), PPP1R15A (protein phosphatase 1 regulatory subunit 15A), CD79A, JunB proto-oncogene, AP-1 transcription factor subunit (JUNB), C-X-C motif chemokine ligand 8 (CXCL8), early growth response 1 (EGR1), G0 / G1 switch 2 (G0S2), paired box 8 (PAX8), activating transcription factor 6 beta (ATF6B), PAX8 antisense RNA 1 (PAX8-AS1), variant U1 micronuclear 19 (RNP19) VU1-19), vitelline membrane outer layer 1 homolog (VMO1), heparin-binding EGF-like growth factor (HBEGF), coiled-coil domain-containing 144A (CCDC144A), shisa family member 8 (SHISA8), nuclear receptor subfamily 4 group A member 2 (NR4A2), prostaglandin E synthase (PTGES), synapsin I (SYN1), C-X-C motif chemokine ligand 2 (CXCL2), peripheral myelin protein 22 (PMP22), CD83, early growth response 3 (EGR3), NUAK-F family kinase 1 (NUAK1), nocturnin (NOCT), atonal bHLH transcription factor 8 (ATOH8), polo-like kinase (PLK2), inhibitor of DNA binding 1 (ID1), adrenergic receptor beta 1 (ADRB1), snail family transcriptional repressor 1 (SNAI1), notch receptor 3 (NOTCH3), activating transcription factor 3 (ATF3), dual specificity phosphatase 2 (DUSP2), circadian rhythm regulator 1 (PER1), TNF superfamily member 9 (TNFSF9), MAF bzip transcription factor F (MAFF), microRNA4420 (MIR4420), glutathione peroxidase (GPX3), TNF-alpha-inducible protein 3 (TNFAIP3), potassium voltage-dependent channel modifier subfamily G member 1 (KCNG1), prostaglandin-endoperoxidase synthase 2 (PTGS2), A-kinase anchor protein 5 (AKAP5), dual specificity phosphatase 1 (DUSP1), diacylglycerol kinase kappa (DGKK), beta-1,4,-N-acetyl-galactosaminyltransferase 3 (B4GAL NT3), tribbles pseudokinase 1 (TRIB1), holobol-12-myristate-13-acetate-inducible protein 1 (PMAIP1), C-X-C motif chemokine receptor 4 (CXCR4), tumor protein p53-inducible nuclear protein 2 (TP53INP2), nuclear factor, interleukin-3-regulated (NFIL3), dual specificity phosphatase 4 (DUSP4), NFKB inhibitor alpha (NFKBIA), arginine vasopressin-inducible 1 (AVPI1), CD79a, ADP-ribosylation factor-like GTPase 4D (ARL4D), binding chain of polymeric IgA and IgM (JCHAIN), BTG anti-proliferative factor 2 (BTG2), TLE family member 1, transcriptional corepressor (TLE1), nuclear export factor 2-like nuclear export factor 1 (NXT1), transfer factor of ERBB2 1 (TOB1), phosphodiesterase 4D (PDE4D), DNAJ heat shock protein family member B1 (DNAJheat shock protein family member B1) B1) (DNAJB1), AT-rich interacting domain 5B (ARID5B), G protein-coupled receptor 153 (GPR153), KLF transcription factor 9 (KLF9), SBDS ribosome maturation factor (SBDS), immediate early response 2 (IER2), TSC22 domain family member 3 (TSC22D3), A-type GABA receptor-related protein-like 1 (GABARAPL1), JunD proto-oncogene, AP-1 transcription factor subunit (JUND), RUNX family transcription factor 3 (RUNX3), BABAM2 antisense RNA1 (BRE-AS1), putative salt-inducible kinase 1B (LOC102724428), FAM46C (FAM46C), and / or general receptor for phosphoinositides 1-related scaffold protein (GRASP) transcript levels are low in the subject compared to the transcript levels in a control sample; predicted to have a high risk of developing an irAE or diagnosed with an irAE; A method comprising:

2. 1. A method for monitoring the risk of developing an irAE associated with ICI treatment in a subject, comprising: a. providing a sample from said subject; b. assessing the level of one or more transcripts in said sample; c. Monitoring the risk of developing an irAE in the subject, wherein the subject: i. the transcript levels of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, DHRS9, FCGR1CP, ANKRD34B, and / or CXCR6 are elevated compared to the transcript levels in a control sample before ICI treatment (baseline); and / or ii. AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R1 5A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC 144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, I D1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, GPX3, TNFAIP3, KCNG 1, PTGS2, AKAP5, DUSP1, DGKK, B4GALNT3, TRIB1, PMAIP1, CXCR4, TP53INP2, NFIL3, DUSP4, NFKBIA, AVPI1, CD79a, ARL4D, JCHAIN, BTG2, TLE1, NXT1, TOB1, PDE4D, DNAJB1, ARID5B, GPR153, KLF9, SBDS, IER2, TSC22D3, JUND, GABARAPLI, RUNX3, BRE-AS1, LOC102724428, FAM46C, and / or GRASP is low in the subject compared to the level of said transcripts in a control sample; predicted to have a high risk of developing an irAE; A method comprising:

3. 3. The method of claim 1, wherein the irAE comprises ICI-associated myositis, ICI-associated myocarditis, or ICI-associated myositis and myocarditis.

4. 3. The method of claim 1, wherein said assessment of transcript levels is performed before ICI treatment.

5. 3. The method of claim 1, wherein the subject is predicted to be at high risk of developing an irAE if the transcript levels of one or more of LILRB4, CISH, and / or PARP9 are elevated compared to the transcript levels in a control sample before ICI treatment (baseline).

6. 3. The method of claim 1, wherein the subject is predicted to be at high risk of developing an irAE if the transcript levels of one or more of LILRB4, CISH, GIMAP7, and / or CXCR6, DHRS9, FCGR1CP, and / or ANKRD34B are elevated compared to the transcript levels in a control sample before ICI treatment (baseline).

7. The subject is a patient having any of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1 3. The method of claim 1, wherein a high risk of developing an irAE is predicted when the transcript levels of one or more of: NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, BRE-AS1, LOC102724428, and / or GRASP are low compared to the transcript levels in a control sample before ICI treatment.

8. 3. The method of claim 1, wherein the subject is predicted to be at high risk of developing an irAE if the transcript levels of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, and / or JUNB are low compared to the transcript levels in a control sample before ICI treatment.

9. 3. The method of claim 1, wherein the subject is predicted to be at high risk of developing an irAE if the transcript levels of one or more of AREG, EREG, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, and / or SHISA8 are low compared to the transcript levels in a control sample before ICI treatment.

10. 3. The method of claim 1, wherein the subject is predicted to be at high risk of developing an irAE if the transcript levels of one or more of AREG, EREG, CXCL8, EGR1, PAX8, ATF6B, VMO1, HBEGF, BRE-AS1, NR4A2, OSM, NOCT, PLK2, LOC102724428, DUSP2, GRASP, PER1, TNFSF9, CSRNP1, MAFF, TNFAIP3, DUSP1, TRIB1, PMAIP1, FAM46C, NXT1, and / or KLF9 are low compared to the transcript levels in a control sample before ICI treatment.

11. The object is i. PARP9 transcript levels are elevated compared to said transcript levels in control samples before ICI treatment (baseline), and / or ii. if the transcript level of one or more of CD79A, CD83, PLK2, PDE4D, TR1B1, EREG, CXCL8, EGR3, JUNB, DUSP1, NFKBIA, TNFSF9, TNFAIP3, IL-10, JUND, FOS, RUNX3, and / or TSC22D3 is low compared to the transcript level in a control sample before ICI treatment (baseline); The method of claim 1 or 2, wherein the patient is predicted to have a high risk of developing an irAE.

12. The object is i. the transcript levels of one or more of PARP9, CISH, CXCR6, LPAR6, and / or ASGR2 are elevated compared to the transcript levels in a control sample before ICI treatment (baseline); and / or ii. KLF9, CXCR4, ATF6B, CD79A, CD83, PLK2, GRASP, PPP1R15A, GPX3, PARP9, BTG2, PTGS2, NOTCH3, AKAP5, PDE4D, SBDS, TR IB1, SNAI1, PAX8, NFIL3, EREG, AREG, DGKK, PTGES, CSRNP1, DNAJB1, CXCL8, OSM, ARID5B, ID1, NR4A2, EGR3, JUNB, TLE 1, CXCL2, DUSP1, GPR153, GOS2, ATF3, NFKBIA, TNFS9, NUAK1, ATOH8, TNFAIP3, ADRB1, HBEGF, IL-10, JUND, FOS, GABARAPL1, PMAIP1, DDIT4, and / or EGR1 are low compared to the transcript levels in a control sample before ICI treatment (baseline); The method of claim 1 or 2, wherein the patient is predicted to be at high risk for irAE.

13. 3. The method of claim 1, wherein the sample is whole blood, serum, plasma, cerebrospinal fluid, pleural fluid, pericardial fluid, peritoneal fluid, bone marrow, tissue, urine, cerebrospinal fluid (CSF), or other bodily fluid.

14. 3. The method of claim 1, wherein the ICI treatment is administered as part of a cancer treatment.

15. 11. The method of claim 10, wherein the ICI treatment comprises administration of an inhibitor of PD-1, PD-L1, TIM-3, LAG-3, CTLA-4, CSF-1R, or any combination thereof.

16. 3. The method of claim 1, wherein the step of assessing transcript levels (step b) comprises RNA-seq, nanopore sequencing, nanostring, multiplex RT-PCR, singleplex RT-PCR, NASBA, fluorometry, or spectrophotometry.

17. 3. The method of claim 1, further comprising assessing the expression of one or more of Mi-2, GAD65, myosin, thyroglobulin, and / or TPO in the sample from the subject.

18. 18. The method of claim 17, wherein said evaluating comprises determining whether expression of one or more autoantibodies is elevated in said sample from said subject compared to said expression in a control sample.

19. 20. The method of any one of claims 1, 2, or 17, further comprising assessing the expression of one or more of CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, and / or CXCL10 in the sample from the subject.

20. 20. The method of claim 19, wherein said evaluating comprises determining whether expression of one or more cytokines is elevated in said sample from said subject compared to said expression in a control sample.

21. 20. The method of any one of claims 1, 2, 17, or 19, further comprising assessing the abundance of one or more of PD-L+ naive B cells, switched memory B cells, and / or CTLA-4+ monocytes in the sample from the subject.

22. 22. The method of claim 21, wherein said assessing comprises determining whether the sample from the subject has a decreased abundance of one or more of PD-L+ naive B cells and / or switched memory B cells, and / or an increased abundance of CTLA-4+ monocytes, compared to said abundance in a control sample.

23. 3. The method of claim 1, further comprising repeating steps (a)-(c) at a second time point, thereby allowing determination of a change in the subject's risk of developing an irAE and / or diagnosis of an irAE in the sample from the subject compared to a control sample.

24. The object, i. the transcript levels of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, and / or CXCR6 are lower or similar to the transcript levels in a control sample before ICI treatment (baseline); and / or ii. AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A , CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A , SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADR B1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, GPX3, TNFAIP3, KCNG1, PTGS2 , AKAP5, DUSP1, DGKK, B4GALNT3, TRIB1, PMAIP1, CXCR4, TP53INP2, NFIL3, DUSP4, NFKBIA, AVPI1, CD79a, ARL4D, JCHAIN, BTG2, TLE1, NXT1, TOB1, PDE4D, DNAJB1, ARID5B, GPR153, KLF9, SBDS, IER2, TSC22D3, JUND, GABARAPLI, RUNX3, BRE-AS1, LOC102724428, FAM46C, and / or GRASP are elevated or equivalent during ICI treatment compared to the transcript levels in a control sample; further comprising predicting that the subject has a low risk of 3. The method of claim 1 or 2.

25. 25. The method of claim 24, further comprising treating the subject with ICI therapy if the subject is predicted to have a low risk of developing an irAE.

26. 3. The method of claim 1, further comprising treating the subject predicted to have a high risk of developing an irAE with a non-ICI therapy, or treating the subject with an ICI therapy and an irAE mitigation therapy, wherein the irAE mitigation therapy is selected from a corticosteroid (e.g., prednisone, methylprednisolone, dexamethasone, budesonide), a TNF inhibitor (e.g., infliximab), hormone replacement (e.g., hydrocortisone, levothyroxine), a CXCL8 inhibitor (e.g., repertaxin), or any combination thereof.

27. 1. A method of treating a subject having cancer, comprising: (a) providing a sample from said subject; (b) assessing the level of one or more transcripts in said sample; (c) predicting the subject's risk of developing an irAE, wherein the subject: i. a low risk is diagnosed if the transcript level of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, and / or CXCR6 is lower than or equivalent to the transcript level in a control sample; ii. AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, C D79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHIS A8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI 1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, GPX3, TNFAIP3, KCNG1, PTGS2, AKAP5, DUS low risk is diagnosed if the transcript level of one or more of P1, DGKK, B4GALNT3, TRIB1, PMAIP1, CXCR4, TP53INP2, NFIL3, DUSP4, NFKBIA, AVPI1, CD79a, ARL4D, JCHAIN, BTG2, TLE1, NXT1, TOB1, PDE4D, DNAJB1, ARID5B, GPR153, KLF9, SBDS, IER2, TSC22D3, JUND, GABARAPL1, RUNX3, BRE-AS1, LOC102724428, FAM46C, and / or GRASP is elevated compared to or equivalent to the transcript level in a control sample before ICI treatment (baseline); iii. The high risk is diagnosed when the transcript level of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, and / or CXCR6 is elevated compared to the transcript level in a control sample; and / or iv. AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15 A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC14 4A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, GPX3, TNFAIP3, KCNG1, PT GS2, AKAP5, DUSP1, DGKK, B4GALNT3, TRIB1, PMAIP1, CXCR4, TP53INP2, NFIL3, DUSP4, NFKBI A, AVPI1, CD79a, ARL4D, JCHAIN, BTG2, TLE1, NXT1, TOB1, PDE4D, DNAJB1, ARID5B, GPR153, K diagnosing an increased risk if the transcript level of one or more of LF9, SBDS, IER2, TSC22D3, JUND, GABARAPL1, RUNX3, BRE-AS1, LOC102724428, FAM46C, and / or GRASP is lower than the transcript level in a control sample; (d) treating said object with (i) ICI therapy if the subject has been diagnosed as being at low risk of developing an irAE; (ii) with a non-ICI therapy if the subject has been diagnosed as being at high risk for developing an irAE; or (iii) ICI therapy and irAE mitigation therapy if the subject is diagnosed as being at high risk of developing an irAE; A step of treating A method comprising:

28. 28. The method of claim 27, wherein the irAE comprises ICI-associated myositis, ICI-associated myocarditis, or ICI-associated myositis and myocarditis.

29. 28. The method of claim 27, wherein the subject is predicted to be at high risk of developing an irAE if the transcript levels of one or more of LILRB4, CISH, and / or PARP9 are elevated compared to the transcript levels in a control sample before ICI treatment (baseline).

30. 28. The method of claim 27, wherein the subject is predicted to be at high risk of developing an irAE if transcript levels of one or more of LILRB4, CISH, GIMAP7, and / or CXCR6 are elevated compared to the transcript levels in a control sample before ICI treatment (baseline).

31. The subject is a patient having any of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, 28. The method of claim 27, wherein a high risk of developing an irAE is predicted when the transcript levels of one or more of NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, BRE-AS1, LOC102724428, and / or GRASP are low compared to the levels of the transcripts in a control sample before ICI treatment.

32. 28. The method of claim 27, wherein the subject is predicted to be at high risk of developing an irAE if the transcript levels of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, and / or JUNB are low compared to the transcript levels in a control sample before ICI treatment.

33. 28. The method of claim 27, wherein the subject is predicted to be at high risk of developing an irAE if the transcript levels of one or more of AREG, EREG, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, and / or SHISA8 are low compared to the transcript levels in a control sample before ICI treatment.

34. 28. The method of claim 27, wherein the subject is predicted to be at high risk of developing an irAE if the transcript levels of one or more of AREG, EREG, CXCL8, EGR1, PAX8, ATF6B, VMO1, HBEGF, BRE-AS1, NR4A2, OSM, NOCT, PLK2, LOC102724428, DUSP2, GRASP, PER1, TNFSF9, CSRNP1, MAFF, TNFAIP3, DUSP1, TRIB1, PMAIP1, FAM46C, NXT1, and / or KLF9 are low compared to the transcript levels in a control sample before ICI treatment.

35. The object is i. PARP9 transcript levels are elevated compared to said transcript levels in control samples before ICI treatment (baseline), and / or ii. if the transcript level of one or more of CD79A, CD83, PLK2, PDE4D, TR1B1, EREG, CXCL8, EGR3, JUNB, DUSP1, NFKBIA, TNFSF9, TNFAIP3, IL-10, JUND, FOS, RUNX3, and / or TSC22D3 is low compared to the transcript level in a control sample before ICI treatment (baseline); 28. The method of claim 27, wherein the patient is predicted to be at high risk for irAE.

36. The object is i. the transcript levels of one or more of PARP9, CISH, CXCR6, LPAR6, and / or ASGR2 are elevated compared to the transcript levels in a control sample before ICI treatment (baseline); and / or ii. KLF9, CXCR4, ATF6B, CD79A, CD83, PLK2, GRASP, PPP1R15A, GPX3, PARP9, BTG2, PTGS2, NOTCH3, AKAP5, PDE4D, SBDS, TR IB1, SNAI1, PAX8, NFIL3, EREG, AREG, DGKK, PTGES, CSRNP1, DNAJB1, CXCL8, OSM, ARID5B, ID1, NR4A2, EGR3, JUNB, TLE 1, CXCL2, DUSP1, GPR153, GOS2, ATF3, NFKBIA, TNFS9, NUAK1, ATOH8, TNFAIP3, ADRB1, HBEGF, IL-10, JUND, FOS, GABARAPL1, PMAIP1, DDIT4, and / or EGR1 are low compared to the transcript levels in a control sample before ICI treatment (baseline); 28. The method of claim 27, wherein the patient is predicted to be at high risk for irAE.

37. 28. The method of claim 27, wherein said assessing further comprises detecting expression of one or more of CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, and / or CXCL10 in said sample from said subject.

38. 38. The method of claim 37, wherein said evaluating comprises determining whether expression of one or more cytokines is elevated in said sample from said subject compared to said expression in a control sample.

39. 38. The method of any one of claims 27 or 37, wherein said assessing further comprises detecting expression of one or more of Mi-2, GAD65, myosin, thyroglobulin, and / or TPO in said sample from said subject.

40. 40. The method of claim 39, wherein said evaluating comprises determining whether expression of one or more autoantibodies is elevated in said sample from said subject compared to said expression in a control sample.

41. 40. The method of any one of claims 27, 37, or 39, further comprising assessing the presence of one or more immune cells in the sample from the subject, wherein the one or more immune cells are PD-L+ naive B cells, switched memory B cells, and / or CTLA-4+ monocytes.

42. 42. The method of claim 41, wherein said assessing comprises determining whether the abundance of one or more of PD-L+ naive B cells and / or switched memory B cells is decreased and / or whether CTLA-4+ monocytes is elevated in said sample from said subject compared to said abundance in a control sample.

43. 28. The method of claim 27, wherein the ICI treatment comprises administration of an inhibitor of PD-1, PD-L1, TIM-3, LAG-3, CTLA-4, CSF-1R, or any combination thereof.

44. 1. A method for identifying the presence of at least one differentially expressed transcript associated with an irAE in a biological sample of a subject having cancer, comprising: a. providing a sample from said subject; b. assessing the level of one or more transcripts in said sample, said assessment comprising: i. whether the transcript level of one or more of LILRB4, CISH, PARP9, RNF145, ASGR2, SLC16A13, LPAR6, GIMAP7, and / or CXCR6 is elevated compared to the transcript level in a control sample; and / or ii. AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1 R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, C CDC144A, SHISA8, NR4A2, PTGES, SYN1, CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PL K2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, GPX3, TNFAIP 3, KCNG1, PTGS2, AKAP5, DUSP1, DGKK, B4GALNT3, TRIB1, PMAIP1, CXCR4, TP53INP2, NFIL3 , DUSP4, NFKBIA, AVPI1, CD79a, ARL4D, JCHAIN, BTG2, TLE1, NXT1, TOB1, PDE4D, DNAJB1, A whether the transcript level of one or more of RID5B, GPR153, KLF9, SBDS, IER2, TSC22D3, JUND, GABARAPL1, RUNX3, BRE-AS1, LOC102724428, FAM46C, and / or GRASP is lower than the transcript level in a control sample; detecting a A method comprising:

45. 45. The method of claim 44, wherein the subject is planning to receive immune checkpoint inhibitor (ICI) treatment.

46. 45. The method of claim 44, wherein the irAE comprises ICI-associated myositis, ICI-associated myocarditis, or ICI-associated myositis and myocarditis.

47. 45. The method of claim 44, further comprising detecting expression of one or more of CXCL2, CXCL5, CXCL6, CCL7, CCL19, IFNγ, IL-6, CXCL9, and / or CXCL10 in the sample from the subject.

48. 48. The method of claim 47, wherein said evaluating comprises determining whether expression of one or more cytokines is elevated in said sample from said subject compared to said expression in a control sample.

49. 48. The method of any one of claims 44 or 47, further comprising detecting expression of one or more of Mi-2, GAD65, myosin, thyroglobulin, and / or TPO in the sample from the subject.

50. 50. The method of claim 49, wherein said evaluating comprises determining whether expression of one or more autoantibodies is elevated in said sample from said subject compared to said expression in a control sample.

51. 50. The method of any one of claims 44, 47, or 49, further comprising assessing the abundance of one or more of PD-L+ naive B cells, switched memory B cells, and / or CTLA-4+ monocytes in the sample from the subject.

52. 52. The method of claim 51, wherein said assessing comprises determining whether the abundance of one or more of PD-L+ naive B cells and / or switched memory B cells is decreased and / or whether the abundance of CTLA-4+ monocytes is increased in said sample from said subject compared to said abundance in a control sample.

53. 46. ​​The method of claim 45, wherein the assessment comprises determining a baseline or pre-treatment profile that correlates with future toxicity.

54. 54. The method of claim 53, wherein the baseline or pre-treatment profile comprises elevated transcript levels of one or more of LILRB4, CISH, and / or PARP9 compared to the transcript levels in a control sample.

55. 54. The method of claim 53, wherein the baseline or pre-treatment profile comprises elevated transcript levels of one or more of many of LILRB4, CISH, GIMAP7, and / or CXCR6 compared to the transcript levels in a control sample.

56. The baseline or pre-treatment profile may include AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, JUNB, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, SHISA8, NR4A2, PTGES, SYN1 , CXCL2, PMP22, CD83, EGR3, NUAK1, NOCT, ATOH8, PLK2, ID1, ADRB1, SNAI1, NOTCH3, ATF3, DUSP2, PER1, TNFSF9, MAFF, MIR4420, BRE-AS1, LOC102724428, and / or GRASP, wherein the transcript level is lower compared to the transcript level in the control sample.

57. 54. The method of claim 53, wherein the baseline or pre-treatment profile comprises a reduced transcript level of one or more of AREG, EREG, OSM, CSRNP1, DDIT4, IL-10, PTGS2, DUSP1, CXCR4, NFIL3, FOS, NFKBIA, PPP1R15A, CD79A, and / or JUNB compared to the transcript level in a control sample.

58. 54. The method of claim 53, wherein the baseline or pre-treatment profile comprises a reduced transcript level of one or more of AREG, EREG, CXCL8, EGR1, G0S2, PAX8, ATF6B, PAX8-AS1, RNVU1-19, VMO1, HBEGF, CCDC144A, and / or SHISA8 compared to the transcript level in a control sample.

59. 54. The method of claim 53, wherein the baseline or pre-treatment profile comprises a reduced transcript level of one or more of AREG, EREG, CXCL8, EGR1, PAX8, ATF6B, VMO1, HBEGF, BRE-AS1, NR4A2, OSM, NOCT, PLK2, LOC102724428, DUSP2, GRASP, PER1, TNFSF9, CSRNP1, MAFF, TNFAIP3, DUSP1, TRIB1, PMAIP1, FAM46C, NXT1, and / or KLF9 compared to the transcript level in a control sample.

60. the baseline or pre-treatment profile comprises: i. the transcript level of PARP9 is elevated compared to the transcript level in a control sample, and / or ii. A reduced transcript level of one or more of CD79A, CD83, PLK2, PDE4D, TR1B1, EREG, CXCL8, EGR3, JUNB, DUSP1, NFKBIA, TNFSF9, TNFAIP3, IL-10, JUND, FOS, RUNX3, and / or TSC22D3 compared to the transcript level in a control sample.

54. The method of claim 53, comprising:

61. the baseline or pre-treatment profile comprises: i. the transcript level of one or more of PARP9, CISH, CXCR6, LPAR6, and / or ASGR2 is elevated compared to the transcript level in a control sample; and / or ii. KLF9, CXCR4, ATF6B, CD79A, CD83, PLK2, GRASP, PPP1R15A, GPX3, PARP9, BTG2, PTGS2, NOTCH3, AKAP5, PDE4D, SB DS, TRIB1, SNAI1, PAX8, NFIL3, EREG, AREG, DGKK, PTGES, CSRNP1, DNAJB1, CXCL8, OSM, ARID5B, ID1, NR4A2, EGR 3, JUNB, TLE1, CXCL2, DUSP1, GPR153, G0S2, ATF3, NFKBIA, TNFS9, NUAK1, ATOH8, TNFAIP3, ADRB1, HBEGF, IL-10, JUND, FOS, GABARAPL1, PMAIP1, DDIT4, and / or EGR1 transcript levels are lower compared to the transcript levels in a control sample.

54. The method of claim 53, comprising:

62. 10. The method of any one of the preceding claims, wherein the control sample is obtained from a subject at low risk of developing an irAE.

63. 10. The method of any one of the preceding claims, wherein the transcript level is a relative transcript level.

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