Treatment of idiopathic inflammatory myopathies using a population of CD19 car-expressing cells

Abstract

The invention provides methods of using a population of CD19 CAR-expressing cells (for example, rapcabtagene autoleucel) for treating idiopathic inflammatory myopathies. Also disclosed are methods of making a population of CD19 CAR-expressing cells.

Description

[0001] PAT059852-PCT-SEC01

[0002] TREATMENT OF IDIOPATHIC INFLAMMATORY MYOPATHIES USING A

[0003] POPULATION OF CD19 CAR-EXPRESSING CELLS

[0004] FIELD OF THE INVENTION

[0005] The present invention relates generally to methods of using a population of CD 19 CAR- expressing cells for treating autoimmune diseases or disorders, compositions comprising the same, and methods of making CD 19 CAR-expressing cells.

[0006] BACKGROUND OF THE INVENTION

[0007] Idiopathic inflammatory myopathies (IIM) are rare autoimmune disorders which include dermatomyositis (DM), antisynthetase syndrome (ASyS), immune mediated necrotizing myopathy (IMNM), polymyositis (PM), cancer-associated myositis, overlap myositis and inclusion body myositis (IBM). Each subtype of IIM can present with different clinical manifestations, treatment responses, and prognoses. However, there are common symptoms shared among the subtypes, such as muscle weakness, skin rash, and other extra-muscular involvement. The most common symptom of IIM is proximal muscle weakness, often accompanied by pain, involving muscles in the upper and lower extremities, with the hip and thigh muscles being the most frequently affected. Neck muscles, typically flexors but sometimes extensors, can also be involved. The onset can be acute, subacute, or chronic. Patients experience difficulty with activities such as getting up from a seated position, climbing steps, or raising their arms or head. Elevated serum levels of creatine kinase, aldolase, lactate dehydrogenase, and aspartate transaminase are often observed.

[0008] Treatment of IIM is challenging due to its systemic nature and impact on multiple organs leading to variable presentations. There are no treatment guidelines for IIM, and currently only two FDA-approved treatments are available: Acthar® Gel (repository corticotropin injection) and intravenous immunoglobulin (IVIG) OCTAGAM® for DM. Even though management of IIM is not guideline-based, noted that first-line therapy nearly always includes GC in combination with either methotrexate or azathioprine. Further therapy includes MMF, tacrolimus or cyclosporin, combination therapy such as azathioprine and methotrexate, RTX, CYC, repository corticotropin injection or other experimental biologic agents. IVIG can be used throughout therapeutic PAT059852-PCT-SEC01 progression, either alone or as a concomitant therapy based on clinical response. Despite treatment with corticosteroids and immunosuppressive agents, many patients remain refractory, which presents in one of two patterns: recurrent disease or resistant disease, in which the former occurs when disease control with treatment is followed by disease recurrence (flares), and the latter occurs when the disease does not respond to the initial therapies and requires more advanced immunosuppressive agents. For these reasons, more effective therapeutic modalities are needed to help severe refractory IIM patients.

[0009] SUMMARY OF THE INVENTION

[0010] Disclosed herein are methods of using a population of CD 19 CAR-expressing cells for treating idiopathic inflammatory myopathies (IIM), e.g., dermatomyositis (DM), antisynthetase syndrome (ASyS), immune mediated necrotizing myopathy (IMNM) with or without secondary Interstitial Lung Disease (ILD), polymyositis (PM), cancer-associated myositis, overlap myositis and inclusion body myositis (IBM)) in a subject. The present disclosure also pertains to methods of making CD 19 CAR-expressing cells, and compositions generated using such methods.

[0011] In one aspect, the disclosure provides a method of treating a subject having idiopathic inflammatory myopathies (IIM), e.g., dermatomyositis (DM), antisynthetase syndrome (ASyS), immune mediated necrotizing myopathy (IMNM) with or without secondary Interstitial Lung Disease (ILD), polymyositis (PM), cancer-associated myositis, overlap myositis and inclusion body myositis (IBM)), the method comprising administering to the subject a population of cells engineered to express a CD 19 CAR (“a population of CD 19 CAR-expressing cells”), said population comprising:

[0012] (a) about the same percentage of naive cells, for example, naive T cells, for example, CD45RA+ CD45RO- CCR7+ T cells, as compared to the percentage of naive cells, for example, naive T cells, for example, CD45RA+ CD45RO- CCR7+ cells, in the same population of cells prior to being engineered to express the CAR;

[0013] (b) a change within about 5% to about 10% of naive cells, for example, naive T cells, for example, CD45RA+ CD45RO- CCR7+ T cells, for example, as compared to the percentage of naive cells, for example, naive T cells, for example, CD45RA+ CD45RO- CCR7+ cells, in the same population of cells prior to being engineered to express the CAR;

[0014] (c) an increased percentage of naive cells, for example, naive T cells, for example, CD45RA+ CD45RO- CCR7+ T cells, for example, increased by at least 1.2, 1.4, 1.6, 1.8, 2.0, PAT059852-PCT-SEC01

[0015] 2.2, 2.4, 2.6, 2.8, or 3-fold, as compared to the percentage of naive cells, for example, naive T cells, for example, CD45RA+ CD45RO- CCR7+ cells, in the same population of cells prior to being engineered to express the CAR;

[0016] (d) about the same percentage of central memory cells, for example, central memory T cells, for example, CD45RA- CCR7+ CD45RO+ T cells, as compared to the percentage of central memory cells, for example, central memory T cells, for example, CD45RA- CCR7+ CD45RO+ T cells, in the same population of cells prior to being engineered to express the CAR;

[0017] (e) a change within about 5% to about 10% of central memory cells, for example, central memory T cells, for example, CD45RA- CCR7+ CD45RO+ T cells, as compared to the percentage of central memory cells, for example, central memory T cells, for example, CD45RA- CCR7+ CD45RO+ T cells, in the same population of cells prior to being engineered to express the CAR;

[0018] (f) a decreased percentage of central memory cells, for example, central memory T cells, for example, CD45RA- CCR7+ CD45RO+ T cells, for example, decreased by at least 20, 25, 30, 35, 40, 45, or 50%, as compared to the percentage of central memory cells, for example, central memory T cells, for example, CD45RA- CCR7+ CD45RO+ T cells, in the same population of cells prior to being engineered to express the CAR;

[0019] (g) about the same percentage of stem memory T cells, for example, CD45RA+CD95+IL-2 receptor P+CCR7+CD62L+ T cells, as compared to the percentage of stem memory T cells, for example, CD45RA+CD95+IL-2 receptor P+CCR7+CD62L+ T cells, in the same population of cells prior to being engineered to express the CAR;

[0020] (h) a change within about 5% to about 10% of stem memory T cells, for example, CD45RA+CD95+IL-2 receptor P+CCR7+CD62L+ T cells, as compared to the percentage of stem memory T cells, for example, CD45RA+CD95+IL-2 receptor P+CCR7+CD62L+ T cells, in the same population of cells prior to being engineered to express the CAR; or

[0021] (i) an increased percentage of stem memory T cells, for example, CD45RA+CD95+IL-2 receptor P+CCR7+CD62L+ T cells, as compared to the percentage of stem memory T cells, for example, CD45RA+CD95+IL-2 receptor P+CCR7+CD62L+ T cells, in the same population of cells prior to being engineered to express the CAR.

[0022] In one aspect, the disclosure provides a method of treating a subject having idiopathic inflammatory myopathies (IIM), e.g., dermatomyositis (DM), antisynthetase syndrome (ASyS), PAT059852-PCT-SEC01 immune mediated necrotizing myopathy (IMNM) with or without secondary Interstitial Lung Disease (ILD), polymyositis (PM), cancer-associated myositis, overlap myositis and inclusion body myositis (IBM)), the method comprising administering to the subject a population of cells engineered to express a CD 19 CAR (“a population of CD 19 CAR-expressing cells”), wherein:

[0023] (a) the median GeneSetScore (Up TEM vs. Down TSCM) of the population of cells is about the same as or differs by no more than (for example, increased by no more than) about 25, 50, 75, 100, or 125% from the median GeneSetScore (Up TEM vs. Down TSCM) of the same population of cells prior to being engineered to express the CAR;

[0024] (b) the median GeneSetScore (Up Treg vs. Down Teff) of the population of cells is about the same as or differs by no more than (for example, increased by no more than) about 25, 50, 100, 150, or 200% from the median GeneSetScore (Up Treg vs. Down Teff) of the population of cells prior to being engineered to express the CAR;

[0025] (c) the median GeneSetScore (Down sternness) of the population of cells is about the same as or differs by no more than (for example, increased by no more than) about 25, 50, 100, 150, 200, or 250% from the median GeneSetScore (Down sternness) of the population of cells prior to being engineered to express the CAR;

[0026] (d) the median GeneSetScore (Up hypoxia) of the population of cells is about the same as or differs by no more than (for example, increased by no more than) about 125, 150, 175, or 200% from the median GeneSetScore (Up hypoxia) of the population of cells prior to being engineered to express the CAR; or

[0027] (e) the median GeneSetScore (Up autophagy) of the population of cells is about the same as or differs by no more than (for example, increased by no more than) about 180, 190, 200, or 210% from the median GeneSetScore (Up autophagy) of the population of cells prior to being engineered to express the CAR.

[0028] In one aspect, the disclosure provides a method of treating a subject having idiopathic inflammatory myopathies (IIM), e.g., dermatomyositis (DM), antisynthetase syndrome (ASyS), immune mediated necrotizing myopathy (IMNM) with or without secondary Interstitial Lung Disease (ILD), polymyositis (PM), cancer-associated myositis, overlap myositis and inclusion body myositis (IBM)), the method comprising administering to the subject rapcabtagene autoleucel. PAT059852-PCT-SEC01

[0029] In one aspect, the disclosure provides a method of treating a subject having idiopathic inflammatory myopathy, the method comprising administering to the subject a population of CD 19 CAR-expressing cells in an amount sufficient to treat the systemic sclerosis. In some embodiments, the idiopathic inflammatory myopathy is dermatomyositis (DM), antisynthetase syndrome (ASyS), immune mediated necrotizing myopathy (IMNM) with or without secondary Interstitial Lung Disease (ILD), polymyositis (PM), cancer-associated myositis, overlap myositis, or inclusion body myositis (IBM). In some embodiments, the population of CD19 CAR-expressing cells is rapcabtagene autoleucel.

[0030] In some embodiments, the population of CD 19 CAR-expressing cells is administered at a dose of about 0.5 x 106to 90 x 106viable CAR-expressing cells, optionally wherein the population of CD 19 CAR-expressing cells is administered at a dose of 5 x 106viable CAR- expressing cells, optionally wherein the population of CAR-expressing cells is administered at a dose of 2.5 x 106viable CAR-expressing cells. In some embodiments, the population of CD 19 CAR-expressing cells is rapcabtagene autoleucel.

[0031] In some embodiments, the population of CD 19 CAR-expressing cells is administered at a dose of about 2.5 x 106to 2.5 x 108viable CAR-expressing cells, for example, about 12.5 x 106viable CAR-expressing cells. In some embodiments, the population of CD19 CAR-expressing cells is rapcabtagene autoleucel.

[0032] In some embodiments, the population of CD 19 CAR-expressing cells is administered at a dose of about 12.5 x 106to 1.25 x 109viable CAR-expressing cells, for example, about 25 x 106viable CAR-expressing cells. In some embodiments, the population of CD19 CAR-expressing cells is rapcabtagene autoleucel.

[0033] In some embodiments, the population of CD 19 CAR-expressing cells is administered at a dose of about 2.5 x 106to 2.5 x 108viable CAR-expressing cells, for example, about 40 x 106viable CAR-expressing cells. In some embodiments, the population of CD19 CAR-expressing cells is rapcabtagene autoleucel.

[0034] In one aspect, the disclosure provides a population of CD 19 CAR-expressing cells or a pharmaceutical composition comprising the same for use in a method of modulating an immune response in a subject having idiopathic inflammatory myopathies (IIM), e.g., dermatomyositis (DM), antisynthetase syndrome (ASyS), immune mediated necrotizing myopathy (IMNM) with or without secondary Interstitial Lung Disease (ILD), polymyositis (PM), cancer-associated PAT059852-PCT-SEC01 myositis, overlap myositis and inclusion body myositis (IBM)), said method comprising administering to the subject an effective amount of the population of CD 19 CAR-expressing cells or an effective amount of the pharmaceutical composition. In some embodiments, the population of CD 19 CAR-expressing cells is rapcabtagene autoleucel.

[0035] In one aspect, the disclosure provides a method of treating a subject having idiopathic inflammatory myopathies (IIM), e.g., dermatomyositis (DM), antisynthetase syndrome (ASyS), immune mediated necrotizing myopathy (IMNM) with or without secondary Interstitial Lung Disease (ILD), polymyositis (PM), cancer-associated myositis, overlap myositis and inclusion body myositis (IBM)) the method comprising administering to the subject: a population of cells that express, or comprise a nucleic acid configured to express, a CD 19 chimeric antigen receptor (CD 19 CAR), optionally wherein the population of cells is rapcabtagene autoleucel, and a second therapy chosen from an antimalarial agent or a stable immunosuppressive, wherein the second therapy and CD 19 CAR cells are present in the subject at the same time, e.g., wherein the second therapy is administered at a time when the CD 19 CAR cells are present in the subject.

[0036] In one aspect, the disclosure provides rapcabtagene autoleucel or a pharmaceutical composition comprising the same for use in a method of modulating an immune response in a subject having idiopathic inflammatory myopathies (IIM), e.g., dermatomyositis (DM), antisynthetase syndrome (ASyS), immune mediated necrotizing myopathy (IMNM) with or without secondary Interstitial Lung Disease (ILD), polymyositis (PM), cancer-associated myositis, overlap myositis and inclusion body myositis (IBM)), said method comprising administering to the subject an effective amount of the population of rapcaptagene autoleucel or an effective amount of the pharmaceutical composition

[0037] In one aspect, the disclosure provides rapcabtagene autoleucel or a pharmaceutical composition comprising the same for use in a method of modulating an immune response in a subject having idiopathic inflammatory myopathies (IIM), e.g., dermatomyositis (DM), antisynthetase syndrome (ASyS), immune mediated necrotizing myopathy (IMNM) with or without secondary Interstitial Lung Disease (ILD), polymyositis (PM), cancer-associated myositis, overlap myositis and inclusion body myositis (IBM)), said method comprising PAT059852-PCT-SEC01 administering to the subject an effective amount of rapcabtagene autoleucel or an effective amount of the pharmaceutical composition.

[0038] Rapcabtagene autoleucel for use in the manufacture of a medicament for treating a subject having idiopathic inflammatory myopathies (IIM), e.g., dermatomyositis (DM), antisynthetase syndrome (ASyS), immune mediated necrotizing myopathy (IMNM) with or without secondary Interstitial Lung Disease (ILD), polymyositis (PM), cancer-associated myositis, overlap myositis and inclusion body myositis (IBM)).

[0039] Rapcabtagene autoleucel for use in the manufacture of a medicament for treating a subject having idiopathic inflammatory myopathy, wherein rapcabtagene autoleucel is formulated for administration in an amount sufficient to treat the idiopathic inflammatory myopathy.

[0040] Rapcabtagene autoleucel for use in the manufacture of a medicament for treating a subject having idiopathic inflammatory myopathies (IIM), e.g., dermatomyositis (DM), antisynthetase syndrome (ASyS), immune mediated necrotizing myopathy (IMNM) with or without secondary Interstitial Lung Disease (ILD), polymyositis (PM), cancer-associated myositis, overlap myositis and inclusion body myositis (IBM)), wherein the rapcabtagene autoleucel is formulated for administration at a dose of 0.5 - 50 x 106viable CAR+ T cells (e.g., 2.5-, 5-, 12.5-, 25-, 40 x 106viable CAR+ T cells).

[0041] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references (for example, sequence database reference numbers) mentioned herein are incorporated by reference in their entirety. For example, all GenBank, Unigene, and Entrez sequences referred to herein, for example, in any Table herein, are incorporated by reference. When one gene or protein references a plurality of sequence accession numbers, all of the sequence variants are encompassed.

[0042] In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Headings, sub-headings or numbered or lettered elements, for example, (a), (b), (i) etc., are presented merely for ease of reading. The use of headings or numbered or lettered elements in this document does not require the steps or elements be performed in alphabetical order or that the steps or elements are necessarily discrete from one another. Other features, PAT059852-PCT-SEC01 objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0043] BRIEF DESCRIPTION OF THE FIGURES

[0044] FIG. 1 is a schematic showing the clinical trial design for a phase 1 / 2 study, open-label, multi-center, to assess safety, efficacy and cellular kinetics of ARM-CD19 CAR T cells in participants with idiopathic inflammatory myopathies.

[0045] FIG. 2 is a schematic comparing the ARM process to a traditional CAR T manufacturing process.

[0046] FIG. 3 is a graph demonstrating major and moderate improvement in Total Improvement Score in 3 subjects with IIM following administration of rapcabtagene autoleucel.

[0047] DETAILED DESCRIPTION

[0048] Definitions

[0049] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains.

[0050] The term “a” and “an” refers to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0051] The term “about” when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or in some instances ±10%, or in some instances ±5%, or in some instances ±1%, or in some instances ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0052] The term “Chimeric Antigen Receptor” or alternatively a “CAR” refers to a recombinant polypeptide construct comprising at least an extracellular antigen-binding domain, a transmembrane domain and a cytoplasmic signaling domain (also referred to herein as “an intracellular signaling domain”) comprising a functional signaling domain derived from a stimulatory molecule as defined below. In some embodiments, the domains in the CAR PAT059852-PCT-SEC01 polypeptide construct are in the same polypeptide chain, for example, comprise a chimeric fusion protein.

[0053] The term “autologous” refers to any material derived from the same individual to whom it is later to be re-introduced into the individual.

[0054] The term “allogeneic” refers to any material derived from a different animal of the same species as the individual to whom the material is introduced. Two or more individuals are said to be allogeneic to one another when the genes at one or more loci are not identical. In some embodiments, allogeneic material from individuals of the same species may be sufficiently unlike genetically to interact antigenically.

[0055] The term “apheresis” as used herein refers to the art-recognized extracorporeal process by which the blood of a donor or patient is removed from the donor or patient and passed through an apparatus that separates out selected constituent(s) and returns the remainder to the circulation of the donor or patient, for example, by re- transfusion. Thus, in the context of “an apheresis sample” refers to a sample obtained using apheresis.

[0056] As used herein, “idiopathic inflammatory myopathy” refers to all types and manifestations of idiopathic inflammatory myopathy. Manifestations include, but are not limited to, dermatomyositis (DM), antisynthetase syndrome (ASyS), immune mediated necrotizing myopathy (IMNM) with or without secondary Interstitial Lung Disease (ILD), polymyositis (PM), cancer-associated myositis, overlap myositis and inclusion body myositis (IBM))

[0057] “Immune effector cell,” as that term is used herein, refers to a cell that is involved in an immune response, for example, in the promotion of an immune effector response. Examples of immune effector cells include T cells, for example, alpha / beta T cells and gamma / delta T cells, B cells, natural killer (NK) cells, natural killer T (NKT) cells, mast cells, and myeloid-derived phagocytes.

[0058] “Immune effector function or immune effector response,” as that term is used herein, refers to function or response, for example, of an immune effector cell, that enhances or promotes an immune attack of a target cell. For example, an immune effector function or response refers a property of a T or NK cell that promotes killing or the inhibition of growth or proliferation, of a target cell. In the case of a T cell, primary stimulation and costimulation are examples of immune effector function or response. PAT059852-PCT-SEC01

[0059] The term “effector function” refers to a specialized function of a cell. Effector function of a T cell, for example, may be cytolytic activity or helper activity including the secretion of cytokines.

[0060] The term “effective amount” or “therapeutically effective amount” are used interchangeably herein, and refer to an amount of a compound, formulation, material, or composition, as described herein effective to achieve a particular biological result.

[0061] The term “endogenous” refers to any material from or produced inside an organism, cell, tissue, or system.

[0062] The term “exogenous” refers to any material introduced from or produced outside an organism, cell, tissue, or system.

[0063] The term “expression” refers to the transcription and / or translation of a particular nucleotide sequence. In some embodiments, expression comprises translation of an mRNA introduced into a cell.

[0064] The term “lentivirus” refers to a genus of the Retroviridae family. Lentiviruses are unique among the retroviruses in being able to infect non-dividing cells; they can deliver a significant amount of genetic information into the DNA of the host cell, so they are one of the most efficient methods of a gene delivery vector. HIV, SIV, and FIV are all examples of lentiviruses.

[0065] The term “lentiviral vector” refers to a vector derived from at least a portion of a lentivirus genome, including especially a self-inactivating lentiviral vector as provided in Milone et al., Mol. Ther. 17(8): 1453-1464 (2009). Other examples of lentivirus vectors that may be used in the clinic, include but are not limited to, for example, the LENTIVECTOR® gene delivery technology from Oxford BioMedica, the LENTIMAX™ vector system from Lentigen and the like. Nonclinical types of lentiviral vectors are also available and would be known to one skilled in the art.

[0066] The term “parenteral” administration of an immunogenic composition includes, for example, subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), or intrasternal injection, intratumoral, or infusion techniques.

[0067] As used herein, “B cell antigen” refers to an antigen associated with a B cell. Non-limiting examples of molecules associated with a B cell include proteins expressed on the surface of B cells, e.g. CD19, BCMA, CD22, CD20, CD10, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a . PAT059852-PCT-SEC01

[0068] As used herein, the term “CD 19” refers to the Cluster of Differentiation 19 protein. The human and murine amino acid and nucleic acid sequences can be found in a public database, such as GenBank, UniProt and Swiss-Prot. For example, the amino acid sequence of human CD19 can be found as UniProt / Swiss-Prot Accession No. Pl 5391 and the nucleic acid sequence encoding of the human CD19 can be found at Accession No. NM 001178098. It is also an early marker of B cell progenitors. See, e.g., Nicholson et al. Mol. Immun. 34 (16-17): 1157-1165 (1997). In one aspect the antigen-binding portion of the CART recognizes and binds an antigen within the extracellular domain of the CD 19 protein. In one aspect, the CD 19 protein is expressed on an autoreactive B-cell. As used herein, “CD 19” includes proteins comprising mutations, e.g., point mutations, fragments, insertions, deletions and splice variants of full length wild-type CD 19.

[0069] As used herein, the terms “treat”, “treatment” and “treating” refer to the reduction or amelioration of the progression, severity and / or duration of an autoimmune disorder, e.g., idiopathic inflammatory myopathies, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of an autoimmune disorder, e.g., idiopathic inflammatory myopathies, resulting from the administration of one or more therapies (for example, one or more therapeutic agents such as a CAR of the invention). In specific embodiments, the terms “treat,” “treatment,” and “treating” refer to the amelioration of at least one measurable physical parameter of an autoimmune disorder, e.g., idiopathic inflammatory myopathies, not necessarily discernible by the patient. In other embodiments the terms “treat”, “treatment” and “treating” - refer to the inhibition of the progression of an autoimmune disorder, e.g., idiopathic inflammatory myopathies, either physically by, for example, stabilization of a discernible symptom, physiologically by, for example, stabilization of a physical parameter, or both.

[0070] The term “subject” is intended to include living organisms in which an immune response can be elicited (for example, mammals, for example, human).

[0071] The term “therapeutic” as used herein means a treatment. A therapeutic effect is obtained by reduction, suppression, remission, or eradication of a disease state.

[0072] The term “prophylaxis” as used herein means the prevention of or protective treatment for a disease or disease state.

[0073] “Refractory” as used herein refers to an autoimmune disease or disorder, for example, idiopathic inflammatory myopathies, which does not respond to a treatment. In embodiments, a PAT059852-PCT-SEC01 refractory autoimmune disease or disorder can be resistant to a treatment before or at the beginning of the treatment. In other embodiments, the refractory autoimmune disease or disorder can become resistant during a treatment. A refractory autoimmune disease or disorder is also called a resistant autoimmune disease or disorder.

[0074] As used herein, “severe refractory idiopathic inflammatory myopathies” or “srllM” refers to a manifestation of idiopathic inflammatory myopathy that has failed to respond (e.g., remains characterized by high disease activity) following at least one standard immunosuppressive therapy (e.g., mycophenolate, cyclophosphamide), glucocorticoids, or at least one biological agent. In some embodiments, the srIMM comprises a manifestation of idiopathic inflammatory myopathy that has failed to respond to two or more standard immunosuppressive therapies in combination with glucocorticoids. In some embodiments, the srIMM comprises a manifestation of idiopathic inflammatory myopathy that has failed to respond to at least one biological agent.

[0075] “Relapsed” or “relapse” as used herein refers to the return or reappearance of a disease (for example, an autoimmune disease or disorder) or the signs and symptoms of a disease such as an autoimmune disease or disorder after a period of improvement or responsiveness, for example, after prior treatment of a therapy, for example, standard of care therapy. The initial period of responsiveness may involve the level of autoantibodies cells falling below a certain threshold. The reappearance may involve the level of autoantibodies rising above a certain threshold.

[0076] “Remission” as used herein refers to a decrease in or disappearance of signs and symptoms of a disease (for example, an autoimmune disease or disorder). Remission may be partial or complete. In partial remission, some, but not all, signs and symptoms of a disease have decreased or disappeared. In complete remission, all signs and symptoms of a disease have disappeared. Remission may be determined according to a defined set of criteria established for a particular disease (for example, an autoimmune disease or disorder).

[0077] Ranges: throughout this disclosure, various embodiments of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have PAT059852-PCT-SEC01 specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. As another example, a range such as 95-99% identity, includes something with 95%, 96%, 97%, 98%, or 99% identity, and includes subranges such as 96-99%, 96-98%, 96- 97%, 97-99%, 97-98%, and 98-99% identity. This applies regardless of the breadth of the range.

[0078] Administered “in combination”, as used herein, means that two (or more) different treatments are delivered to the subject during the course of the subject's affliction with the disorder, for example, the two or more treatments are delivered after the subject has been diagnosed with the disorder and before the disorder has been cured or eliminated or treatment has ceased for other reasons. In some embodiments, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous” or “concurrent delivery”. In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In some embodiments of either case, the treatment is more effective because of combined administration. For example, the second treatment is more effective, for example, an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment. In some embodiments, delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive. The delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered.

[0079] As used herein, a “naive T cell” refers to a T cell that is antigen-inexperienced. In some embodiments, an antigen-inexperienced T cell has encountered its cognate antigen in the thymus but not in the periphery. In some embodiments, naive T cells are precursors of memory cells. In some embodiments, naive T cells express both CD45RA and CCR7, but do not express CD45RO. In some embodiments, naive T cells may be characterized by expression of CD62L, CD27, CCR7, CD45RA, CD28, and CD127, and the absence of CD95 or CD45RO isoform. In some embodiments, naive T cells express CD62L, IL-7 receptor-a, IL-6 receptor, and CD 132, but do not express CD25, CD44, CD69, or CD45RO. In some embodiments, naive T cells PAT059852-PCT-SEC01 express CD45RA, CCR7, and CD62L and do not express CD95 or IL-2 receptor 0. In some embodiments, surface expression levels of markers are assessed using flow cytometry.

[0080] The term “central memory T cells” refers to a subset of T cells that in humans are CD45RO positive and express CCR7. In some embodiments, central memory T cells express CD95. In some embodiments, central memory T cells express IL-2R, IL-7R, and / or IL-15R. In some embodiments, central memory T cells express CD45RO, CD95, IL-2 receptor 0, CCR7, and CD62L. In some embodiments, surface expression levels of markers are assessed using flow cytometry.

[0081] The term “stem memory T cells,” “stem cell memory T cells,” “stem cell-like memory T cells,” “memory stem T cells,” “T memory stem cells,” “T stem cell memory cells,” or “TSCM cells” refers to a subset of memory T cells with stem cell-like ability, for example, the ability to self-renew and / or the multipotent capacity to reconstitute memory and / or effector T cell subsets. In some embodiments, stem memory T cells express CD45RA, CD95, IL-2 receptor 0, CCR7, and CD62L. In some embodiments, surface expression levels of markers are assessed using flow cytometry. In some embodiments, exemplary stem memory T cells are disclosed in Gattinoni et al., Nat Med. 2017 January 06; 23(1): 18-27, herein incorporated by reference in its entirety.

[0082] For clarity purposes, unless otherwise noted, classifying a cell or a population of cells as “not expressing,” or having an “absence of’ or being “negative for” a particular marker may not necessarily mean an absolute absence of the marker. The skilled artisan can readily compare the cell against a positive and / or a negative control, and / or set a predetermined threshold, and classify the cell or population of cells as not expressing or being negative for the marker when the cell has an expression level below the predetermined threshold or a population of cells has an overall expression level below the predetermined threshold using conventional detection methods, e.g., using flow cytometry.

[0083] As used herein, the term “GeneSetScore (Up TEM vs. Down TSCM)” of a cell refers to a score that reflects the degree at which the cell shows an effector memory T cell (TEM) phenotype vs. a stem cell memory T cell (TSCM) phenotype. A higher GeneSetScore (Up TEM vs. Down TSCM) indicates an increasing TEM phenotype, whereas a lower GeneSetScore (Up TEM vs. Down TSCM) indicates an increasing TSCM phenotype. In some embodiments, the GeneSetScore (Up TEM vs. Down TSCM) is determined by measuring the expression of one or more genes that are up-regulated in TEM cells and / or down-regulated in TSCM cells, for PAT059852-PCT-SEC01 example, one or more genes selected from the group consisting of MXRA7, CLIC1, NAT13, TBC1D2B, GLCCI1, DUSP10, APOBEC3D, CACNB3, ANXA2P2, TPRG1, EOMES, MATK, ARHGAP10, ADAM8, MAN1A1, SLFN12L, SH2D2A, EIF2C4, CD58, MYO1F, RAB27B, ERN1, NPC1, NBEAL2, APOBEC3G, SYTL2, SLC4A4, PIK3AP1, PTGDR, MAF, PLEKHA5, ADRB2, PLXND1, GNAO1, THBS1, PPP2R2B, CYTH3, KLRF1, FLJ16686, AUTS2, PTPRM, GNLY, and GFPT2. In some embodiments, the GeneSetScore (Up TEM vs. Down TSCM) is determined for each cell using RNA-seq, for example, single-cell RNA-seq (scRNA-seq), for example, as exemplified of WO / 2020 / 047452 in Example 10 with respect to FIG. 39A, hereby incorporated by reference in its entirety. In some embodiments, the GeneSetScore (Up TEM vs. Down TSCM) is calculated by taking the mean log normalized gene expression value of all of the genes in the gene set.

[0084] As used herein, the term “GeneSetScore (Up Treg vs. Down Teff)” of a cell refers to a score that reflects the degree at which the cell shows a regulatory T cell (Treg) phenotype vs. an effector T cell (Teff) phenotype. A higher GeneSetScore (Up Treg vs. Down Teff) indicates an increasing Treg phenotype, whereas a lower GeneSetScore (Up Treg vs. Down Teff) indicates an increasing Teff phenotype. In some embodiments, the GeneSetScore (Up Treg vs. Down Teff) is determined by measuring the expression of one or more genes that are up-regulated in Treg cells and / or down-regulated in Teff cells, for example, one or more genes selected from the group consisting of C12orf75, SELPLG, SWAP70, RGS1, PRR11, SPATS2L, SPATS2L, TSHR, C14orfl45, CASP8, SYT11, ACTN4, ANXA5, GLRX, HLA-DMB, PMCH, RAB11FIP1, IL32, FAM160B1, SHMT2, FRMD4B, CCR3, TNFRSF13B, NTNG2, CLDND1, BARD1, FCER1G, TYMS, ATP1B1, GJB6, FGL2, TK1, SLC2A8, CDKN2A, SKAP2, GPR55, CDCA7, S100A4, GDPD5, PMAIP1, ACOT9, CEP55, SGMS1, ADPRH, AKAP2, HDAC9, IKZF4, CARD17, VAV3, OBFC2A, ITGB1, CIITA, SETD7, HLA-DMA, CCR10, KIAA0101, SLC14A1, PTTG3P, DUSP10, FAM164A, PYHIN1, MYO1F, SLC1A4, MYBL2, PTTG1, RRM2, TP53INP1, CCR5, ST8SIA6, TOX, BFSP2, ITPRIPL1, NCAPH, HLA-DPB2, SYT4, NINJ2, FAM46C, CCR4, GBP5, C15orf53, LMCD1, MKI67, NUSAP1, PDE4A, E2F2, CD58, ARHGEF12, LOC100188949, FAS, HLA-DPB1, SELP, WEE1, HLA-DPA1, FCRL1, ICA1, CNTNAP1, OAS1, METTL7A, CCR6, HLA-DRB4, ANXA2P3, STAM, HLA-DQB2, LGALS1, ANXA2, PI 16, DUSP4, LAYN, ANXA2P2, PTPLA, ANXA2P1, ZNF365, LAIR2, LOC541471, RASGRP4, BCAS1, UTS2, MIAT, PRDM1, SEMA3G, FAM129A, HPGD, PAT059852-PCT-SEC01

[0085] NCF4, LGALS3, CEACAM4, JAKMIP1, TIGIT, HLA-DRA, IKZF2, HLA-DRB1, FANK1, RTKN2, TRIBI, FCRL3, and FOXP3. In some embodiments, the GeneSetScore (Up Treg vs. Down Teff) is determined using RNA-seq, for example, single-cell RNA-seq (scRNA-seq) , for example, as exemplified of WO / 2020 / 047452 in Example 10 with respect to FIG. 39B, hereby incorporated by reference in its entirety. In some embodiments, the GeneSetScore (Up Treg vs. Down Teff) is calculated by taking the mean log normalized gene expression value of all of the genes in the gene set.

[0086] As used herein, the term “GeneSetScore (Down sternness)” of a cell refers to a score that reflects the degree at which the cell shows a sternness phenotype. A lower GeneSetScore (Down sternness) indicates an increasing sternness phenotype. In some embodiments, the GeneSetScore (Down sternness) is determined by measuring the expression of one or more genes that are upregulated in a differentiating stem cell vs downregulated in a hematopoietic stem cell, for example, one or more genes selected from the group consisting of ACE, BATF, CDK6, CHD2, ERCC2, HOXB4, ME0X1, SFRP1, SP7, SRF, TALI, and XRCC5. In some embodiments, the GeneSetScore (Down sternness) is determined using RNA-seq, for example, single-cell RNA-seq (scRNA-seq) , for example, as exemplified of WO / 2020 / 047452 in Example 10 with respect to FIG. 39C, hereby incorporated by reference in its entirety. In some embodiments, the GeneSetScore (Down sternness) is calculated by taking the mean log normalized gene expression value of all of the genes in the gene set.

[0087] As used herein, the term “GeneSetScore (Up hypoxia)” of a cell refers to a score that reflects the degree at which the cell shows a hypoxia phenotype. A higher GeneSetScore (Up hypoxia) indicates an increasing hypoxia phenotype. In some embodiments, the GeneSetScore (Up hypoxia) is determined by measuring the expression of one or more genes that are up- regulated in cells undergoing hypoxia, for example, one or more genes selected from the group consisting of ABCB1, ACAT1, ADM, ADORA2B, AK2, AK3, ALDH1A1, ALDH1A3, ALDOA, ALDOC, ANGPT2, ANGPTL4, ANXA1, ANXA2, ANXA5, ARHGAP5, ARSE, ART1, BACE2, BATF3, BCL2L1, BCL2L2, BHLHE40, BHLHE41, BIK, BIRC2, BNIP3, BNIP3L, BPI, BTG1, Cllorf2, C7orf68, CA12, CA9, CALD1, CCNG2, CCT6A, CD99, CDK1, CDKN1A, CDKN1B, CITED2, CLK1, CNOT7, COL4A5, COL5A1, COL5A2, COL5A3, CP, CTSD, CXCR4, D4S234E, DDIT3, DDIT4, 1-Dec, DKC1, DR1, EDN1, EDN2, EFNA1, EGF, EGR1, EIF4A3, ELF3, ELL2, ENG, ENO1, ENO3, ENPEP, EPO, ERRFI1, ETS1, F3, FABP5, PAT059852-PCT-SEC01

[0088] FGF3, FKBP4, FLT1, FN1, FOS, FTL, GAPDH, GBE1, GLRX, GPI, GPRC5A, HAP1, HBP1, HDAC1, HDAC9, HERC3, HERPUD1, HGF, HIF1A, HK1, HK2, HLA-DQB1, HM0X1, HMOX2, HSPA5, HSPD1, HSPH1, HYOU1, ICAM1, ID2, IFI27, IGF2, IGFBP1, IGFBP2, IGFBP3, IGFBP5, IL6, IL8, INSIGI, IRF6, ITGA5, JUN, KDR, KRT14, KRT18, KRT19, LDHA, LDHB, LEP, LGALS1, LONP1, LOX, LRP1, MAP4, MET, MIF, MMP13, MMP2, MMP7, MPI, MT1L, MTL3P, MUC1, MXI1, NDRG1, NFIL3, NFKB1, NFKB2, NOS1, NOS2, NOS2P1, NOS2P2, NOS3, NR3C1, NR4A1, NT5E, ODC1, P4HA1, P4HA2, PAICS, PDGFB, PDK3, PFKFB1, PFKFB3, PFKFB4, PFKL, PGAM1, PGF, PGK1, PGK2, PGM1, PIM1, PIM2, PKM2, PLAU, PLAUR, PLIN2, PLOD2, PNN, PNP, POLM, PPARA, PPAT, PROK1, PSMA3, PSMD9, PTGS1, PTGS2, QSOX1, RBPJ, RELA, RIOK3, RNASEL, RPL36A, RRP9, SAT1, SERPINB2, SERPINE1, SGSM2, SIAH2, SIN3A, SIRPA, SLC16A1, SLC16A2, SLC20A1, SLC2A1, SLC2A3, SLC3A2, SLC6A10P, SLC6A16, SLC6A6, SLC6A8, SORL1, SPP1, SRSF6, SSSCA1, STC2, STRA13, SYT7, TBPL1, TCEAL1, TEK, TF, TFF3, TFRC, TGFA, TGFB1, TGFB3, TGFBI, TGM2, TH, THBS1, THBS2, TIMM17A, TNFAIP3, TP53, TPBG, TPD52, TPI1, TXN, TXNIP, UMPS, VEGFA, VEGFB, VEGFC, VIM, VPS11, and XRCC6. In some embodiments, the GeneSetScore (Up hypoxia) is determined using RNA-seq, for example, single-cell RNA-seq (scRNA-seq) , for example, as exemplified of WO / 2020 / 047452 in Example 10 with respect to FIG. 39D, hereby incorporated by reference in its entirety. In some embodiments, the GeneSetScore (Up hypoxia) is calculated by taking the mean log normalized gene expression value of all of the genes in the gene set.

[0089] As used herein, the term “GeneSetScore (Up autophagy)” of a cell refers to a score that reflects the degree at which the cell shows an autophagy phenotype. A higher GeneSetScore (Up autophagy) indicates an increasing autophagy phenotype. In some embodiments, the GeneSetScore (Up autophagy) is determined by measuring the expression of one or more genes that are up-regulated in cells undergoing autophagy, for example, one or more genes selected from the group consisting of ABL1, ACBD5, ACINI, ACTRT1, ADAMTS7, AKR1E2, ALKBH5, ALPK1, AMBRA1, ANXA5, ANXA7, ARSB, ASB2, ATG10, ATG12, ATG13, ATG14, ATG16L1, ATG16L2, ATG2A, ATG2B, ATG3, ATG4A, ATG4B, ATG4C, ATG4D, ATG5, ATG7, ATG9A, ATG9B, ATP13A2, ATP1B1, ATPAF1-AS1, ATPIF1, BECN1, BECN1P1, BLOC1S1, BMP2KL, BNIP1, BNIP3, BOC, Cllorf2, Cl lorf41, C12orf44, C12orf5, C14orfl33, Clorf210, C5, C6orfl06, C7orf59, C7orf68, C8orf59, C9orf72, CA7, PAT059852-PCT-SEC01

[0090] CALCB, CALCOCO2, CAPS, CCDC36, CD163L1, CD93, CDC37, CDKN2A, CHAF1B, CHMP2A, CHMP2B, CHMP3, CHMP4A, CHMP4B, CHMP4C, CHMP6, CHST3, CISD2, CLDN7, CLEC16A, CLN3, CLVS1, COX8A, CPA3, CRNKL1, CSPG5, CTSA, CTSB, CTSD, CXCR7, DAP, DKKL1, DNAAF2, DPF3, DRAM1, DRAM2, DYNLL1, DYNLL2, DZANK1, EI24, EIF2S1, EPG5, EPM2A, FABP1, FAM125A, FAM131B, FAM134B, FAM13B, F AMI 76 A, FAM176B, FAM48A, FANCC, FANCF, FANCL, FBXO7, FCGR3B, FGF14, FGF7, FGFBP1, FIS1, FNBP1L, FOXO1, FUNDCI, FUNDC2, FXR2, GAB ARAP, GABARAPL1, GABARAPL2, GABARAPL3, GABRA5, GDF5, GMIP, HAP1, HAPLN1, HBXIP, HCAR1, HDAC6, HGS, HIST1H3A, HIST1H3B, HIST1H3C, HIST1H3D, HIST1H3E, HIST1H3F, HIST1H3G, HIST1H3H, HIST1H3I, HIST1H3J, HK2, HMGB1, HPR, HSF2BP, HSP90AA1, HSPA8, IFI16, IPPK, IRGM, IST1, ITGB4, ITPKC, KCNK3, KCNQ1, KIAA0226, KIAA1324, KRCC1, KRT15, KRT73, LAMP1, LAMP2, LAMTOR1, LAMTOR2, LAMTOR3, LARP1B, LENG9, LGALS8, LIX1, LIX1L, LMCD1, LRRK2, LRSAM1, LSM4, MAP1A, MAP1LC3A, MAP1LC3B, MAP1LC3B2, MAP1LC3C, MAP1S, MAP2K1, MAP3K12, MARK2, MBD5, MDH1, MEX3C, MFN1, MFN2, MLST8, MRPS10, MRPS2, MSTN, MTERFD1, MTMR14, MTMR3, MTOR, MTSS1, MYH11, MYLK, MYOMI, NBR1, NDUFB9, NEFM, NHLRC1, NME2, NPC1, NR2C2, NRBF2, NTHL1, NUP93, OBSCN, OPTN, P2RX5, PACS2, PARK2, PARK7, PDK1, PDK4, PEX13, PEX3, PFKP, PGK2, PHF23, PHYHIP, PI4K2A, PIK3C3, PIK3CA, PIK3CB, PIK3R4, PINK1, PLEKHM1, PLOD2, PNPO, PPARGC1A, PPY, PRKAA1, PRKAA2, PRKAB1, PRKAB2, PRKAG1, PRKAG2, PRKAG3, PRKD2, PRKG1, PSEN1, PTPN22, RAB12, RAB1A, RAB1B, RAB23, RAB24, RAB33B, RAB39, RAB7A, RB1CC1, RBM18, REEP2, REP15, RFWD3, RGS19, RHEB, RIMS3, RNF185, RNF41, RPS27A, RPTOR, RRAGA, RRAGB, RRAGC, RRAGD, S100A8, S100A9, SCN1A, SERPINB10, SESN2, SFRP4, SH3GLB1, SIRT2, SLC1A3, SLC1A4, SLC22A3, SLC25A19, SLC35B3, SLC35C1, SLC37A4, SLC6A1, SLCO1A2, SMURF1, SNAP29, SNAPIN, SNF8, SNRPB, SNRPB2, SNRPD1, SNRPF, SNTG1, SNX14, SPATAI 8, SQSTM1, SRPX, STAM, STAM2, STAT2, STBD1, STK11, STK32A, STOM, STX12, STX17, SUPT3H, TBC1D17, TBC1D25, TBC1D5, TCIRG1, TEAD4, TECPR1, TECPR2, TFEB, TM9SF1, TMBIM6, TMEM203, TMEM208, TMEM39A, TMEM39B, TMEM59, TMEM74, TMEM93, TNIK, TOLLIP, TOMM20, TOMM22, TOMM40, TOMM5, TOMM6, TOMM7, TOMM70A, TP53INP1, TP53INP2, TRAPPC8, TREM1, TRIM17, TRIM5, TSG101, TXLNA, UBA52, PAT059852-PCT-SEC01

[0091] UBB, UBC, UBQLN1, UBQLN2, UBQLN4, ULK1, ULK2, ULK3, USP10, USP13, USP30, UVRAG, VAMP7, VAMP8, VDAC1, VMP1, VPS11, VPS16, VPS18, VPS25, VPS28, VPS33A, VPS33B, VPS36, VPS37A, VPS37B, VPS37C, VPS37D, VPS39, VPS41, VPS4A, VPS4B, VTA1, VTT1A, VTI1B, WDFY3, WDR45, WDR45L, WIPI1, WIPI2, XBP1, YIPF1, ZCCHC17, ZFYVE1, ZKSCAN3, ZNF189, ZNF593, and ZNF681. In some embodiments, the GeneSetScore (Up autophagy) is determined using RNA-seq, for example, single-cell RNA-seq (scRNA-seq) , for example, as exemplified of WO / 2020 / 047452 in Example 10 with respect to FIG. 39E, hereby incorporated by reference in its entirety. In some embodiments, the GeneSetScore (Up autophagy) is calculated by taking the mean log normalized gene expression value of all of the genes in the gene set.

[0092] As used herein, the term “GeneSetScore (Up resting vs. Down activated)” of a cell refers to a score that reflects the degree at which the cell shows a resting T cell phenotype vs. an activated T cell phenotype. A higher GeneSetScore (Up resting vs. Down activated) indicates an increasing resting T cell phenotype, whereas a lower GeneSetScore (Up resting vs. Down activated) indicates an increasing activated T cell phenotype. In some embodiments, the GeneSetScore (Up resting vs. Down activated) is determined by measuring the expression of one or more genes that are up-regulated in resting T cells and / or down- regulated in activated T cells, for example, one or more genes selected from the group consisting of ABCA7, ABCF3, ACAP2, AMT, ANKH, ATF7IP2, ATG14, ATP1A1, ATXN7, ATXN7L3B, BCL7A, BEX4, BSDC1, BTG1, BTG2, BTN3A1, Cllorf21, C19orf22, C21orf2, CAMK2G, CARS2, CCNL2, CD248, CD5, CD55, CEP164, CHKB, CLK1, CLK4, CTSL1, DBP, DCUN1D2, DENND1C, DGKD, DLG1, DUSP1, EAPP, ECE1, ECHDC2, ERBB2IP, FAM117A, FAM134B, FAM134C, FAM169A, FAM190B, FAU, FLJ10038, FOXJ2, FOXJ3, FOXL1, FOXO1, FXYD5, FYB, HLA-E, HSPA1L, HYAL2, ICAM2, IFIT5, IFITM1, IKBKB, IQSEC1, IRS4, KIAA0664L3, KIAA0748, KLF3, KLF9, KRT18, LEF1, LINC00342, LIPA, LIPT1, LLGL2, LMBR1L, LPAR2, LTBP3, LYPD3, LZTFL1, MANBA, MAP2K6, MAP3K1, MARCH8, MAU2, MGEA5, MMP8, MPO, MSL1, MSL3, MYH3, MYLIP, NAGPA, NDST2, NISCH, NKTR, NLRP1, NOSIP, NPIP, NUMA1, PAIP2B, PAPD7, PBXIP1, PCIF1, PI4KA, PLCL2, PLEKHA1, PLEKHF2, PNISR, PPFIBP2, PRKCA, PRKCZ, PRKD3, PRMT2, PTP4A3, PXN, RASA2, RASA3, RASGRP2, RBM38, REPIN1, RNF38, RNF44, ROR1, RPL30, RPL32, RPLP1, RPS20, RPS24, RPS27, RPS6, RPS9, RXRA, RYK, SCAND2, SEMA4C, SETD1B, PAT059852-PCT-SEC01

[0093] SETD6, SETX, SF3B1, SH2B1, SLC2A4RG, SLC35E2B, SLC46A3, SMAGP, SMARCE1, SMPD1, SNPH, SP140L, SPATA6, SPG7, SREK1IP1, SRSF5, STAT5B, SVIL, SYF2, SYNJ2BP, TAF1C, TBC1D4, TCF20, TECTA, TES, TMEM127, TMEM159, TMEM30B, TMEM66, TMEM8B, TP53TG1, TPCN1, TRIM22, TRIM44, TSC1, TSC22D1, TSC22D3, TSPYL2, TTC9, TTN, UBE2G2, USP33, USP34, VAMP1, VILL, VIPR1, VPS13C, ZBED5, ZBTB25, ZBTB40, ZC3H3, ZFP161, ZFP36L1, ZFP36L2, ZHX2, ZMYM5, ZNF136, ZNF148, ZNF318, ZNF350, ZNF512B, ZNF609, ZNF652, ZNF83, ZNF862, and ZNF91. In some embodiments, the GeneSetScore (Up resting vs. Down activated) is determined using RNA-seq, for example, single-cell RNA-seq (scRNA-seq) , for example, as exemplified of WO / 2020 / 047452 in Example 10 with respect to FIG. 38D, hereby incorporated by reference in its entirety. In some embodiments, the GeneSetScore (Up resting vs. Down activated) is calculated by taking the mean log normalized gene expression value of all of the genes in the gene set.

[0094] As used herein, the term “GeneSetScore (Progressively up in memory differentiation)” of a cell refers to a score that reflects the stage of the cell in memory differentiation. A higher GeneSetScore (Progressively up in memory differentiation) indicates an increasing late memory T cell phenotype, whereas a lower GeneSetScore (Progressively up in memory differentiation) indicates an increasing early memory T cell phenotype. In some embodiments, the GeneSetScore (Up autophagy) is determined by measuring the expression of one or more genes that are up-regulated during memory differentiation, for example, one or more genes selected from the group consisting of MTCH2, RAB6C, KIAA0195, SETD2, C2orf24, NRD1, GNA13, COP A, SELT, TNIP1, CBFA2T2, LRP10, PRKCI, BRE, ANKS1A, PNPLA6, ARL6IP1, WDFY1, MAPK1, GPR153, SHKBP1, MAP1LC3B2, PIP4K2A, HCN3, GTPBP1, TLN1, C4orf34, KIF3B, TCIRG1, PPP3CA, ATG4D, TYMP, TRAF6, C17orf76, WIPF1, FAM108A1, MYL6, NRM, SPCS2, GGT3P, GALK1, CLIP4, ARL4C, YWHAQ, LPCAT4, ATG2A, IDS, TBC1D5, DMPK, ST6GALNAC6, REEP5, ABHD6, KIAA0247, EMB, TSEN54, SPIRE2, PIWIL4, ZSCAN22, ICAM1, CHD9, LPIN2, SETD8, ZC3H12A, ULBP3, IL15RA, HLA- DQB2, LCP1, CHP, RUNX3, TMEM43, REEP4, MEF2D, ABL1, TMEM39A, PCBP4, PLCD1, CHST12, RASGRP1, Clorf58, Cl lorf63, C6orfl29, FHOD1, DKFZp434F142, PIK3CG, ITPR3, BTG3, C4orf50, CNNM3, IFI16, AK1, CDK2AP1, REL, BCL2L1, MVD, TTC39C, PLEKHA2, FKBP11, EML4, FANCA, CDCA4, FUCA2, MFSD10, TBCD, CAPN2, IQGAP1, PAT059852-PCT-SEC01

[0095] CHST11, PIK3R1, MYO5A, KIR2DL3, DLG3, MXD4, RALGDS, S1PR5, WSB2, CCR3, TIP ARP, SP140, CD151, SOX13, KRTAP5-2, NF1, PEA15, PARP8, RNF166, UEVLD, LIMK1, CACNB1, TMX4, SLC6A6, LBA1, SV2A, LLGL2, IRF1, PPP2R5C, CD99, RAPGEF1, PPP4R1, OSBPL7, FOXP4, SLA2, TBC1D2B, ST7, JAZF1, GGA2, PI4K2A, CD68, LPGAT1, STX11, ZAK, FAM160B1, RORA, C8orf80, APOBEC3F, TGFBI, DNAJC1, GPR114, LRP8, CD69, CMIP, NAT13, TGFBI, FLJ00049, ANTXR2, NR4A3, IL12RB1, NTNG2, RDX, MLLT4, GPRIN3, ADCY9, CD300A, SCD5, ABB, PTPN22, LGALS1, SYTL3, BMPR1A, TBK1, PMAIP1, RASGEF1A, GCNT1, GABARAPL1, STOM, CALHM2, ABCA2, PPP1R16B, SYNE2, PAM, C12orf75, CLCF1, MXRA7, APOBEC3C, CLSTN3, ACOT9, HIP1, LAG3, TNFAIP3, DCBLD1, KLF6, CACNB3, RNF19A, RAB27A, FADS3, DLG5, APOBEC3D, TNFRSF1B, ACTN4, TBKBP1, ATXN1, ARAP2, ARHGEF12, FAM53B, MAN1A1, FAM38A, PLXNC1, GRLF1, SRGN, HLA-DRB5, B4GALT5, WIPI1, PTPRJ, SLFN11, DUSP2, ANXA5, AHNAK, NEO1, CLIC1, EIF2C4, MAP3K5, IL2RB, PLEKHG1, MYO6, GTDC1, EDARADD, GALM, TARP, ADAM8, MSC, HNRPLL, SYT11, ATP2B4, NHSL2, MATK, ARHGAP18, SLFN12L, SPATS2L, RAB27B, PIK3R3, TP53INP1, MBOAT1, GYG1, KATNAL1, FAM46C, ZC3HAV1L, ANXA2P2, CTNNA1, NPC1, C3AR1, CRIM1, SH2D2A, ERN1, YPEL1, TBX21, SLC1A4, FASLG, PHACTR2, GALNT3, ADRB2, PIK3AP1, TLR3, PLEKHA5, DUSP10, GNAO1, PTGDR, FRMD4B, ANXA2, EOMES, CADM1, MAF, TPRG1, NBEAL2, PPP2R2B, PELO, SLC4A4, KLRF1, FOSL2, RGS2, TGFBR3, PRF1, MYO1F, GAB3, C17orf66, MICAL2, CYTH3, TOX, HLA-DRA, SYNE1, WEE1, PYHIN1, F2R, PLD1, THBS1, CD58, FAS, NETO2, CXCR6, ST6GALNAC2, DUSP4, AUTS2, Clorf21, KLRG1, TNIP3, GZMA, PRR5L, PRDM1, ST8SIA6, PLXND1, PTPRM, GFPT2, MYBL1, SLAMF7, FLJ16686, GNLY, ZEB2, CST7, IL18RAP, CCL5, KLRD1, and KLRB1. In some embodiments, the GeneSetScore (Progressively up in memory differentiation) is determined using RNA-seq, for example, as exemplified of WO / 2020 / 047452 in Example 10 with respect to FIG. 40B, hereby incorporated by reference in its entirety. In some embodiments, the GeneSetScore (Progressively up in memory differentiation) is calculated by taking the mean log normalized gene expression value of all of the genes in the gene set.

[0096] As used herein, the term “GeneSetScore (Up TEM vs. Down TN)” of a cell refers to a score that reflects the degree at which the cell shows an effector memory T cell (TEM) phenotype vs. a naive T cell (TN) phenotype. A higher GeneSetScore (Up TEM vs. Down TN) PAT059852-PCT-SEC01 indicates an increasing TEM phenotype, whereas a lower GeneSetScore (Up TEM vs. Down TN) indicates an increasing TN phenotype. In some embodiments, the GeneSetScore (Up TEM vs. Down TN) is determined by measuring the expression of one or more genes that are up-regulated in TEM cells and / or down-regulated in TN cells, for example, one or more genes selected from the group consisting of MY05A, MXD4, STK3, S1PR5, GLCCI1, CCR3, SOX13, KRTAP5-2, PEA15, PARP8, RNF166, UEVLD, LIMK1, SLC6A6, SV2A, KPNA2, OSBPL7, ST7, GGA2, PI4K2A, CD68, ZAK, RORA, TGFBI, DNAJC1, JOSD1, ZFYVE28, LRP8, OSBPL3, CMIP, NAT13, TGFBI, ANTXR2, NR4A3, RDX, ADCY9, CHN1, CD300A, SCD5, PTPN22, LGALS1, RASGEF1A, GCNT1, GLUL, ABCA2, CLDND1, PAM, CLCF1, MXRA7, CLSTN3, ACOT9, METRNL, BMPR1A, LRIG1, APOBEC3G, CACNB3, RNF19A, RAB27A, FADS3, ACTN4, TBKBP1, FAM53B, MAN1A1, FAM38A, GRLF1, B4GALT5, WIPI1, DUSP2, ANXA5, AHNAK, CLIC1, MAP3K5, ST8SIA1, TARP, ADAM8, MATK, SLFN12L, PIK3R3, FAM46C, ANXA2P2, CTNNA1, NPC1, SH2D2A, ERN1, YPEL1, TBX21, STOM, PHACTR2, GBP5, ADRB2, PIK3AP1, DUSP10, PTGDR, EOMES, MAF, TPRG1, NBEAL2, NCAPH, SLC4A4, FOSL2, RGS2, TGFBR3, MYO1F, C17orf66, CYTH3, WEE1, PYHIN1, F2R, THBS1, CD58, AUTS2, FAM129A, TNIP3, GZMA, PRR5L, PRDM1, PLXND1, PTPRM, GFPT2, MYBL1, SLAMF7, ZEB2, CST7, CCL5, GZMK, and KLRB1. In some embodiments, the GeneSetScore (Up TEM vs. Down TN) is determined using RNA-seq, for example, singlecell RNA-seq (scRNA-seq) , for example, as exemplified of WO / 2020 / 047452 in Example 10 with respect to FIG. 40C, hereby incorporated by reference in its entirety. In some embodiments, the GeneSetScore (Up TEM vs. Down TN) is calculated by taking the mean log normalized gene expression value of all of the genes in the gene set.

[0097] In the context of GeneSetScore values (e.g., median GeneSetScore values), when a positive GeneSetScore is reduced by 100%, the value becomes 0. When a negative GeneSetScore is increased by 100%, the value becomes 0. For example, as disclosed in WO / 2020 / 047452, the median GeneSetScore of the Dayl sample is -0.084; the median GeneSetScore of the Day9 sample is 0.035; and the median GeneSetScore of the input sample is -0.1. In WO / 2020 / 047452 in FIG. 39A, increasing the median GeneSetScore of the input sample by 100% leads to a GeneSetScore value of 0; and increasing the median GeneSetScore of the input sample by 200% leads to a GeneSetScore value of 0.1. In WO / 2020 / 047452 in FIG. 39A, decreasing the median GeneSetScore of the Day9 sample by 100% leads to a GeneSetScore PAT059852-PCT-SEC01 value of 0; and decreasing the median GeneSetScore of the Day9 sample by 200% leads to a GeneSetScore value of -0.035.

[0098] Various embodiments of the compositions and methods herein are described in further detail below. Additional definitions are set out throughout the specification.

[0099] CD19 CAR-Expressing Cells

[0100] The present disclosure provides CAR-expressing cell compositions and their use in medicaments or methods for treating, among other diseases, idiopathic inflammatory myopathies (IIM), e.g., dermatomyositis (DM), antisynthetase syndrome (ASyS), immune mediated necrotizing myopathy (IMNM) with or without secondary Interstitial Lung Disease (ILD), polymyositis (PM), cancer-associated myositis, overlap myositis and inclusion body myositis (IBM)) involving cells or tissues which express an antigen as described herein. In some embodiments, provided herein are pharmaceutical compositions comprising a CAR-expressing cell, for example, a plurality of CD 19 CAR-expressing cells, in combination with one or more pharmaceutically or physiologically acceptable carriers, diluents or excipients. In some embodiments, the CD 19 CAR-expressing cells is rapcabtagene autoleucel.

[0101] In some embodiments, the antigen-binding domain of the CD 19 CAR has the same or a similar binding specificity as the FMC63 scFv fragment described in Nicholson et al. Mol. Immun. 34 (16-17): 1157-1165 (1997). In some embodiments, the antigen-binding domain of the CD19 CAR includes the scFv fragment described in Nicholson et al. Mol. Immun. 34 (16- 17): 1157-1165 (1997). In some embodiments, the CD19 CAR includes an antigen-binding domain (for example, a humanized antigen-binding domain) according to Table 3 of WO2014 / 153270, incorporated herein by reference. In some embodiments, the CD19 CAR comprises an amino acid sequence provided as SEQ ID NO: 12 in PCT publication WO2012 / 079000, incorporated herein by reference.

[0102] In some embodiments, the population of CAR T cells that specifically bind to CD 19 comprises rapcabtagene autoleucel. The rapcabtagene autoleucel is made using autologous T cells obtained from peripheral blood mononuclear cells from a subject (e.g., from a subject having an autoimmune disease or disorder) by leukapheresis and subsequently transduced with a self-inactivating, non-replicating lentiviral vector encoding a T cell chimeric antigen receptor PAT059852-PCT-SEC01 targeting CD 19. The expressed transgene comprises a CD8a leader sequence, a murine antiCD 19 single chain variable fragment (scFv) derived from the mouse hybridoma FMC63, a CD8a hinge and transmembrane region, and a 4- IBB (CD 137) and CD3^ (TCRQ signaling domain, and is under control of the elongation factor 1 alpha (EFla) promoter. The construct is flanked by 5' and 3' long terminal repeats (LTRs) and also contains a \| / packaging signal, a Rev response element (RRE), a central polypurine tract (cPPT) sequence, and an optimized Woodchuck hepatitis virus posttranscriptional regulatory element (WPRE). The leukapheresis material is enriched for CD4 / CD8 T cells by positive immunoselection, activated by CD3 and CD28 agonists and transduced with the vector. Without further cell propagation, the T cells are washed, formulated for infusion, and cryopreserved. Rapcabtagene autoleucel is composed of >80% T cells and <1% B cells, with a mixture of transgene positive (>3.4%) and negative T cells. The CD4+ and CD8+ naive T cell subsets (CD45RA+CCR7+) present in the leukapheresis material are largely retained. In some embodiments, the rapcabtagene autoleucel is made by the ARM manufacturing process described herein.

[0103] In some embodiments, the CD19 CAR-expressing cell population has:

[0104] (a) about the same percentage of naive cells, for example, naive T cells, for example, CD45RA+ CD45RO- CCR7+ T cells, as compared to the percentage of naive cells, for example, naive T cells, for example, CD45RA+ CD45RO- CCR7+ cells, in the same population of cells prior to being engineered to express the CAR;

[0105] (b) a change within about 5% to about 10% of naive cells, for example, naive T cells, for example, CD45RA+ CD45RO- CCR7+ T cells, for example, as compared to the percentage of naive cells, for example, naive T cells, for example, CD45RA+ CD45RO- CCR7+ cells, in the same population of cells prior to being engineered to express the CAR;

[0106] (c) an increased percentage of naive cells, for example, naive T cells, for example, CD45RA+ CD45RO- CCR7+ T cells, for example, increased by at least 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, or 3-fold, as compared to the percentage of naive cells, for example, naive T cells, for example, CD45RA+ CD45RO- CCR7+ cells, in the same population of cells prior to being engineered to express the CAR;

[0107] (d) about the same percentage of central memory cells, for example, central memory T cells, for example, CD45RA- CCR7+ CD45RO+ T cells, as compared to the percentage of PAT059852-PCT-SEC01 central memory cells, for example, central memory T cells, for example, CD45RA- CCR7+ CD45RO+ T cells, in the same population of cells prior to being engineered to express the CAR;

[0108] (e) a change within about 5% to about 10% of central memory cells, for example, central memory T cells, for example, CD45RA- CCR7+ CD45RO+ T cells, as compared to the percentage of central memory cells, for example, central memory T cells, for example, CD45RA- CCR7+ CD45RO+ T cells, in the same population of cells prior to being engineered to express the CAR;

[0109] (f) a decreased percentage of central memory cells, for example, central memory T cells, for example, CD45RA- CCR7+ CD45RO+ T cells, for example, decreased by at least 20, 25, 30, 35, 40, 45, or 50%, as compared to the percentage of central memory cells, for example, central memory T cells, for example, CD45RA- CCR7+ CD45RO+ T cells, in the same population of cells prior to being engineered to express the CAR;

[0110] (g) about the same percentage of stem memory T cells, for example, CD45RA+CD95+IL-2 receptor P+CCR7+CD62L+ T cells, as compared to the percentage of stem memory T cells, for example, CD45RA+CD95+IL-2 receptor P+CCR7+CD62L+ T cells, in the same population of cells prior to being engineered to express the CAR;

[0111] (h) a change within about 5% to about 10% of stem memory T cells, for example, CD45RA+CD95+IL-2 receptor P+CCR7+CD62L+ T cells, as compared to the percentage of stem memory T cells, for example, CD45RA+CD95+IL-2 receptor P+CCR7+CD62L+ T cells, in the same population of cells prior to being engineered to express the CAR; or

[0112] (i) an increased percentage of stem memory T cells, for example, CD45RA+CD95+IL-2 receptor P+CCR7+CD62L+ T cells, as compared to the percentage of stem memory T cells, for example, CD45RA+CD95+IL-2 receptor P+CCR7+CD62L+ T cells, in the same population of cells prior to being engineered to express the CAR.

[0113] In some embodiments, the CD 19 CAR-expressing population of cells made via the ARM process described herein shows a higher percentage of naive cells, for example, naive T cells, for example, CD45RA+ CD45RO- CCR7+ T cells (for example, at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50% higher), compared with cells made by an otherwise similar method which lasts, for example, more than 26 hours (for example, which lasts more than 5, 6, 7, 8, 9, 10, 11, or 12 days) or which involves expanding the population of cells in PAT059852-PCT-SEC01 vitro for, for example, more than 3 days (for example, expanding the population of cells in vitro for 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days).

[0114] In some embodiments, the CD 19 CAR-expressing population of cells made via the ARM process described herein shows a lower percentage of central memory cells, for example, central memory T cells, for example, CD95+ central memory T cells (for example, at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50% lower), compared with cells made by an otherwise similar method which lasts, for example, more than 26 hours (for example, which lasts more than 5, 6, 7, 8, 9, 10, 11, or 12 days) or which involves expanding the population of cells in vitro for, for example, more than 3 days (for example, expanding the population of cells in vitro for 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days).

[0115] In some embodiments, the CD 19 CAR-expressing population of cells made via the ARM process described herein after being administered in vivo, persists longer or expands at a higher level (for example, at least 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% higher), compared with cells made by an otherwise similar method which lasts, for example, more than 26 hours (for example, which lasts more than 5, 6, 7, 8, 9, 10, 11, or 12 days) or which involves expanding the population of cells in vitro for, for example, more than 3 days (for example, expanding the population of cells in vitro for 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days).

[0116] Any known CD 19 CAR, for example, the CD 19 antigen-binding domain of any known CD 19 CAR, in the art can be used in accordance with the present disclosure. Examples include tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel, relmacabtagene autoleucel, CC-97540, AT101, CABA-201, KYV-101, IMPT-514, or MB- CART19.1. Further exemplary CD 19 CARs include CD 19 CARs described herein or an antiCD F CAR described in Xu et al. Blood 123.24(2014):3750-9; Kochenderfer et al. Blood 122.25(2013):4129-39, Cruz et al. Blood 122.17(2013):2965-73, NCT00586391, NCT01087294, NCT02456350, NCT00840853, NCT02659943, NCT02650999, NCT02640209, NCT01747486, NCT02546739, NCT02656147, NCT02772198, NCT00709033, NCT02081937, NCT00924326, NCT02735083, NCT02794246, NCT02746952, NCT01593696, NCT02134262, NCT01853631, NCT02443831, NCT02277522, NCT02348216, NCT02614066, NCT02030834, NCT02624258, NCT02625480, NCT02030847, NCT02644655, NCT02349698, NCT02813837, NCT02050347, NCT01683279, NCT02529813, NCT02537977, NCT02799550, NCT02672501, NCT02819583, PAT059852-PCT-SEC01

[0117] NCT02028455, NCT01840566, NCT01318317, NCT01864889, NCT02706405, NCT01475058, NCT01430390, NCT02146924, NCT02051257, NCT02431988, NCT01815749, NCT02153580, NCT01865617, NCT02208362, NCT02685670, NCT02535364, NCT02631044, NCT02728882, NCT02735291, NCT01860937, NCT02822326, NCT02737085, NCT02465983, NCT02132624, NCT02782351, NCT01493453, NCT02652910, NCT02247609, NCT01029366, NCT01626495, NCT02721407, NCT01044069, NCT00422383, NCT01680991, NCT02794961, or NCT02456207, NCT05338931, NCT05869955, NCT06056921, NCT06106906, NCT06121297, NCT06152172, NCT06189157, NCT05459870, NCT06153095, each of which is incorporated herein by reference in its entirety.

[0118] Methods of Treating

[0119] The present application discloses methods of treating method of treating a subject having idiopathic inflammatory myopathies (IIM), e.g., dermatomyositis (DM), antisynthetase syndrome (ASyS), immune mediated necrotizing myopathy (IMNM) with or without secondary Interstitial Lung Disease (ILD), polymyositis (PM), cancer-associated myositis, overlap myositis and inclusion body myositis (IBM)), the method comprising administering to the subject a population of cells engineered to express a CD 19 CAR (“a population of CD 19 CAR-expressing cells”). In some embodiments, the method further comprises identifying the subject as a responder or a non-responder, and / or one who has achieved remission, based on a measure of one or more of the parameters of efficacy disclosed herein. In some embodiments, the measure of one or more of the parameters disclosed herein is obtained from a sample acquired from the subject. In some embodiments of any of the methods disclosed herein, the subject is evaluated prior to receiving, during, or after receiving, the CD 19 CAR-expressing cell therapy. In some embodiments, the CD 19 CAR-expressing cell therapy is rapcabtag ene autoleucel.

[0120] In some embodiments, the identification of a subject as a responder, non-responder and / or one who has achieved remission, following administration of the CD 19 CAR-expressing cells according to the methods described herein can be determined by evaluating the subject according to clinical criteria. Efficacy may be evaluated, for example, by the Total Improvement Score (US), Muscle Strength Testing - Manual Muscle Testing (MMT-8), Myositis Function Index (FI-3), Myositis Damage Index (MDI), Physician’s Global Assessment (PhGA), Forced Vital Capacity (FVC), Modified Cutaneous Dermatomyositis Disease Area and Severity Index PAT059852-PCT-SEC01

[0121] (CDASI), Extramuscular Assessment - Myositis Disease Activity Assessment Tool (MDAAT), Patient-Reported Outcome Measurement Information System Fatigue Short Form 7a (PROMIS F-SF), Medical Outcome Short Form Health Survey (SF-36), the Health Assessment Questionnaire - Disability Index (HAQ-DI), Patient’s Global Assessment (PGA), Living with Pulmonary Fibrosis (L-PF), and / or laboratory evaluations, such as muscle enzymes. The above criteria are explained in further detail below.

[0122] The International Myositis Assessment and Clinical Studies Group (IMACS) (Disease Activity Core Set Measures (nih.gov)) has developed a standardized clinical response criteria to assess minimal, moderate and major total improvement score (TIS). These six criteria are (1) Physician Global Activity (PhGA) - Visual Analog Scale, (2) Patient Global Activity (PaGA) - Visual Analog Scale, (3) Manual Muscle Testing (MMT-8), (4) HAQ-DI, (5) Muscle Enzymes, and (6) Myositis Disease Activity Assessment Tool (MDAAT) - Visual Analog Scale. The absolute percentage change in each criteria is combined with varying weights to obtain a TIS on a scale of 0-100 which corresponds to the degree of improvement, with higher scores corresponding to a greater degree of improvement. TIS threshold of 20 or higher is defined as minimal improvement, 40 or higher as moderate improvement and 60 or higher as major improvement.

[0123] In some embodiments, administration of CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) to a subject according to the methods described herein results in an improvement according to the TIS endpoint as compared to baseline. In some embodiments, the baseline TIS endpoint of the patient is the TIS endpoint measured prior to the first administration of the CD 19 CAR-expressing cells. In some embodiments, the baseline TIS endpoint of the patient is the first TIS endpoint measured after administration of the CD 19 CAR-expressing cells.

[0124] In some embodiments, the improvement according to TIS score is no further worsening. In some embodiments, the TIS increases from the baseline score. In some embodiments, the TIS score is increased by 5 or more points. In some embodiments, the TIS score is increased by 10 or more points. In some embodiments, the TIS score is increased by 15 or more points. In some embodiments, the TIS score is increased by 20 or more points. In some embodiments, the TIS score is increased by 25 or more points. In some embodiments, the TIS score is increased by 30 or more points. In some embodiments, the TIS score is increased by 35 or more points. In some embodiments, the TIS score is increased by 40 or more points. In some embodiments, the TIS PAT059852-PCT-SEC01 score is increased by 45 or more points. In some embodiments, the TIS score is increased by 50 or more points. In some embodiments, the US score is increased by 55 or more points. In some embodiments, the US score is increased by 60 or more points. In some embodiments, the TIS score is increased by 65 or more points. In some embodiments, the TIS score is increased by 70 or more points. In some embodiments, the US score is increased by 75 or more points. In some embodiments, the US score is increased by 80 or more points. In some embodiments, the TIS score is increased by 85 or more points. In some embodiments, the TIS score is increased by 90 or more points. In some embodiments, the US score is increased by 95 or more points. In some embodiments, the US score is increased by 100 points.

[0125] In some embodiments, a subject is identified as showing improvement as measured by an increase of the TIS score from baseline following administration of the CD 19 CAR-expressing cells (e.g., rapcabtagene autoleucel) to the subject according to the methods described herein. In some embodiments, the increase of the US score is achieved within 3 months of administration. In some embodiments, increase of the TIS score is achieved within 6 months of administration. In some embodiments, the increase of the US score is achieved within 9 months of administration. In some embodiments, the increase of the US score is achieved within 12 months of administration. In some embodiments, the increase of the TIS score is achieved within 18 months of administration. In some embodiments, the increase of the US score is achieved within 24 months of administration.

[0126] In some embodiments, a subject shows an increase of the TIS score of at least 40 points from baseline after no more than 52 weeks. In some embodiments, a subject shows an increase of the TIS score of at least 50 points from baseline after no more than 52 weeks. In some embodiments, a subject shows an increase of the TIS score of at least 60 points from baseline after no more than 52 weeks. In some embodiments, a subject shows an increase of the TIS score of at least 70 points from baseline after no more than 52 weeks. In some embodiments, a subject shows an increase of the US score of at least 80 points from baseline after no more than 52 weeks. In some embodiments, a subject shows an increase of the US score of at least 90 points from baseline after no more than 52 weeks. In some embodiments, a subject shows an increase of the TIS score of at least 100 points from baseline after no more than 52 weeks.

[0127] In some embodiments, the increase of the TIS score from baseline achieved by a subject following administration of the CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) is PAT059852-PCT-SEC01 sustained for 3 months or more. In some embodiments, increase of the TIS score is sustained for 6 months or more. In some embodiments, the increase of the TIS score is sustained for 9 months or more. In some embodiments, the increase of the TIS score is sustained for 12 months or more. In some embodiments, the increase of the US score is sustained for 18 months or more. In some embodiments, the increase of the TIS score is sustained for 24 months or more. In some embodiments, the increase of the TIS score is sustained indefinitely.

[0128] The Myositis Damage Index (MDI) scores damage, which is defined as persistent or permanent change in anatomy, physiology, and function that develops from previously active disease, complications of therapy, or other events. The MDI measures specific manifestations in 11 organ systems and each includes a visual analogue scale (VAS) to quantify damage severity in a given organ system. Each of the 11 organ systems has 3-6 items scored as present or absent. For the VAS, scores for each organ system are determined by measuring the distance the vertical line is from the left-hand side of the horizontal VAS. The length of the VAS should also be measured, so that the score can be adjusted to a denominator of 10 cm. For items in the damage index, the score is 1 point if present, 0 if absent. Higher scores are associated with more severe disease.

[0129] In some embodiments, administration of CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) to a subject according to the methods described herein results in an improvement in MDI as compared to baseline. In some embodiments, the baseline MDI of the patient is the MDI measured prior to the first administration of the CD 19 CAR-expressing cells. In some embodiments, the baseline MDI of the patient is the first MDI measured after administration of the CD 19 CAR-expressing cells.

[0130] I In some embodiments, the improvement according to MDI is no further worsening. In some embodiments, the improvement according to MDI is at least 5% from baseline. In some embodiments, the improvement according to MDI is at least 10% from baseline. In some embodiments, the improvement according to MDI is at least 15% from baseline. In some embodiments, the improvement according to MDI is at least 20% from baseline. In some embodiments, the improvement according to MDI endpoint is at least 25% from baseline. In some embodiments, the improvement according to MDI is at least 30% from baseline. In some embodiments, the improvement according to MDI endpoint is at least 35% from baseline. In some embodiments, the improvement according to MDI is at least 40% from baseline. In some PAT059852-PCT-SEC01 embodiments, the improvement according to MDI is at least 45% from baseline. In some embodiments, the improvement according to MDI is at least 50% from baseline. In some embodiments, the improvement according to MDI is at least 55% from baseline. In some embodiments, the improvement according to the MDI is at least 60% from baseline. In some embodiments, the improvement according to the MDI is at least 65% from baseline. In some embodiments, the improvement according to the MDI is at least 70% from baseline. In some embodiments, the improvement according to the MDI is at least 75% from baseline. In some embodiments, the improvement according to the MDI is at least 80% from baseline. In some embodiments, the improvement according to the MDI is at least 85% from baseline. In some embodiments, the improvement according to the MDI is at least 90% from baseline. In some embodiments, the improvement according to the MDI is at least 95% from baseline. In some embodiments, the improvement according to the MDI is at least 100% from baseline.

[0131] In some embodiments, a subject is identified as improved according to MDI following administration of the CD 19 CAR-expressing cells (e.g., rapcabtagene autoleucel) to the subject according to the methods described herein. In some embodiments, the improvement in MDI is achieved within 3 months of administration. In some embodiments, the improvement in MDI is achieved within 6 months of administration. In some embodiments, the improvement in MDI is achieved within 9 months of administration. In some embodiments, the improvement in MDI is achieved within 12 months of administration. In some embodiments, the improvement in MDI is achieved within 18 months of administration. In some embodiments, the improvement in MDI is achieved within 24 months of administration.

[0132] In some embodiments, the improvement in MDI achieved by a subject following administration of the CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) is sustained for 3 months or more. In some embodiments, the improvement in MDI is sustained for 6 months or more. In some embodiments improvement in MDI is sustained for 9 months or more. In some embodiments, the improvement in MDI is sustained for 12 months or more. In some embodiments, the improvement in MDI is sustained for 18 months or more. In some embodiments, the improvement in MDI is sustained for 24 months or more. In some embodiments, the improvement in MDI is sustained indefinitely.

[0133] Modified CDASI (CDASI ver02) is an instrument designed to capture the extent of cutaneous disease in DM. It is a one-page validated, quantitative outcome measure that has three PAT059852-PCT-SEC01 activities (erythema, scale, and presence of erosion / ulceration) and two damage measures (presence of poikiloderma and / or calcinosis) assessed over 15 anatomical sites. Separately, it also measures three specific areas: Gottron's hands, periungual and alopecia. The total score of the modified CDASI ranges from 0 to 132 and the activity and damage sub-scores range from 0 to 100 and 0 to 32, respectively. (Yassaee et al 2010). The level of disease activity can be interpreted as low, moderate, or high. (Anyanwu et al. 2015).

[0134] In some embodiments, administration of CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) to a subject according to the methods described herein results in an improvement in the CDASI score as compared to baseline. In some embodiments, the baseline CDASI score of the patient is the CDASI score measured prior to the first administration of the CD 19 CAR- expressing cells. In some embodiments, the baseline CDASI score of the patient is the first CDASI score measured after administration of the CD 19 CAR-expressing cells.

[0135] In some embodiments, the improvement in the CDASI score is no further worsening. In some embodiments, the improvement in the CDASI score is a decrease of at least 4 point from baseline. In some embodiments, the improvement in the CDASI score is a decrease of at least 6 points from baseline. In some embodiments, the improvement in the CDASI score is a decrease of at least 8 points from baseline. In some embodiments, the improvement in the CDASI score is a decrease of at least 10 points from baseline. In some embodiments, the improvement in the CDASI score is a decrease of at least 15 points from baseline. In some embodiments, the improvement in the CDASI score is a decrease of at least 20 points from baseline. In some embodiments, the improvement in the CDASI score is a decrease of at least 25 points from baseline. In some embodiments, the improvement in the CDASI score is a decrease of at least 30 points from baseline. In some embodiments, the improvement in the CDASI score is a decrease of at least 35 points from baseline. In some embodiments, the improvement in the CDASI score is a decrease of at least 40 points from baseline. In some embodiments, the improvement in the CDASI score is a decrease of at least 45 points from baseline. In some embodiments, the improvement in the CDASI score is a decrease of at least 50 points from baseline. In some embodiments, the improvement in the CDASI score is a decrease of at least 55 points from baseline. In some embodiments, the improvement in the CDASI score is a decrease of at least 60 points from baseline. In some embodiments, the improvement in the CDASI score is a decrease of at least 65 points from baseline. In some embodiments, the improvement in the CDASI score PAT059852-PCT-SEC01 is a decrease of at least 70 points from baseline. In some embodiments, the improvement in the CDASI score is a decrease of at least 75 points from baseline. In some embodiments, the improvement in the CDASI score is a decrease of at least 80 points from baseline. In some embodiments, the improvement in the CDASI score is a decrease of at least 85 points from baseline. In some embodiments, the improvement in the CDASI score is a decrease of at least 90 points from baseline. In some embodiments, the improvement in the CDASI score is a decrease of at least 95 points from baseline. In some embodiments, the improvement in the CDASI score is a decrease of at least 100 points from baseline. In some embodiments, the improvement in the CDASI score is a decrease of at least 105 points from baseline. In some embodiments, the improvement in the CDASI score is a decrease of at least 110 points from baseline. In some embodiments, the improvement in the CDASI score is a decrease of at least 115 points from baseline. In some embodiments, the improvement in the CDASI score is a decrease of at least 120 points from baseline. In some embodiments, the improvement in the CDASI score is a decrease of at least 125 points from baseline. In some embodiments, the improvement in the CDASI score is a decrease of at least 130 points from baseline.

[0136] In some embodiments, the improvement achieved by a subject results in an overall CDSAI score of below 40 points. In some embodiments, the improvement achieved by a subject results in an overall CDSAI score of below 35 points. In some embodiments, the improvement achieved by a subject results in an overall CDSAI score of below 30 points. In some embodiments, the improvement achieved by a subject results in an overall CDSAI score of below 25 points. In some embodiments, the improvement achieved by a subject results in an overall CDSAI score of below 20 points. In some embodiments, the improvement achieved by a subject results in an overall CDSAI score of below 15 points. In some embodiments, the improvement achieved by a subject results in an overall CDSAI score of below 10 points. In some embodiments, the improvement achieved by a subject results in an overall CDSAI score of below 5 points.

[0137] In some embodiments, a subject is identified as improved according to the CDASI score following administration of the CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) to the subject according to the methods described herein. In some embodiments, the improvement in the CDASI score is achieved within 3 months of administration. In some embodiments, the improvement in the CDASI score is achieved within 6 months of administration. In some PAT059852-PCT-SEC01 embodiments, the improvement in the CDASI score is achieved within 9 months of administration. In some embodiments, the improvement in the CDASI score is achieved within 12 months of administration. In some embodiments, the improvement in the CDASI score is achieved within 18 months of administration. In some embodiments, the improvement in the CDASI score is achieved within 24 months of administration.

[0138] In some embodiments, the improvement in the CDASI score achieved by a subject following administration of the CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) is sustained for 3 months or more. In some embodiments, the improvement in the CDASI score is sustained for 6 months or more. In some embodiments improvement in the CDASI score is sustained for 9 months or more. In some embodiments, the improvement in the CDASI score is sustained for 12 months or more. In some embodiments, the improvement in the CDASI score is sustained for 18 months or more. In some embodiments, the improvement in the CDASI score is sustained for 24 months or more. In some embodiments, the improvement in the CDASI score is sustained indefinitely.

[0139] The Myositis Disease Activity Assessment Tool (MDAAT) assesses disease activity of extra-muscular organ systems and muscle to assess patients with idiopathic inflammatory myositis. This tool measures the blinded assessor's assessment of disease activity using a visual analog scale (VAS) (Isenberg et al 2004, Sultan et al 2008). The tool consists of a 10-cm VAS for each organ system to score the overall severity of activity in each and a global extra-muscular VAS. Scores are derived by measuring the distance the vertical line is from the left-hand side of the horizontal VAS. The length of the VAS should also be measured, so that the score can be adjusted to a denominator of 10 cm.

[0140] In some embodiments, administration of CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) to a subject according to the methods described herein results in an improvement in MDAAT score as compared to baseline. In some embodiments, the baseline MDAAT score of the patient is the MDAAT score measured prior to the first administration of the CD 19 CAR- expressing cells. In some embodiments, the baseline MDAAT score of the patient is the first MDAAT score measured after administration of the CD 19 CAR-expressing cells.

[0141] In some embodiments, the improvement according to MDAAT score is no further worsening. In some embodiments, the improvement according to MDAAT score is at least 5% from baseline. In some embodiments, the improvement according to MDAAT score is at least PAT059852-PCT-SEC01

[0142] 10% from baseline. In some embodiments, the improvement according to MDAAT score is at least 15% from baseline. In some embodiments, the improvement according to MDAAT score is at least 20% from baseline. In some embodiments, the improvement according to MDAAT score endpoint is at least 25% from baseline. In some embodiments, the improvement according to MDAAT score is at least 30% from baseline. In some embodiments, the improvement according to MDAAT score endpoint is at least 35% from baseline. In some embodiments, the improvement according to MDAAT score is at least 40% from baseline. In some embodiments, the improvement according to MDAAT score is at least 45% from baseline. In some embodiments, the improvement according to MDAAT score is at least 50% from baseline. In some embodiments, the improvement according to MDAAT score is at least 55% from baseline. In some embodiments, the improvement according to the MDAAT score is at least 60% from baseline. In some embodiments, the improvement according to the MDAAT score is at least 65% from baseline. In some embodiments, the improvement according to the MDAAT score is at least 70% from baseline. In some embodiments, the improvement according to the MDAAT score is at least 75% from baseline. In some embodiments, the improvement according to the MDAAT score is at least 80% from baseline. In some embodiments, the improvement according to the MDAAT score is at least 85% from baseline. In some embodiments, the improvement according to the MDAAT score is at least 90% from baseline. In some embodiments, the improvement according to the MDAAT score is at least 95% from baseline. In some embodiments, the improvement according to the MDAAT score is at least 100% from baseline.

[0143] In some embodiments, a subject is identified as improved according to MDAAT score following administration of the CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) to the subject according to the methods described herein. In some embodiments, the improvement in MDAAT score is achieved within 3 months of administration. In some embodiments, the improvement in MDAAT score is achieved within 6 months of administration. In some embodiments, the improvement in MDAAT score is achieved within 9 months of administration. In some embodiments, the improvement in MDAAT score is achieved within 12 months of administration. In some embodiments, the improvement in MDAAT score is achieved within 18 months of administration. In some embodiments, the improvement in MDAAT score is achieved within 24 months of administration. PAT059852-PCT-SEC01

[0144] In some embodiments, the improvement in MDAAT score achieved by a subject following administration of the CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) is sustained for 3 months or more. In some embodiments, the improvement in MDAAT score is sustained for 6 months or more. In some embodiments improvement in MDAAT score is sustained for 9 months or more. In some embodiments, the improvement in MDAAT score is sustained for 12 months or more. In some embodiments, the improvement in MDAAT score is sustained for 18 months or more. In some embodiments, the improvement in MDAAT score is sustained for 24 months or more. In some embodiments, the improvement in MDAAT score is sustained indefinitely.

[0145] Manual Muscle Testing (MMT-8) assesses muscle strength using 8 proximal, distal, and axial muscles. The designated proximal and distal muscles will be tested bilaterally using a 0 - 10 point scale for each muscle (potential score 0-140). Axial (neck flexors) will also be tested (potential score 0-10) to arrive at a maximum MMT-8 score of 150. The score for each muscle group is based on the Kendall 10-point scale, with 0-3 indicating severe weakness, 4-6 indicating moderate weakness, and 7-9 indicating mild weakness. A score of 10 means no detectable weakness.

[0146] In some embodiments, administration of CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) to a subject according to the methods described herein results in an improvement in MMT-8 score as compared to baseline. In some embodiments, the baseline MMT-8 score of the patient is the MMT-8 score measured prior to the first administration of the CD19 CAR- expressing cells. In some embodiments, the baseline MMT-8 score of the patient is the first MMT-8 score measured after administration of the CD 19 CAR-expressing cells.

[0147] In some embodiments, the improvement according to MMT-8 score is no further worsening. In some embodiments, the improvement according to MMT-8 score is at least 5% from baseline. In some embodiments, the improvement according to MMT-8 score is at least 10% from baseline. In some embodiments, the improvement according to MMT-8 score is at least 15% from baseline. In some embodiments, the improvement according to MMT-8 score is at least 20% from baseline. In some embodiments, the improvement according to MMT-8 score endpoint is at least 25% from baseline. In some embodiments, the improvement according to MMT-8 score is at least 30% from baseline. In some embodiments, the improvement according to MMT-8 score endpoint is at least 35% from baseline. In some embodiments, the improvement PAT059852-PCT-SEC01 according to MMT-8 score is at least 40% from baseline. In some embodiments, the improvement according to MMT-8 score is at least 45% from baseline. In some embodiments, the improvement according to MMT-8 score is at least 50% from baseline. In some embodiments, the improvement according to MMT-8 score is at least 55% from baseline. In some embodiments, the improvement according to the MMT-8 score is at least 60% from baseline. In some embodiments, the improvement according to the MMT-8 score is at least 65% from baseline. In some embodiments, the improvement according to the MMT-8 score is at least 70% from baseline. In some embodiments, the improvement according to the MMT-8 score is at least 75% from baseline. In some embodiments, the improvement according to the MMT-8 score is at least 80% from baseline. In some embodiments, the improvement according to the MMT-8 score is at least 85% from baseline. In some embodiments, the improvement according to the MMT-8 score is at least 90% from baseline. In some embodiments, the improvement according to the MMT-8 score is at least 95% from baseline. In some embodiments, the improvement according to the MMT-8 score is at least 100% from baseline.

[0148] In some embodiments, a subject is identified as improved according to MMT-8 score following administration of the CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) to the subject according to the methods described herein. In some embodiments, the improvement in MMT-8 score is achieved within 3 months of administration. In some embodiments, the improvement in MMT-8 score is achieved within 6 months of administration. In some embodiments, the improvement in MMT-8 score is achieved within 9 months of administration. In some embodiments, the improvement in MMT-8 score is achieved within 12 months of administration. In some embodiments, the improvement in MMT-8 score is achieved within 18 months of administration. In some embodiments, the improvement in MMT-8 score is achieved within 24 months of administration.

[0149] In some embodiments, the improvement in MMT-8 score achieved by a subject following administration of the CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) is sustained for 3 months or more. In some embodiments, the improvement in MMT-8 score is sustained for 6 months or more. In some embodiments improvement in MMT-8 score is sustained for 9 months or more. In some embodiments, the improvement in MMT-8 score is sustained for 12 months or more. In some embodiments, the improvement in MMT-8 score is sustained for 18 months or PAT059852-PCT-SEC01 more. In some embodiments, the improvement in MMT-8 score is sustained for 24 months or more. In some embodiments, the improvement in MMT-8 score is sustained indefinitely.

[0150] The Myositis Function Index FI-3 (Ernste et al 2021), a performance outcome measure, is a reliable method for the functional assessment of IIM patients for muscle impairment of the major muscle groups in the neck and upper and lower extremities in patients at various stages of disease. Three tasks are performed unilaterally on the dominant side: shoulder flexion, neck flexion and hip flexion and a total score will be calculated. Scoring is based on the number of correctly performed repetitions varying from 0 to 60 repetitions for shoulder flexion, 0 to 60 for hip flexion and 0 to 30 for neck flexion for a total number of repetitions of 150 at the completion of the test which reflects normal muscle endurance. The total score of the FI-3 is then calculated by dividing the total number of repetitions by 3.

[0151] In some embodiments, administration of CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) to a subject according to the methods described herein results in an improvement in FI-3 score as compared to baseline. In some embodiments, the baseline FI-3 score of the patient is the FI-3 score measured prior to the first administration of the CD 19 CAR-expressing cells. In some embodiments, the baseline FI-3 score of the patient is the first FI-3 score measured after administration of the CD 19 CAR-expressing cells.

[0152] In some embodiments, the improvement according to FI-3 score is no further worsening. In some embodiments, the improvement according to FI-3 score is at least 5% from baseline. In some embodiments, the improvement according to FI-3 score is at least 10% from baseline. In some embodiments, the improvement according to FI-3 score is at least 15% from baseline. In some embodiments, the improvement according to FI-3 score is at least 20% from baseline. In some embodiments, the improvement according to FI-3 score endpoint is at least 25% from baseline. In some embodiments, the improvement according to FI-3 score is at least 30% from baseline. In some embodiments, the improvement according to FI-3 score endpoint is at least 35% from baseline. In some embodiments, the improvement according to FI-3 score is at least

[0153] 40% from baseline. In some embodiments, the improvement according to FI-3 score is at least

[0154] 45% from baseline. In some embodiments, the improvement according to FI-3 score is at least

[0155] 50% from baseline. In some embodiments, the improvement according to FI-3 score is at least

[0156] 55% from baseline. In some embodiments, the improvement according to the FI-3 score is at least 60% from baseline. In some embodiments, the improvement according to the FI-3 score is PAT059852-PCT-SEC01 at least 65% from baseline. In some embodiments, the improvement according to the FI-3 score is at least 70% from baseline. In some embodiments, the improvement according to the FI-3 score is at least 75% from baseline. In some embodiments, the improvement according to the FI- 3 score is at least 80% from baseline. In some embodiments, the improvement according to the FI-3 score is at least 85% from baseline. In some embodiments, the improvement according to the FI-3 score is at least 90% from baseline. In some embodiments, the improvement according to the FI-3 score is at least 95% from baseline. In some embodiments, the improvement according to the FI-3 score is at least 100% from baseline.

[0157] In some embodiments, a subject is identified as improved according to FI-3 score following administration of the CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) to the subject according to the methods described herein. In some embodiments, the improvement in FI-3 score is achieved within 3 months of administration. In some embodiments, the improvement in FI-3 score is achieved within 6 months of administration. In some embodiments, the improvement in FI-3 score is achieved within 9 months of administration. In some embodiments, the improvement in FI-3 score is achieved within 12 months of administration. In some embodiments, the improvement in FI-3 score is achieved within 18 months of administration. In some embodiments, the improvement in FI-3 score is achieved within 24 months of administration.

[0158] In some embodiments, the improvement in FI-3 score achieved by a subject following administration of the CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) is sustained for 3 months or more. In some embodiments, the improvement in FI-3 score is sustained for 6 months or more. In some embodiments improvement in FI-3 score is sustained for 9 months or more. In some embodiments, the improvement in FI-3 score is sustained for 12 months or more. In some embodiments, the improvement in FI-3 score is sustained for 18 months or more. In some embodiments, the improvement in FI-3 score is sustained for 24 months or more. In some embodiments, the improvement in FI-3 score is sustained indefinitely.

[0159] The Patient Global Activity Score (PGA) is a patient-reported outcome (PRO) that measures a patient's overall disease activity in idiopathic inflammatory myopathies (IIMs). Patients are typically asked a question similar to “considering all the ways that myositis affects you, please rate the overall activity of your disease today by placing a mark on the line (10 cm visual analog scale)” or “Howe have been feeling in general this past week, in relation to you PAT059852-PCT-SEC01 myositis.” The PGA is then measured on a visual analogue scale ranging from 0-10 cm or 0-100 mm with higher scores representing worse subjective health.

[0160] In some embodiments, administration of CD 19 CAR-expressing cells (e.g., rapcabtagene autoleucel) to a subject according to the methods described herein results in an improvement in PGA score as compared to baseline. In some embodiments, the baseline PGA score of the patient is the PGA score measured prior to the first administration of the CD 19 CAR-expressing cells. In some embodiments, the baseline PGA score of the patient is the first PGA score measured after administration of the CD 19 CAR-expressing cells.

[0161] In some embodiments, the improvement according to PGA score is no further worsening. In some embodiments, the improvement according to PGA score is at least 5% from baseline. In some embodiments, the improvement according to PGA score is at least 10% from baseline. In some embodiments, the improvement according to PGA score is at least 15% from baseline. In some embodiments, the improvement according to PGA score is at least 20% from baseline. In some embodiments, the improvement according to PGA score endpoint is at least 25% from baseline. In some embodiments, the improvement according to PGA score is at least 30% from baseline. In some embodiments, the improvement according to PGA score endpoint is at least 35% from baseline. In some embodiments, the improvement according to PGA score is at least

[0162] 40% from baseline. In some embodiments, the improvement according to PGA score is at least

[0163] 45% from baseline. In some embodiments, the improvement according to PGA score is at least

[0164] 50% from baseline. In some embodiments, the improvement according to PGA score is at least

[0165] 55% from baseline. In some embodiments, the improvement according to the PGA score is at least 60% from baseline. In some embodiments, the improvement according to the PGA score is at least 65% from baseline. In some embodiments, the improvement according to the PGA score is at least 70% from baseline. In some embodiments, the improvement according to the PGA score is at least 75% from baseline. In some embodiments, the improvement according to the PGA score is at least 80% from baseline. In some embodiments, the improvement according to the PGA score is at least 85% from baseline. In some embodiments, the improvement according to the PGA score is at least 90% from baseline. In some embodiments, the improvement according to the PGA score is at least 95% from baseline. In some embodiments, the improvement according to the PGA score is at least 100% from baseline. PAT059852-PCT-SEC01

[0166] In some embodiments, a subject is identified as improved according to PGA score following administration of the CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) to the subject according to the methods described herein. In some embodiments, the improvement in PGA score is achieved within 3 months of administration. In some embodiments, the improvement in PGA score is achieved within 6 months of administration. In some embodiments, the improvement in PGA score is achieved within 9 months of administration. In some embodiments, the improvement in PGA score is achieved within 12 months of administration. In some embodiments, the improvement in PGA score is achieved within 18 months of administration. In some embodiments, the improvement in PGA score is achieved within 24 months of administration.

[0167] In some embodiments, the improvement in PGA score achieved by a subject following administration of the CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) is sustained for 3 months or more. In some embodiments, the improvement in PGA score is sustained for 6 months or more. In some embodiments improvement in PGA score is sustained for 9 months or more. In some embodiments, the improvement in PGA score is sustained for 12 months or more. In some embodiments, the improvement in PGA score is sustained for 18 months or more. In some embodiments, the improvement in PGA score is sustained for 24 months or more. In some embodiments, the improvement in PGA score is sustained indefinitely.

[0168] The Physician Global Activity Score (PhGA) is a patient-reported outcome (PRO) that measures a patient's overall disease activity in idiopathic inflammatory myopathies (IIMs). Patients are typically asked a question similar to “considering all the ways that myositis affects you, please rate the overall activity of your disease today by placing a mark on the line (10 cm visual analog scale)” or “Howe have been feeling in general this past week, in relation to you myositis.” The PhGA is then measured on a visual analogue scale ranging from 0-10 cm or 0- 100 mm with higher scores representing worse subjective health.

[0169] In some embodiments, administration of CD 19 CAR-expressing cells (e.g., rapcabtagene autoleucel) to a subject according to the methods described herein results in an improvement in PhGA score as compared to baseline. In some embodiments, the baseline PhGA score of the patient is the PhGA score measured prior to the first administration of the CD 19 CAR-expressing cells. In some embodiments, the baseline PhGA score of the patient is the first PhGA score measured after administration of the CD 19 CAR-expressing cells. PAT059852-PCT-SEC01

[0170] In some embodiments, the improvement according to PhGA score is no further worsening. In some embodiments, the improvement according to PhGA score is at least 5% from baseline. In some embodiments, the improvement according to PhGA score is at least 10% from baseline. In some embodiments, the improvement according to PhGA score is at least 15% from baseline. In some embodiments, the improvement according to PhGA score is at least 20% from baseline. In some embodiments, the improvement according to PhGA score endpoint is at least 25% from baseline. In some embodiments, the improvement according to PhGA score is at least 30% from baseline. In some embodiments, the improvement according to PhGA score endpoint is at least 35% from baseline. In some embodiments, the improvement according to PhGA score is at least 40% from baseline. In some embodiments, the improvement according to PhGA score is at least 45% from baseline. In some embodiments, the improvement according to PhGA score is at least 50% from baseline. In some embodiments, the improvement according to PhGA score is at least 55% from baseline. In some embodiments, the improvement according to the PhGA score is at least 60% from baseline. In some embodiments, the improvement according to the PhGA score is at least 65% from baseline. In some embodiments, the improvement according to the PhGA score is at least 70% from baseline. In some embodiments, the improvement according to the PhGA score is at least 75% from baseline. In some embodiments, the improvement according to the PhGA score is at least 80% from baseline. In some embodiments, the improvement according to the PhGA score is at least 85% from baseline. In some embodiments, the improvement according to the PhGA score is at least 90% from baseline. In some embodiments, the improvement according to the PhGA score is at least 95% from baseline. In some embodiments, the improvement according to the PhGA score is at least 100% from baseline.

[0171] In some embodiments, a subject is identified as improved according to PhGA score following administration of the CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) to the subject according to the methods described herein. In some embodiments, the improvement in PhGA score is achieved within 3 months of administration. In some embodiments, the improvement in PhGA score is achieved within 6 months of administration. In some embodiments, the improvement in PhGA score is achieved within 9 months of administration. In some embodiments, the improvement in PhGA score is achieved within 12 months of administration. In some embodiments, the improvement in PhGA score is achieved within 18 PAT059852-PCT-SEC01 months of administration. In some embodiments, the improvement in PhGA score is achieved within 24 months of administration.

[0172] In some embodiments, the improvement in PhGA score achieved by a subject following administration of the CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) is sustained for 3 months or more. In some embodiments, the improvement in PhGA score is sustained for 6 months or more. In some embodiments improvement in PhGA score is sustained for 9 months or more. In some embodiments, the improvement in PhGA score is sustained for 12 months or more. In some embodiments, the improvement in PhGA score is sustained for 18 months or more. In some embodiments, the improvement in PhGA score is sustained for 24 months or more, n some embodiments, the improvement in PhGA score is sustained indefinitely.

[0173] Forced vital capacity (FVC) is an important parameter of pulmonary functions and used as a major outcome measure in most of the clinical trials on idiopathic inflammatory myopathy. FVC is the amount of air that can be forcibly exhaled from the lungs after the taking a deep breath. FVC is measured through the use of a spirometer. FVC readings that lower than normal indicate restricted breathing, wherein normal is determined to be equal to or greater than 80% of a reference value (Quanjer et al 2012).

[0174] In some embodiments, administration of CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) to a subject according to the methods described herein results in an improvement in FVC percentage as compared to baseline. In some embodiments, the baseline FVC percentage of the patient is the FVC percentage measured prior to the first administration of the CD 19 CAR- expressing cells. In some embodiments, the baseline FVC percentage of the patient is the first FVC percentage measured after administration of the CD19 CAR-expressing cells.

[0175] In some embodiments, the improvement according to FVC percentage is no further worsening of FVC percentage. In some embodiments, the improvement according to FVC percentage is at least 5% from baseline. In some embodiments, the improvement according to FVC percentage is at least 10% from baseline. In some embodiments, the improvement according to FVC percentage is at least 15% from baseline. In some embodiments, the improvement according to FVC percentage is at least 20% from baseline. In some embodiments, the improvement according to FVC percentage endpoint is at least 25% from baseline. In some embodiments, the improvement according to FVC percentage is at least 30% from baseline. In some embodiments, the improvement according to FVC percentage endpoint is at least 35% PAT059852-PCT-SEC01 from baseline. In some embodiments, the improvement according to FVC percentage is at least 40% from baseline. In some embodiments, the improvement according to FVC percentage is at least 45% from baseline. In some embodiments, the improvement according to FVC percentage is at least 50% from baseline. In some embodiments, the improvement according to FVC percentage is at least 55% from baseline. In some embodiments, the improvement according to the FVC percentage is at least 60% from baseline. In some embodiments, the improvement according to the FVC percentage is at least 65% from baseline. In some embodiments, the improvement according to the FVC percentage is at least 70% from baseline. In some embodiments, the improvement according to the FVC percentage is at least 75% from baseline. In some embodiments, the improvement according to the FVC percentage is at least 80% from baseline. In some embodiments, the improvement according to the FVC percentage is at least 85% from baseline. In some embodiments, the improvement according to the FVC percentage is at least 90% from baseline. In some embodiments, the improvement according to the FVC percentage is at least 95% from baseline. In some embodiments, the improvement according to the FVC percentage is at least 100% from baseline.

[0176] In some embodiments, a subject is identified as improved according to FVC percentage following administration of the CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) to the subject according to the methods described herein. In some embodiments, the improvement in FVC percentage is achieved within 3 months of administration. In some embodiments, the improvement in FVC percentage is achieved within 6 months of administration. In some embodiments, the improvement in FVC percentage is achieved within 9 months of administration. In some embodiments, the improvement in FVC percentage is achieved within 12 months of administration. In some embodiments, the improvement in FVC percentage is achieved within 18 months of administration. In some embodiments, the improvement in FVC percentage is achieved within 24 months of administration.

[0177] In some embodiments, the improvement in FVC percentage achieved by a subject following administration of the CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) is sustained for 3 months or more. In some embodiments, the improvement in FVC percentage is sustained for 6 months or more. In some embodiments improvement in FVC percentage is sustained for 9 months or more. In some embodiments, the improvement in FVC percentage is sustained for 12 months or more. In some embodiments, the improvement in FVC percentage is PAT059852-PCT-SEC01 sustained for 18 months or more. In some embodiments, the improvement in FVC percentage is sustained for 24 months or more, n some embodiments, the improvement in FVC percentage is sustained indefinitely.

[0178] Fatigue is a frequently experienced symptom of IIM, and the Patient-Reported Outcome Measurement Information System® Fatigue Short Form 7a (PROMIS F-SF) is used to assess the study treatment's effect on fatigue. The PROMIS F-SF is a 7-item form with a recall period of the past seven days that assess a range of self-reported symptoms, from mild feelings of tiredness to an overwhelming, debilitating, and sustained sense of exhaustion that likely decreases one’s ability to execute daily activities and function normally in family or social roles (Celia et al 2010). Fatigue is divided into the experience of fatigue (frequency, duration, and intensity) and the impact of fatigue on physical, mental, and social activities. Response options are on a 5-point Likert scale, ranging from 1 = never to 5 = always. One item, “How often did you have enough energy to exercise strenuously,” is reverse scored. The total score is used in the analysis and is obtained by summing keyed scores of all items. Scores can range from 7 to 35, with higher scores indicating greater fatigue.

[0179] In some embodiments, administration of CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) to a subject according to the methods described herein results in an improvement in the PROMIS F-SF score as compared to baseline. In some embodiments, the baseline PROMIS F-SF score of the patient is the PROMIS F-SF score measured prior to the first administration of the CD19 CAR-expressing cells. In some embodiments, the baseline PROMIS F-SF score of the patient is the first PROMIS F-SF score measured after administration of the CD19 CAR- expressing cells.

[0180] In some embodiments, the improvement in the PROMIS F-SF score is no further worsening. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 1 point from baseline. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 2 points from baseline. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 3 points from baseline. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 4 points from baseline. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 5 points from baseline. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 6 points from baseline. In some embodiments, the improvement in the PAT059852-PCT-SEC01

[0181] PROMIS F-SF score is a decrease of at least 7 points from baseline. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 8 points from baseline. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 9 points from baseline. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 10 points from baseline. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 11 points from baseline. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 12 points from baseline. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 13 points from baseline. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 14 points from baseline. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 15 points from baseline. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 16 points from baseline. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 17 points from baseline. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 18 points from baseline. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 19 points from baseline. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 20 points from baseline. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 21 points from baseline. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 22 points from baseline. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 23 points from baseline. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 24 points from baseline. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 25 points from baseline. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 26 points from baseline. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 27 points from baseline. In some embodiments, the improvement in the PROMIS F-SF score is a decrease of at least 28 points from baseline.

[0182] In some embodiments, a subject is identified as improved according to the PROMIS F-SF score following administration of the CD 19 CAR-expressing cells (e.g., rapcabtag ene autoleucel) to the subject according to the methods described herein. In some embodiments, the improvement in the PROMIS F-SF score is achieved within 3 months of administration. In some PAT059852-PCT-SEC01 embodiments, the improvement in the PROMIS F-SF score is achieved within 6 months of administration. In some embodiments, the improvement in the PROMIS F-SF score is achieved within 9 months of administration. In some embodiments, the improvement in the PROMIS F-SF score is achieved within 12 months of administration. In some embodiments, the improvement in the PROMIS F-SF score is achieved within 18 months of administration. In some embodiments, the improvement in the PROMIS F-SF score is achieved within 24 months of administration.

[0183] In some embodiments, the improvement in the PROMIS F-SF score achieved by a subject following administration of the CD 19 CAR-expressing cells (e.g., rapcabtag ene autoleucel) is sustained for 3 months or more. In some embodiments, the improvement in the PROMIS F-SF score is sustained for 6 months or more. In some embodiments improvement in the PROMIS F-SF score is sustained for 9 months or more. In some embodiments, the improvement in the PROMIS F-SF score is sustained for 12 months or more. In some embodiments, the improvement in the PROMIS F-SF score is sustained for 18 months or more. In some embodiments, the improvement in the PROMIS F-SF score is sustained for 24 months or more, n some embodiments, the improvement in the PROMIS F-SF score is sustained indefinitely.

[0184] The 36-Item Short Form Survey (SF-36) is an outcome measure instrument that is often used, well-researched, self-reported measure of health. The SF-36 yields scores for eight scales: Physical Functioning (PF), Role Limitations due to Physical Health (RP), Bodily Pain (BP), General Health (GH), Vitality (VT), Social Functioning (SF), Role Limitations due to Emotional Health (RE), and Mental Health (MH). These scale scores can be combined to produce two component summary scores: the Physical Component Summary (PCS) and the Mental Component Summary (MCS), whose calculation produces a T-score ranging from 0 to 100, with a mean score of 50 and SD of 10, representing the reference score for the US general population. Higher scores indicate better health.

[0185] In some embodiments, a subject is identified as showing improvement as measured by an increase of the SF-36 score from baseline following administration of the CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) to the subject according to the methods described herein. In some embodiments, the baseline SF-36 score of the patient is the SF-36 score measured prior to the first administration of the CD 19 CAR-expressing cells. In some embodiments, the baseline PAT059852-PCT-SEC01

[0186] SF-36 score of the patient is the first SF-36 score measured after administration of the CD 19 CAR-expressing cells.

[0187] In some embodiments, the SF-36 score does not worsen. In some embodiments, the SF- 36 score is increased by 5 or more points. In some embodiments, the SF-36 score is increased by 10 or more points. In some embodiments, the SF-36 score is increased by 15 or more points. In some embodiments, the SF-36 score is increased by 20 or more points. In some embodiments, the SF-36 score is increased by 25 or more points. In some embodiments, the SF-36 score is increased by 30 or more points. In some embodiments, the SF-36 score is increased by 35 or more points. In some embodiments, the SF-36 score is increased by 40 or more points. In some embodiments, the SF-36 score is increased by 45 or more points. In some embodiments, the SF- 36 score is increased by 50 or more points.

[0188] In some embodiments, a subject is identified as showing improvement as measured by an increase of the SF-36 score from baseline following administration of the CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) to the subject according to the methods described herein. In some embodiments, the increase of the SF-36 score is achieved within 3 months of administration. In some embodiments, increase of the SF-36 score is achieved within 6 months of administration. In some embodiments, the increase of the SF-36 score is achieved within 9 months of administration. In some embodiments, the increase of the SF-36 score is achieved within 12 months of administration. In some embodiments, the increase of the SF-36 score is achieved within 18 months of administration. In some embodiments, the increase of the SF- 36score is achieved within 24 months of administration.

[0189] In some embodiments, the increase of the SF-36 score from baseline achieved by a subject following administration of the CD 19 CAR-expressing cells (e.g., rapcabtagene autoleucel) is sustained for 3 months or more. In some embodiments, increase of the SF-36 score is sustained for 6 months or more. In some embodiments, the increase of the SF-36 score is sustained for 9 months or more. In some embodiments, the increase of the SF-36 score is sustained for 12 months or more. In some embodiments, the increase of the SF-36 score is sustained for 18 months or more. In some embodiments, the increase of the SF-36 score is sustained for 24 months or more. In some embodiments, the increase of the SF-36 score is sustained indefinitely. PAT059852-PCT-SEC01

[0190] The Health Assessment Questionnaire - Disability Index (HAQ-DI) consists of 20 questions referring to eight component domains related to measuring difficulty in performing daily activities: dressing / grooming, arising, eating, walking, hygiene, reach, grip, and activities (Cole et al 2006). Each question is rated on a 0-3 scale, where 0 indicates “without difficulty” and 3 indicates “unable to do,” and additional points can be added if aids or devices are needed for specific activities. The highest score reported by the participant for any component question of the eight categories determines the score for that category. The eight scores from the eight sections are summed and divided by 8 with the total score indicates the patient’s self-assessed level of disability. A score below 0.5 is considered normal whereas a score above 1.5 indicates severe disability. A negative change from baseline indicates improvement.

[0191] In some embodiments, administration of CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) to a subject according to the methods described herein results in an improvement in the HAQ-DI score as compared to baseline. In some embodiments, the baseline HAQ-DI score of the patient is the HAQ-DI score measured prior to the first administration of the CD 19 CAR- expressing cells. In some embodiments, the baseline HAQ-DI score of the patient is the first HAQ-DI score measured after administration of the CD 19 CAR-expressing cells.

[0192] In some embodiments, the HAQ-DI score does not further worsen. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 0.2 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 0.25 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 0.3 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 0.35 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 0.4 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 0.45 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 0.5 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 0.55 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 0.6 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 0.65 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 0.7 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least PAT059852-PCT-SEC01

[0193] 0.75 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 0.8 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 0.85 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 0.9 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 1.0 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least

[0194] 1.1 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 1.15 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 1.2 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 1.25 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 1.3 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 1.35 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 1.4 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 1.45 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 1.5 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 1.55 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 1.6 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 1.65 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 1.7 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 1.75 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 1.8 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 1.85 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 1.9 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 2.0 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 2.1 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 2.15 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least

[0195] 2.2 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a PAT059852-PCT-SEC01 decrease of at least 2.25 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 2.3 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 2.35 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 2.4 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 2.45 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 2.5 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 2.55 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 2.6 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 2.65 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 2.7 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 2.75 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 2.8 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 2.85 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 2.9 points from baseline. In some embodiments, the improvement in the HAQ-DI score is a decrease of at least 3.0 points from baseline.

[0196] In some embodiments, a subject is identified as improved according to the HAQ-DI score following administration of the CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) to the subject according to the methods described herein. In some embodiments, the improvement in the HAQ-DI score is achieved within 3 months of administration. In some embodiments, the improvement in the HAQ-DI score is achieved within 6 months of administration. In some embodiments, the improvement in the HAQ-DI score is achieved within 9 months of administration. In some embodiments, the improvement in the HAQ-DI score is achieved within 12 months of administration. In some embodiments, the improvement in the HAQ-DI score is achieved within 18 months of administration. In some embodiments, the improvement in the HAQ-DI score is achieved within 24 months of administration.

[0197] In some embodiments, the improvement in the HAQ-DI score achieved by a subject following administration of the CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) is sustained for 3 months or more. In some embodiments, the improvement in the HAQ-DI score is PAT059852-PCT-SEC01 sustained for 6 months or more. In some embodiments improvement in the HAQ-DI score is sustained for 9 months or more. In some embodiments, the improvement in the HAQ-DI score is sustained for 12 months or more. In some embodiments, the improvement in the HAQ-DI score is sustained for 18 months or more. In some embodiments, the improvement in the HAQ-DI score is sustained for 24 months or more, n some embodiments, the improvement in the HAQ-DI score is sustained indefinitely.

[0198] The Living with Pulmonary Fibrosis (L-PF) questionnaire is a 44-item questionnaire with two modules: Symptoms (23 items) and Impacts (21 items) intended for use in patients with all forms of progressive fibrosing ILD. The Symptoms module assesses shortness of breath, cough and fatigue in the past 24 hours. The Impacts module assesses multiple aspects of HRQoL with a recall period of 1 week. Items in both modules have response options on a five-option numeric rating score with an anchor of 0 “Not at all” to 4 “Extremely”. Domain and total scores range from 0 to 100, with higher scores indicating greater impairment (Swigris et al 2022).

[0199] In some embodiments, administration of CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) to a subject according to the methods described herein results in an improvement in the L-PF score as compared to baseline. In some embodiments, the baseline L-PF score of the patient is the L-PF score measured prior to the first administration of the CD 19 CAR-expressing cells. In some embodiments, the baseline L-PF score of the patient is the first L-PF score measured after administration of the CD 19 CAR-expressing cells.

[0200] In some embodiments, the L-PF score does not further worsen. In some embodiments, the improvement in the L-PF score is a decrease of at least 5 points from baseline. In some embodiments, the improvement in the L-PF score is a decrease of at least 10 points from baseline. In some embodiments, the improvement in the L-PF score is a decrease of at least 15 points from baseline. In some embodiments, the improvement in the L-PF score is a decrease of at least 20 points from baseline. In some embodiments, the improvement in the L-PF score is a decrease of at least 25 points from baseline. In some embodiments, the improvement in the L-PF score is a decrease of at least 30 points from baseline. In some embodiments, the improvement in the L-PF score is a decrease of at least 35 points from baseline. In some embodiments, the improvement in the L-PF score is a decrease of at least 40 points from baseline. In some embodiments, the improvement in the L-PF score is a decrease of at least 45 points from baseline. In some embodiments, the improvement in the L-PF score is a decrease of at least 50 PAT059852-PCT-SEC01 points from baseline. In some embodiments, the improvement in the L-PF score is a decrease of at least 55 points from baseline. In some embodiments, the improvement in the L-PF score is a decrease of at least 60 points from baseline. In some embodiments, the improvement in the L-PF score is a decrease of at least 65 points from baseline. In some embodiments, the improvement in the L-PF score is a decrease of at least 70 points from baseline. In some embodiments, the improvement in the L-PF score is a decrease of at least 75 points from baseline. In some embodiments, the improvement in the L-PF score is a decrease of at least 80 points from baseline. In some embodiments, the improvement in the L-PF score is a decrease of at least 85 points from baseline. In some embodiments, the improvement in the L-PF score is a decrease of at least 90 points from baseline. In some embodiments, the improvement in the L-PF score is a decrease of at least 95 points from baseline. In some embodiments, the improvement in the L-PF score is a decrease of 100 points from baseline.

[0201] In some embodiments, a subject is identified as improved according to the L-PF score following administration of the CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) to the subject according to the methods described herein. In some embodiments, the improvement in the L-PF score is achieved within 3 months of administration. In some embodiments, the improvement in the L-PF score is achieved within 6 months of administration. In some embodiments, the improvement in the L-PF score is achieved within 9 months of administration. In some embodiments, the improvement in the L-PF score is achieved within 12 months of administration.

[0202] In some embodiments, the improvement in the L-PF score achieved by a subject following administration of the CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) is sustained for 3 months or more. In some embodiments, the improvement in the L-PF score is sustained for 6 months or more. In some embodiments improvement in the L-PF score is sustained for 9 months or more. In some embodiments, the improvement in the L-PF score is sustained for 12 months or more. In some embodiments, the improvement in the L-PF score is sustained for 18 months or more. In some embodiments, the improvement in the L-PF score is sustained for 24 months or more, n some embodiments, the improvement in the L-PF score is sustained indefinitely.

[0203] Muscle enzymes are elevated in patients with idiopathic inflammatory myopathies. The most often tested muscle enzymes are creatine phosphokinase (CK), lactate dehydrogenase (LD), PAT059852-PCT-SEC01 aspartate transaminase (AST) and alanine transaminase (ALT), and aldolase. A reduction in these muscle enzymes is associated with clinically significant improvement.

[0204] In some embodiments, administration of CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) to a subject according to the methods described herein results in a reduction in muscle enzyme levels as compared to baseline. In some embodiments, the baseline muscle enzyme level of the patient is the muscle enzymes measured prior to the first administration of the CD 19 CAR-expressing cells. In some embodiments, the baseline muscle enzyme level of the patient is the first muscle enzyme level measured after administration of the CD 19 CAR- expressing cells.

[0205] In some embodiments, improvement based on a reduction in muscle enzyme levels relative to baseline is determined by reference by at least one of the following measures: CK level, LD level, AST level, ALT level, or aldolase. In some embodiments, improvement based on a reduction in muscle enzyme levels relative to baseline is determined by reference by at least two of the following measures: CK level, LD level, AST level, ALT level, or aldolase. In some embodiments, improvement based on a reduction in muscle enzyme levels relative to baseline is determined by reference by at least three of the following measures: CK level, LD level, AST level, ALT level, or aldolase. In some embodiments, improvement based on a reduction in muscle enzyme levels relative to baseline is determined by reference by at least four of the following measures: CK level, LD level, AST level, ALT level, or aldolase. In some embodiments, improvement based on a reduction in muscle enzyme levels relative to baseline is determined by reference to all five of the following measures: CK level, LD level, AST level, ALT level, or aldolase.

[0206] In some embodiments, the CK level, LD level, AST level, ALT level, or aldolase level of the subject is reduced following administration of the CD 19 CAR-expressing cells (e.g., rapcabtagene autoleucel) according to the methods described herein. In some embodiments, the CK level, LD level, AST level, ALT level, or aldolase level is reduced are reduced from elevated at baseline to a normal range. In some embodiments, the CK level, LD level, AST level, ALT level, or aldolase level is reduced by at least 5% from baseline. In some embodiments, the CK level, LD level, AST level, ALT level, or aldolase level is reduced by at least 10% from baseline. In some embodiments, the CK level, LD level, AST level, ALT level, or aldolase level is reduced by at least 15% from baseline. In some embodiments, the CK level, LD level, AST PAT059852-PCT-SEC01 level, ALT level, or aldolase level is reduced by at least 20% from baseline. In some embodiments, the CK level, LD level, AST level, ALT level, or aldolase level is reduced by at least 25% from baseline. In some embodiments, the CK level, LD level, AST level, ALT level, or aldolase level is reduced by at least 30% from baseline. In some embodiments, the CK level, LD level, AST level, ALT level, or aldolase level is reduced by at least 35% from baseline. In some embodiments, the CK level, LD level, AST level, ALT level, or aldolase level is reduced by at least 40% from baseline. In some embodiments, the CK level, LD level, AST level, ALT level, or aldolase level is reduced by at least 45% from baseline. In some embodiments, the CK level, LD level, AST level, ALT level, or aldolase level is reduced by at least 50% from baseline. In some embodiments, the CK level, LD level, AST level, ALT level, or aldolase level is reduced by at least 55% from baseline. In some embodiments, the CK level, LD level, AST level, ALT level, or aldolase level is reduced by at least 60% from baseline. In some embodiments, the CK level, LD level, AST level, ALT level, or aldolase level is reduced by at least 65% from baseline. In some embodiments, the CK level, LD level, AST level, ALT level, or aldolase level is reduced by at least 70% from baseline. In some embodiments, the CK level, LD level, AST level, ALT level, or aldolase level is reduced by at least 75% from baseline. In some embodiments, the CK level, LD level, AST level, ALT level, or aldolase level is reduced by at least 80% from baseline. In some embodiments, the CK level, LD level, AST level, ALT level, or aldolase level is reduced by at least 85% from baseline. In some embodiments, the CK level, LD level, AST level, ALT level, or aldolase level is reduced by at least 90% from baseline. In some embodiments, the CK level, LD level, AST level, ALT level, or aldolase level is reduced by at least 95% from baseline. In some embodiments, the CK level, LD level, AST level, ALT level, or aldolase level is reduced by at least 100% from baseline.

[0207] In some embodiments, a subject is identified as improved according to a reduction in muscle enzyme levels following administration of the CD 19 CAR-expressing cells (e.g., rapcabtag ene autoleucel) to the subject according to the methods described herein. In some embodiments, the reduction in muscle enzyme levels is achieved within 3 months of administration. In some embodiments, the reduction in muscle enzyme levels is achieved within 6 months of administration. In some embodiments, the reduction in muscle enzyme levels is achieved within 9 months of administration. In some embodiments, the reduction in muscle enzyme levels is achieved within 12 months of administration. In some embodiments, the PAT059852-PCT-SEC01 reduction in muscle enzyme levels is achieved within 18 months of administration. In some embodiments, the reduction in muscle enzyme levels is achieved within 24 months of administration.

[0208] In some embodiments, the reduction in muscle enzyme levels achieved by a subject following administration of the CD19 CAR-expressing cells (e.g., rapcabtagene autoleucel) is sustained for 3 months or more. In some embodiments, the reduction in muscle enzyme levels is sustained for 6 months or more. In some embodiments reduction in muscle enzyme levels is sustained for 9 months or more. In some embodiments, the reduction in muscle enzyme levels is sustained for 12 months or more. In some embodiments, the reduction in muscle enzyme levels is sustained for 18 months or more. In some embodiments, the reduction in muscle enzyme levels is sustained for 24 months or more, n some embodiments, the reduction in muscle enzyme levels is sustained indefinitely.

[0209] Dosage regimen

[0210] In some embodiments, a dose of viable CD 19 CAR-expressing cells comprises about 0.5 x 106viable CAR-expressing cells to about 1.25 x 109viable CAR-expressing cells (for example, 0.5 x 106viable CAR-expressing cells to 1.25 x 109viable CAR-expressing cells). In some embodiments, a dose of viable CAR-expressing cells comprises about 1 x 106, about 2.5 x 106, about 5 x 106, about 1.25 x 107, about 2.5 x 107, about 5 x 107, about 5.75 x 107, or about 8 x 107viable CAR-expressing cells. In some embodiments, a dose of viable CAR-expressing cells comprises about 0.5 x 106to 90 x 106viable CAR-expressing cells. In some embodiments, a dose of viable CAR-expressing cells comprises about 5 x 106viable CAR-expressing cells. In some embodiments, a dose of viable CAR-expressing cells comprises about 2.5 x 106to 2.5 x 108viable CAR-expressing cells. In some embodiments, a dose of viable CAR-expressing cells comprises about 1.25 x 107viable CAR-expressing cells. In some embodiments, a dose of viable CAR-expressing cells comprises about 1.25 x 107to 1.25 x 109viable CAR-expressing cells. In some embodiments, a dose of viable CAR-expressing cells comprises about 1.25 x 108viable CAR-expressing cells. In some embodiments, a dose of viable CAR-expressing cells comprises about 2.5 x 106to 2.5 x 108viable CAR-expressing cells. In some embodiments, a dose of viable CAR-expressing cells comprises about 1 x 107or 5 x 107viable CAR-expressing cells. In some embodiments, the viable CD 19 CAR-expressing cells are rapcabtagene autoleucel. PAT059852-PCT-SEC01

[0211] In some embodiments, a dose of CAR-expressing cells comprises about 1 x 106, 1.1 x

[0212] 106, 2 x 106, 3.6 x 106, 5 x 106, 1 x 107, 1.8 x 107, 2 x 107, 5 x 107, 1 x 108, 2 x 108, or 5 x 108cells / kg. In some embodiments, a dose of CAR-expressing cells comprises at least about 1 x 106, 1.1 x 106, 2 x 106, 3.6 x 106, 5 x 106, 1 x 107, 1.8 x 107, 2 x 107, 5 x 107, 1 x 108, 2 x 108, or 5 x 108cells / kg. In some embodiments, a dose of CD 19 CAR-expressing cells up to about 1 x 106, 1.1 x 106, 2 x 106, 3.6 x 106, 5 x 106, 1 x 107, 1.8 x 107, 2 x 107, 5 x 107, 1 x 108, 2 x 108, or 5 x 108cells / kg. In some embodiments, a dose of CD 19 CAR-expressing cells comprises about 1.1 X 106- 1.8 X 107cells / kg. In some embodiments, a dose of CD 19 CAR-expressing cells comprises about 1 x 107, 2 x 107, 5 x 107, 1 x 108, 2 x 108, 5 x 108, 1 x 109, 2 x 109, or 5 x 109cells. In some embodiments, a dose of CD 19 CAR-expressing cells comprises at least about 1 x

[0213] 107, 2 x 107, 5 x 107, 1 x 108, 2 x 108, 5 x 108, 1 x 109, 2 x 109, or 5 x 109cells. In some embodiments, a dose of CD 19 CAR expressing cells comprises up to about 1 x 107, 2 x l07, 5 x 107, 1 x 108, 2 x 108, 5 x 108, 1 x 109, 2 x 109, or 5 x 109cells. In some embodiments, the CD 19 CAR-expressing cells are rapcabtagene autoleucel.

[0214] The level of CAR-positive cells can be determined according to the methods disclosed in Example 8 of WO / 2021 / 173985. Briefly, for CAR T cells manufactured using a continuous Activated Rapid Manufacturing (ARM) process, e.g., ARM-CD19 CAR T cells, a sentinel vial of cryopreserved cells may be thawed and cultured for up to 5 days and the CAR expression analyzed by flow cytometry. The measurement of CAR expression on, e.g., day 2 or day 3 may be used to determine the dose of viable CAR-positive T cells.

[0215] In some embodiments, the disclosure provides a method of treating a patient, e.g., a patient having idiopathic inflammatory myopathies (IIM), e.g., dermatomyositis (DM), antisynthetase syndrome (ASyS), immune mediated necrotizing myopathy (IMNM) with or without secondary Interstitial Lung Disease (ILD), polymyositis (PM), cancer-associated myositis, overlap myositis and inclusion body myositis (IBM)), comprising administering to said patient CAR-expressing cells produced as described herein, at a dose of viable CAR-expressing or CAR-positive cells (for example, viable CD 19 CAR-expressing cells, viable CD 19 CARpositive cells, or any dual CARs thereof) from about 0.5 x 106viable CAR-expressing or CARpositive cells to about 50 x 106viable CAR-expressing or CAR-positive cells (for example, from about 0.5 x 106viable CD 19 CAR-expressing or CAR-positive cells to about 90 x 106viable PAT059852-PCT-SEC01

[0216] CD 19 CAR-expressing or CAR-positive cells), e.g. at a dose of viable CAR-expressing or CARpositive cells (for example, viable CD 19 CAR-expressing cells or viable CD 19 CAR-positive cells) from about 2 x 106viable CAR-expressing or CAR-positive cells to about 40 x 106viable CAR-expressing or CAR-positive cells.

[0217] In some embodiments, the disclosure provides a method of treating a patient, e.g., a patient having idiopathic inflammatory myopathies (IIM), e.g., dermatomyositis (DM), antisynthetase syndrome (ASyS), immune mediated necrotizing myopathy (IMNM) with or without secondary Interstitial Lung Disease (ILD), polymyositis (PM), cancer-associated myositis, overlap myositis and inclusion body myositis (IBM)), comprising administering to said patient CAR-expressing or CAR-positive cells produced as described herein, at a dose of viable CAR-expressing or CAR-positive cells from about 0.5 x 106viable CAR-expressing or CARpositive cells to about 50 x 106viable CAR-expressing or CAR-positive cells (for example, from about 0.5 x 106viable CD 19 CAR-expressing or CAR-positive cells to about 50 x 106viable CD 19 CAR-expressing or CAR-positive cells).

[0218] In some embodiments, the disclosure provides a method of treating a patient, e.g., a patient having idiopathic inflammatory myopathies (IIM), e.g., dermatomyositis (DM), antisynthetase syndrome (ASyS), immune mediated necrotizing myopathy (IMNM) with or without secondary Interstitial Lung Disease (ILD), polymyositis (PM), cancer-associated myositis, overlap myositis and inclusion body myositis (IBM)), comprising administering to said patient CAR-expressing or CAR-positive cells produced as described herein, at a dose of from about 2.5 x 106viable CD 19 CAR-expressing or CAR-positive cells to about 40 x 106viable CD 19 CAR-expressing or CAR-positive cells.

[0219] In some embodiments, the disclosure provides a method of treating a patient, e.g., a patient having idiopathic inflammatory myopathies (IIM), e.g., dermatomyositis (DM), antisynthetase syndrome (ASyS), immune mediated necrotizing myopathy (IMNM) with or without secondary Interstitial Lung Disease (ILD), polymyositis (PM), cancer-associated myositis, overlap myositis and inclusion body myositis (IBM)), comprising administering to said patient CAR-expressing or CAR-positive cells produced as described herein, at a dose of from about 5 x 106viable CD 19 CAR-expressing or CAR-positive cells to about 12.5 x 106viable CD 19 CAR-expressing or CAR-positive cells. PAT059852-PCT-SEC01

[0220] In some embodiments, the disclosure provides a method of treating a patient, e.g., a patient having idiopathic inflammatory myopathies (IIM), e.g., dermatomyositis (DM), antisynthetase syndrome (ASyS), immune mediated necrotizing myopathy (IMNM) with or without secondary Interstitial Lung Disease (ILD), polymyositis (PM), cancer-associated myositis, overlap myositis and inclusion body myositis (IBM)), comprising administering to said patient CAR-expressing or CAR-positive cells produced as described herein, at a dose of from about 25 x 106viable CD 19 CAR-expressing or CAR-positive cells to about 40 x 106viable CD 19 CAR-expressing or CAR-positive cells.

[0221] Patient selection

[0222] In some embodiments of any of the methods of treating a subject, or composition for use disclosed herein, the subject has idiopathic inflammatory myopathies (IIM), e.g., dermatomyositis (DM), antisynthetase syndrome (ASyS), immune mediated necrotizing myopathy (IMNM) with or without secondary Interstitial Lung Disease (ILD), polymyositis (PM), cancer-associated myositis, overlap myositis and inclusion body myositis (IBM)). In some embodiments, the subject having IMM has previously been administered one or more of mycophenolic acid or its derivatives, methotrexate, azathioprine, cyclophosphamide, repository corticotropin injection, tocilizumab, nintedanib, rituximab, abatacept, cyclosporine, tacrolimus, subcutaneous immunoglobulin (SCIG), or intravenous immunoglobulins (IVIG). In some embodiments, the subject has been identified as not responding to treatment comprising two or more immunosuppressive therapies (e.g., mycophenolate or cyclophosphamide) in combination with a glucocorticoid) and one biological agent. In some embodiments, the subject has not previously received a therapy comprising a CD 19 CAR, an adoptive T cell therapy, or a gene therapy product.

[0223] In some embodiments, prior to administration of the CD 19 CAR therapy, the subject receives lymphodepleting therapy. In some embodiments, the subject receives a lympodepleting therapy about two weeks prior to administration of the CD 19 CAR. In some embodiments, the lympodepleting therapy comprises fludarabine (e.g., 25 mg / m2IV daily for three doses) and cyclophosphamide (e.g., 250 mg / m2IV daily for three doses). In some embodiments, the CD 19 CAR therapy is rapcabtagene autoleucel. PAT059852-PCT-SEC01

[0224] Evaluating CAR Safety

[0225] In some embodiments of any of the therapeutic methods disclosed herein, the method further involves evaluating the safety of the CAR-expressing cell therapy in a subject. In some embodiments, safety of the CAR-expressing cell therapy is evaluated by measuring or recording one or more of a subject’s vital signs, adverse events experienced by the subject, various laboratory parameters, and / or an electrocardiogram of the subject.

[0226] In some embodiments, the subject does not experience an adverse event of grade 4 or higher. In some embodiments, the subject does not experience cytokine release syndrome (CRS). In some embodiments, the subject does not experience CRS of grade 3 or higher. In some embodiments, the subject does not experience immune effector cell-associated neurotoxicity syndrome (ICANS).

[0227] Methods of Manufacturing

[0228] Provided herein are methods of manufacturing immune effector cells (for example, T cells or NK cells) engineered to express a CAR, for example, a CAR described herein, compositions comprising such cells, and methods of using such cells for treating a disease, such as systemic sclerosis (e.g., limited cutaneous systemic sclerosis, diffuse cutaneous systemic sclerosis, rapidly progressing systemic sclerosis (IMM) with significant lung involvement, severe refractory systemic sclerosis), in a subject. In some embodiments, the methods disclosed herein may manufacture immune effector cells engineered to express a CAR in less than 24 hours. Without wishing to be bound by theory, the methods provided herein preserve the undifferentiated phenotype of T cells, such as naive T cells, during the manufacturing process. These CAR-expressing cells with an undifferentiated phenotype may persist longer and / or expand better in vivo after infusion. In some embodiments, CART cells produced by the manufacturing methods provided herein comprise a higher percentage of stem cell memory T cells, compared to CART cells produced by the traditional manufacturing process, e.g., as measured using scRNA-seq. (FIG. 2). In some embodiments, CART cells produced by the manufacturing methods provided herein comprise a higher percentage of effector T cells, compared to CART cells produced by the traditional manufacturing process, e.g., as measured using scRNA-seq. (FIG. 2). In some embodiments, CART cells produced by the manufacturing methods provided herein better preserve the sternness of T cells, compared to CART cells produced by the traditional manufacturing process. (FIG. 2). In some embodiments, CART cells PAT059852-PCT-SEC01 produced by the manufacturing methods provided herein show a lower level of hypoxia, compared to CART cells produced by the traditional manufacturing process, e.g., as measured using scRNA-seq. (FIG. 2). In some embodiments, CART cells produced by the manufacturing methods provided herein show a lower level of autophagy, compared to CART cells produced by the traditional manufacturing process. (FIG. 2).

[0229] In some embodiments, the CART cells manufactured by the methods disclosed herein may be administered to a subject with minimal ex vivo expansion, for example, less than 1 day, less than 12 hours, less than 8 hours, less than 6 hours, less than 4 hours, less than 3 hours, less than 2 hours, less than 1 hour, or no ex vivo expansion. Accordingly, the methods described herein provide a fast manufacturing process of making improved CAR-expressing cell products for use in treating a disease in a subject.

[0230] In some embodiments, the present disclosure provides methods of making a population of cells (for example, T cells) that express a chimeric antigen receptor (CAR) comprising: (i) contacting a population of cells (for example, T cells, for example, T cells isolated from a frozen or fresh leukapheresis product from a subject having systemic sclerosis (e.g., limited cutaneous systemic sclerosis, diffuse cutaneous systemic sclerosis, rapidly progressing systemic sclerosis (IMM) with significant lung involvement, severe refractory systemic sclerosis) with (A) an agent that stimulates a CD3 / TCR complex and / or (B) an agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells; (ii) contacting the population of cells (for example, T cells) with a nucleic acid molecule (for example, a DNA or RNA molecule) encoding the CAR, thereby providing a population of cells (for example, T cells) comprising the nucleic acid molecule, and (iii) harvesting the population of cells (for example, T cells) for storage (for example, reformulating the population of cells in cryopreservation media) or administration, wherein: (a) step (ii) is performed together with step (i) or no later than 20 hours after the beginning of step (i), for example, no later than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 hours after the beginning of step (i), for example, no later than 18 hours after the beginning of step (i), and step (iii) is performed no later than 26 hours after the beginning of step (i), for example, no later than 22, 23, or 24 hours after the beginning of step (i), for example, no later than 24 hours after the beginning of step (i); (b) step (ii) is performed together with step (i) or no later than 20 hours after the beginning of step (i), for example, no later than 12, 13, 14, 15, 16, 17, or 18 hours after the beginning of step (i), for example, no later than 18 hours after PAT059852-PCT-SEC01 the beginning of step (i), and step (iii) is performed no later than 30, 36, or 48 hours after the beginning of step (ii), for example, no later than 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 hours after the beginning of step (ii); or (c) the population of cells from step (iii) are not expanded, or expanded by no more than 5, 10, 15, 20, 25, 30, 35, or 40%, for example, no more than 10%, for example, as assessed by the number of living cells, compared to the population of cells at the beginning of step (i).

[0231] In some embodiments, the nucleic acid molecule in step (ii) is a DNA molecule. In some embodiments, the nucleic acid molecule in step (ii) is an RNA molecule. In some embodiments, the nucleic acid molecule in step (ii) is on a viral vector, for example, a viral vector chosen from a lentivirus vector, an adenoviral vector, or a retrovirus vector. In some embodiments, the nucleic acid molecule in step (ii) is on a non-viral vector. In some embodiments, the nucleic acid molecule in step (ii) is on a plasmid. In some embodiments, the nucleic acid molecule in step (ii) is not on any vector. In some embodiments, step (ii) comprises transducing the population of cells (for example, T cells) a viral vector comprising a nucleic acid molecule encoding the CAR.

[0232] In some embodiments, the population of cells (for example, T cells) is collected from an apheresis sample (for example, a leukapheresis sample) from a subject having systemic sclerosis (e.g., limited cutaneous systemic sclerosis, diffuse cutaneous systemic sclerosis, rapidly progressing systemic sclerosis (IMM) with significant lung involvement, severe refractory systemic sclerosis).

[0233] In some embodiments, the apheresis sample (for example, a leukapheresis sample) is collected from the subject and shipped as a fresh product or a frozen sample (for example, a cryopreserved sample) to a cell manufacturing facility. Then the T cells (for example, CD4+ T cells and / or CD8+ T cells) are selected from the apheresis sample, for example, using a cell sorting machine (for example, a CliniMACS® Prodigy® device). The selected T cells (for example, CD4+ T cells and / or CD8+ T cells) are then seeded for CART manufacturing using the process described herein. In some embodiments, the selected T cells (for example, CD4+ T cells and / or CD8+ T cells) undergo one or more rounds of freeze-thaw before being seeded for CART manufacturing.

[0234] In some embodiments, cells (for example, T cells) are contacted with anti-CD3 and anti- CD28 antibodies for, for example, 12 hours, followed by transduction with a vector (for example, a lentiviral vector) encoding a CAR. 24 hours after culture initiation, the cells are PAT059852-PCT-SEC01 washed and formulated for storage or administration. Without wishing to be bound by theory, brief CD3 and CD28 stimulation may promote efficient transduction of self-renewing T cells. Compared to traditional CART manufacturing approaches, the activation process provided herein does not involve prolonged ex vivo expansion. (FIG. 2). Similar to the cytokine process, the activation process provided herein also preserves undifferentiated T cells during CART manufacturing.

[0235] In some embodiments, the population of cells is contacted with (A) an agent that stimulates a CD3 / TCR complex and / or (B) an agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells. In some embodiments, the agent that stimulates a CD3 / TCR complex is an agent that stimulates CD3. In some embodiments, the agent that stimulates a costimulatory molecule and / or growth factor receptor is an agent that stimulates CD28, ICOS, CD27, HVEM, LIGHT, CD40, 4-1BB, 0X40, DR3, GITR, CD30, HM1 , CD2, CD226, or any combination thereof. In some embodiments, the agent that stimulates a costimulatory molecule and / or growth factor receptor is an agent that stimulates CD28.

[0236] In some embodiments, the agent that stimulates a CD3 / TCR complex is chosen from an antibody (for example, a single-domain antibody (for example, a heavy chain variable domain antibody), a peptibody, a Fab fragment, or a scFv), a small molecule, or a ligand (for example, a naturally existing, recombinant, or chimeric ligand). In some embodiments, the agent that stimulates a costimulatory molecule and / or growth factor receptor is chosen from an antibody (for example, a single-domain antibody (for example, a heavy chain variable domain antibody), a peptibody, a Fab fragment, or a scFv), a small molecule, or a ligand (for example, a naturally existing, recombinant, or chimeric ligand). In some embodiments, the agent that stimulates a CD3 / TCR complex does not comprise a bead. In some embodiments, the agent that stimulates a costimulatory molecule and / or growth factor receptor does not comprise a bead. In some embodiments, the agent that stimulates a CD3 / TCR complex comprises an anti-CD3 antibody. In some embodiments, the agent that stimulates a costimulatory molecule and / or growth factor receptor comprises an anti-CD28 antibody. In some embodiments, the agent that stimulates a CD3 / TCR complex comprises an anti-CD3 antibody covalently attached to a colloidal polymeric nanomatrix. In some embodiments, the agent that stimulates a costimulatory molecule and / or PAT059852-PCT-SEC01 growth factor receptor comprises an anti-CD28 antibody covalently attached to a colloidal polymeric nanomatrix.

[0237] In some embodiments, the agent that stimulates a costimulatory molecule and / or growth factor receptor is an agent that stimulates CD28, ICOS, CD27, CD25, 4-1BB, IL6RA, IL6RB, or CD2. In some embodiments, the agent that stimulates a costimulatory molecule and / or growth factor receptor comprises one or more of a CD28, ICOS, CD27, CD25, 4-1BB, IL6RB, and / or CD2 antigen binding domain, such as but not limited to an anti- CD28, anti-ICOS, anti-CD27, anti-CD25, anti-4-lBB, anti-IL6RA, anti-IL6RB, or anti-CD2 antibody or an antibody fragment comprising one or more CDRs, heavy chain, and / or light chain thereof - such as but not limited to an anti- CD28, anti-ICOS, anti-CD27, anti-CD25, anti-4-lBB, anti-IL6RA, anti-IL6RB, or anti-CD2 antibody provided in Table 27 of WO / 2021 / 173985, hereby incorporated by reference in its entirety. In some embodiments, the agent that stimulates a CD3 / TCR complex and the agent that stimulates a costimulatory molecule and / or growth factor receptor comprise T Cell TransAct™. In some embodiments, the agent that stimulates a CD3 / TCR complex and the agent that stimulates a costimulatory molecule and / or growth factor receptor are comprised in a multispecific binding molecule. In some embodiments, the multispecific binding molecule comprises a CD3 antigen binding domain and a CD28 or CD2 antigen-binding domain

[0238] In some embodiments, the population of cells is contacted with a nucleic acid molecule encoding a CAR. In some embodiments, the population of cells is transduced with a DNA molecule encoding a CAR. In some embodiments, contacting the population of cells with the nucleic acid molecule encoding the CAR occurs simultaneously with contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, contacting the population of cells with the nucleic acid molecule encoding the CAR occurs no later than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0.5 hours after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, contacting the population of cells with the nucleic acid molecule encoding the CAR occurs no later than 20 hours after the beginning of contacting the PAT059852-PCT-SEC01 population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, contacting the population of cells with the nucleic acid molecule encoding the CAR occurs no later than 19 hours after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, contacting the population of cells with the nucleic acid molecule encoding the CAR occurs no later than 18 hours after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, contacting the population of cells with the nucleic acid molecule encoding the CAR occurs no later than 17 hours after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, contacting the population of cells with the nucleic acid molecule encoding the CAR occurs no later than 16 hours after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, contacting the population of cells with the nucleic acid molecule encoding the CAR occurs no later than 15 hours after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, contacting the population of cells with the nucleic acid molecule encoding the CAR occurs no later than 14 hours after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, contacting the population of cells with the nucleic acid molecule encoding the CAR occurs no later than 14 hours after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, contacting the population of cells with the nucleic acid PAT059852-PCT-SEC01 molecule encoding the CAR occurs no later than 13 hours after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, contacting the population of cells with the nucleic acid molecule encoding the CAR occurs no later than 12 hours after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, contacting the population of cells with the nucleic acid molecule encoding the CAR occurs no later than 11 hours after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, contacting the population of cells with the nucleic acid molecule encoding the CAR occurs no later than 10 hours after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, contacting the population of cells with the nucleic acid molecule encoding the CAR occurs no later than 9 hours after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, contacting the population of cells with the nucleic acid molecule encoding the CAR occurs no later than 8 hours after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, contacting the population of cells with the nucleic acid molecule encoding the CAR occurs no later than 7 hours after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, contacting the population of cells with the nucleic acid molecule encoding the CAR occurs no later than 6 hours after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells PAT059852-PCT-SEC01 described above. In some embodiments, contacting the population of cells with the nucleic acid molecule encoding the CAR occurs no later than 5 hours after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, contacting the population of cells with the nucleic acid molecule encoding the CAR occurs no later than 4 hours after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, contacting the population of cells with the nucleic acid molecule encoding the CAR occurs no later than 3 hours after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, contacting the population of cells with the nucleic acid molecule encoding the CAR occurs no later than 2 hours after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, contacting the population of cells with the nucleic acid molecule encoding the CAR occurs no later than 1 hour after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, contacting the population of cells with the nucleic acid molecule encoding the CAR occurs no later than 30 minutes after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above.

[0239] In some embodiments, the population of cells is harvested for storage or administration. In some embodiments, the population of cells is harvested for storage or administration no later than 72, 60, 48, 36, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, or 18 hours after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, the population of cells is PAT059852-PCT-SEC01 harvested for storage or administration no later than 26 hours after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, the population of cells is harvested for storage or administration no later than 25 hours after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, the population of cells is harvested for storage or administration no later than 24 hours after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, the population of cells is harvested for storage or administration no later than 23 hours after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, the population of cells is harvested for storage or administration no later than 22 hours after the beginning of contacting the population of cells with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above.

[0240] In some embodiments, the population of cells is not expanded ex vivo. In some embodiments, the population of cells is expanded by no more than 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, or 60%, for example, as assessed by the number of living cells, compared to the population of cells before it is contacted with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, the population of cells is expanded by no more than 5%, for example, as assessed by the number of living cells, compared to the population of cells before it is contacted with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, the population of cells is expanded by no more than 10%, for example, as assessed by the number of living cells, compared to the population of cells before it is contacted with the agent that PAT059852-PCT-SEC01 stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, the population of cells is expanded by no more than 15%, for example, as assessed by the number of living cells, compared to the population of cells before it is contacted with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, the population of cells is expanded by no more than 20%, for example, as assessed by the number of living cells, compared to the population of cells before it is contacted with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, the population of cells is expanded by no more than 25%, for example, as assessed by the number of living cells, compared to the population of cells before it is contacted with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, the population of cells is expanded by no more than 30%, for example, as assessed by the number of living cells, compared to the population of cells before it is contacted with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, the population of cells is expanded by no more than 35%, for example, as assessed by the number of living cells, compared to the population of cells before it is contacted with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above. In some embodiments, the population of cells is expanded by no more than 40%, for example, as assessed by the number of living cells, compared to the population of cells before it is contacted with the agent that stimulates a CD3 / TCR complex and / or the agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells described above.

[0241] In some embodiments, the activation process is conducted in serum free cell media. In some embodiments, the activation process is conducted in cell media comprising one or more cytokines chosen from: IL-2, IL-15 (for example, hetIL-15 (IL15 / sIL-15Ra)), or IL-6 (for example, IL-6 / sIL-6Ra). In some embodiments, the activation process is conducted in cell media comprising a LSD1 inhibitor. In some embodiments, the activation process is conducted in cell PAT059852-PCT-SEC01 media comprising a MALT1 inhibitor. In some embodiments, the serum free cell media comprises a serum replacement. In some embodiments, the serum replacement is CTS™ Immune Cell Serum Replacement (ICSR). In some embodiments, the level of ICSR can be, for example, up to 5%, for example, about 1%, 2%, 3%, 4%, or 5%.

[0242] In some embodiments, the present disclosure provides methods of making a population of cells (for example, T cells) that express a chimeric antigen receptor (CAR) comprising: (a) providing an apheresis sample (for example, a fresh or cryopreserved leukapheresis sample) collected from a subject with systemic sclerosis (e.g., limited cutaneous systemic sclerosis, diffuse cutaneous systemic sclerosis, rapidly progressing systemic sclerosis (IMM) with significant lung involvement, severe refractory systemic sclerosis); (b) selecting T cells from the apheresis sample (for example, using negative selection, positive selection, or selection without beads); (c) seeding isolated T cells at, for example, 1 x 106to 1 x 107cells / mL; (d) contacting T cells with an agent that stimulates T cells, for example, an agent that stimulates a CD3 / TCR complex and / or an agent that stimulates a costimulatory molecule and / or growth factor receptor on the surface of the cells (for example, contacting T cells with anti-CD3 and / or anti-CD28 antibody, for example, contacting T cells with TransAct); (e) contacting T cells with a nucleic acid molecule (for example, a DNA or RNA molecule) encoding the CAR (for example, contacting T cells with a virus comprising a nucleic acid molecule encoding the CAR) for, for example, 6-48 hours, for example, 20-28 hours; and (f) washing and harvesting T cells for storage (for example, reformulating T cells in cryopreservation media) or administration. In some embodiments, step (f) is performed no later than 30, 36, or 48 hours after the beginning of step (d) or (e), for example, no later than 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 hours after the beginning of step (d) or (e).

[0243] In some embodiments of the aforementioned methods, the methods are performed in a closed system. In some embodiments, T cell separation, activation, transduction, incubation, and washing are all performed in a closed system. In some embodiments of the aforementioned methods, the methods are performed in separate devices. In some embodiments, T cell separation, activation and transduction, incubation, and washing are performed in separate devices. PAT059852-PCT-SEC01

[0244] In some embodiments of the aforementioned methods, the methods further comprise adding an adjuvant or a transduction enhancement reagent in the cell culture medium to enhance transduction efficiency. In some embodiments, the adjuvant or transduction enhancement reagent comprises a cationic polymer. In some embodiments, the adjuvant or transduction enhancement reagent is chosen from: LentiBOOST™ (Sirion Biotech), vectofusin-1, F108 (Poloxamer 338 or Pluronic® F-38), protamine sulfate, hexadimethrine bromide (Polybrene), PEA, Pluronic F68, Pluronic Fl 27, Synperonic or LentiTrans™. In some embodiments, the transduction enhancement reagent is LentiBOOST™ (Sirion Biotech). In some embodiments, the transduction enhancement reagent is Fl 08 (Poloxamer 338 or Pluronic® F-38)

[0245] In some embodiments of the aforementioned methods, the transducing the population of cells (for example, T cells) with a viral vector comprises subjecting the population of cells and viral vector to a centrifugal force under conditions such that transduction efficiency is enhanced. In an embodiment, the cells are transduced by spinoculation.

[0246] In some embodiments of the aforementioned methods, cells (e.g., T cells) are activated and transduced in a cell culture flask comprising a gas-permeable membrane at the base that supports large media volumes without substantially compromising gas exchange. In some embodiments, cell growth is achieved by providing access, e.g., substantially uninterrupted access, to nutrients through convection.

[0247] Pharmaceutical Compositions

[0248] The methods described herein can further include formulating a CD 19 CAR-expressing cell in a pharmaceutical composition. Pharmaceutical compositions may comprise a CD 19 CAR-expressing cell, for example, a plurality of CD 19 CAR-expressing cells, as described herein, in combination with one or more pharmaceutically or physiologically acceptable carriers, diluents or excipients. Such compositions may comprise buffers such as neutral buffered saline, phosphate buffered saline and the like; carbohydrates such as glucose, mannose, sucrose or dextrans, mannitol; proteins; polypeptides or amino acids such as glycine; antioxidants; chelating agents such as EDTA or glutathione; adjuvants (for example, aluminum hydroxide); and preservatives. Compositions can be formulated, for example, for intravenous administration. PAT059852-PCT-SEC01

[0249] In some embodiments, the pharmaceutical composition is substantially free of, for example, there are no detectable levels of a contaminant, for example, selected from the group consisting of endotoxin, mycoplasma, replication competent lentivirus (RCL), p24, VSV-G nucleic acid, HIV gag, residual anti-CD3 / anti-CD28 coated beads, mouse antibodies, pooled human serum, bovine serum albumin, bovine serum, culture media components, vector packaging cell or plasmid components, a bacterium and a fungus. In some embodiments, the bacterium is at least one selected from the group consisting of Alcaligenes faecalis, Candida albicans, Escherichia coli, Haemophilus influenza, Neisseria meningitides, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumonia, and Streptococcus pyogenes group A.

[0250] When “an immunologically effective amount” or “therapeutic amount” is indicated, the precise amount of the compositions to be administered can be determined by a physician with consideration of individual differences in age, weight, and condition of the patient (subject). It can generally be stated that a pharmaceutical composition comprising the immune effector cells (for example, T cells, NK cells) described herein may be administered at a dosage of about 0.5 x 106to 50 x 106viable CAR-expressing cells, in some instances about 12.5 x 106viable CAR- expressing cells, including all integer values within those ranges. T cell compositions may also be administered multiple times at these dosages. The cells can be administered by using infusion techniques that are commonly known in immunotherapy (see, for example, Rosenberg et al., New Eng. J. of Med. 319: 1676, 1988).

[0251] The administration of the subject compositions may be carried out in any convenient manner. The compositions described herein may be administered to a patient trans arterially, subcutaneously, intradermally, intratumorally, intranodally, intramedullary, intramuscularly, by intravenous (i.v.) injection, or intraperitoneally, for example, by intradermal or subcutaneous injection. The compositions of immune effector cells (for example, T cells, NK cells) may be injected directly into a lymph node or site of disease. PAT059852-PCT-SEC01

[0252] EXAMPLES

[0253] The invention is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only, and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

[0254] Example 1: Description of the Activated Rapid Manufacturing (ARM) process

[0255] In some embodiments, CART cells are manufactured using a continuous Activated Rapid Manufacturing (ARM) process, over approximately 2 days, which will potentially allow for a greater number of less differentiated T cells (T naive and TSCM (stem central memory T) cells) to be returned to a patient for in vivo cellular expansion. The short manufacturing time period allows the early differentiated T cells profile to proliferate in the body for their desired terminal differentiated state rather that in an ex vivo culture vessel.

[0256] In some embodiments, CART cells are manufactured using cryopreserved leukapheresis source material, for example, non-mobilized autologous peripheral blood leukapheresis (LKPK) material. Cryopreserved source material undergoes processing steps for T cell enrichment on the first day of production (Day 0) by means of anti-CD4 / anti-CD8 immunomagnetic system. Positive fraction is then seeded in G-rex culture vessel, activated with an anti-CD3 / CD28 system (TransACT™) and on the same day transduced with a lentiviral vector (LV) encoding a CAR. On the following day, after 20-28 hours of transduction, the T cells are harvested, washed four times, formulated in freezing medium, and then frozen by a Controlled Rate Freezer (CRF). From the start of the process on Day 0 to the initiation of harvest on the following day, cells are cultured for 20 - 28 hours with a target of 24 hours after Day 0 seeding.

[0257] Media for Day 0 were prepared according to Table 1.

[0258] Table 1: Media type and point of use during CART manufacturing PAT059852-PCT-SEC01

[0259] The cryopreserved leukapheresis material is thawed. The thawed cells are diluted with the Rapid Buffer (Table 21) and washed on the CliniMACS® Prodigy® device. The T cells are selected by CliniMACS® CD4 and CD8 microbeads. Once the program is finished for T cell selection (approximately 3h 40 min to 4h 40 min), the reapplication bag containing the cells suspended in Rapid Media (Table 21) are transferred in a transfer pack. A sample is taken for viability and cell count. The cell count and viability data from the positive fraction bag is used to determine the cell concentration when seeding the culture vessel for activation and vector transduction.

[0260] Following positive selection of T cells via the CliniMACS® microbeads (CD4 and CD8), the cells are seeded in the culture vessel, G-Rex. Once the cells are seeded, the activation reagent (TransACT™) is then added to the culture vessel. The cells are then transduced with a lentiviral vector encoding a CAR at a target MOI of 1.0 (0.8-1.2). Following the vector addition, the culture vessel is transported to an incubator where it is incubated for a target of 24 hours (operating range 20-28 hours) at a nominal temperature of 37 °C (operating range 36-38 °C) with nominal 5% CO2 (operating range 4.5-5.5%). Following the incubation, the cells are washed with Harvest Wash Solution (Table 1) four times to remove any non-integrated vector and residual viral particles, as well as any other process related impurities. Then, the cells are eluted and a sample for cell count and viability is taken for testing and the results are used to determine the volume required to re-suspend the cells for final formulation with CryoStor® CS10. The cells are then centrifugated to remove the Harvest Wash Solution and proceed with cryopreservation.

[0261] In some embodiments, the CAR expressed in CART cells binds to CD 19. In some embodiments, the CAR made by the ARM process is rapcabtagene autoleucel. In some embodiments, IL-2 used in the Rapid Media (RM) (Table 1) can be replaced with IL-15, hetlL- 15 (IL-15 / sIL-15Ra), IL-6, or IL-6 / sIL-6Ra. PAT059852-PCT-SEC01

[0262] Example 2: Phase 1 / 2 study, open-label, multi-center, to assess safety, efficacy and cellular kinetics of rapcabtagene autoleucel cells in participants with severe, refractory idiopathic inflammatory myopathies

[0263] This study evaluates the efficacy, safety and tolerability of i.v. rapcabtagene autoleucel (administered once following lymphodepletion) in participants with severe refractory active idiopathic inflammatory myopathies. Rapcabtagene autoleucel is an autologous CD19-directed CAR-T cell therapy that is comprised of CD4+ / CD8+ T cells that have undergone ex vivo T cell activation and gene modification. Rapcabtagene autoleucel utilizes the FMC63 scFv domain for CD 19 recognition and the same lentiviral vector as tisagenlecleucel (Kymriah, CTL019) and is manufactured via the activated rapid manufacturing (ARM) process. The ARM process reduces the turnaround time compared to traditional manufacturing processes (FIG.2) and preserves T cell sternness, the ability to self-renew and mature, resulting in a product with greater proliferative potential and fewer exhausted T cells compared to traditionally manufactured CAR- T cells. With ARM, CAR-T cell expansion occurs primarily within a patient’s body (in vivo), eliminating the need for an extended culture time outside of the body (ex vivo). These unique characteristics may lead to better and more durable responses, improved long-term outcomes and a reduced risk of severe adverse events compared to CAR-T cell products manufactured via traditional manufacturing methods. Non-clinical studies show that rapcabtagene autoleucel is a product with potentially superior antitumor efficacy, a similar safety profile, and delayed expansion compared to other CD19-directed CAR-T cell therapy relying on a traditional manufacturing process (e.g. tisagenlecleucel).

[0264] Overall Study Design

[0265] This is a 104- week, randomized, open-label, assessor-blinded, controlled, Phase 2 study with a group-sequential design, which is comprised of two periods:

[0266] • A screening period lasting up to 6 weeks.

[0267] • Randomized treatment period and primary follow-up period lasting up to 104 weeks.

[0268] Two Cohorts are planned: Lead-in (Cohort 1) and Randomized (Cohort 2). In Cohort 2, participants will be randomized 2: 1 to receive rapcabtagene autoleucel infusion or comparator Up to a total of 117 participants will be randomized in Cohort 2 targeting enrollment of at least PAT059852-PCT-SEC01

[0269] 10 MSA-positive participants per subtype (DM, ASyS or IMNM) and including approximately 78 participants (68 MSA-positive and 10 MS A- negative) in the rapcabtagene autoleucel arm and 39 participants (34 MSA-positive and 5 MSA-negative) in the comparator arm. The enrollment for MS A- negative participants will be stopped when 15 MS A- negative participants have been randomized or the enrollment target of 102 MSA-positive participants is reached, whichever comes first. All participants must provide written informed consent prior to start of any study-related activities.

[0270] Cohort 1

[0271] The first six MSA-positive participants assessed as eligible at the end of the screening period will be enrolled into a Lead-in Cohort 1 with the initial three participants enrolled sequentially into a sentinel group, dosed 28 days apart, followed by the next set of three participants recruited concurrently into a safety group. All six participants will receive rapcabtagene autoleucel treatment (no randomization is performed). Stopping rules will be implemented and meeting any of them will result in an expedited DMC review.

[0272] The first lead-in participant receiving rapcabtagene autoleucel infusion will be observed and monitored according to the Schedule of Activities (vital signs, ECG, laboratory parameters, physical examination, and AEs) over 4 weeks / 28 days post infusion for detection of any safety events. This clinical information will be evaluated by the treating Investigator and the sponsor. If no relevant safety issues are detected from the first lead-in participant within the period of the first 28 days post infusion, rapcabtagene autoleucel treatment of the second lead-in participant will proceed (leukapheresis; LD; infusion), after sponsor’s approval. The second lead-in participant will be monitored during the 28-day post infusion period.

[0273] The same process as defined above will apply prior to rapcabtagene autoleucel treatment of the third lead-in participant and during the 28-day period following rapcabtagene autoleucel infusion. Once 28 days have elapsed after the dosing of the third participant with rapcabtagene autoleucel, the subsequent 3 participants will be enrolled and dosed without a protocol-mandated interval between them. However, detection of stopping rules will continue to result in an expeditious review by the DMC and the next participant will be dosed only after the DMC has reviewed the Lead-in Cohort participants and recommended that it is safe to proceed.

[0274] Cohort 2 PAT059852-PCT-SEC01

[0275] After completion of 28 days post-dosing of the sixth participant in the Lead-in Cohort 1 and following a positive DMC recommendation, recruitment of the randomized Cohort 2 will be initiated with stopping rules as previously defined. This cohort will have a screening period and a randomized treatment period and primary follow-up period lasting up to 104 weeks. Participants will be randomized 2: 1 to rapcabtagene autoleucel or comparator.

[0276] Participants assigned to the rapcabtagene autoleucel arm must undergo leukapheresis as soon as possible after randomization. Depending on the therapy used prior to or during Screening, wash-out of immunomodulatory / immunosuppressive medication and tapering of GC for up to 7 days may be required before leukapheresis. GC must be tapered to 20 mg prednisone / day prior to randomization. GC doses must then be limited to <10 mg prednisone / day (or equivalent) for at least 3 days prior to leukapheresis and LD; a GC doses of <10 mg prednisone / day (or equivalent) for 1 week is preferable. Once the leukapheresis product has been confirmed to be suitable for rapcabtagene autoleucel manufacturing, the manufacturing process will commence.

[0277] For participants randomized to the comparator arm, the Investigator will choose the most appropriate treatment option for each participant based on the participant’s medical history as well as myositis-related medical history and treatment history. The four therapies that may be used as the comparator arm are rituximab, cyclophosphamide, MMF / MPA, or tacrolimus. The Investigator should not choose a treatment option with a lack of response in the participant’s treatment history. The rationale for the choice will need to be documented in the source document. In the comparator arm, after Baseline, each participant will return to the site according to visit schedule.

[0278] After Week 52, participants in the comparator arm, in case of a confirmed deterioration defined as deterioration on two or more consecutive visits, at least 4 weeks apart, any time after Week 12 or progression of ILD as defined below, may receive rapcabtagene autoleucel treatment in a separate study. To receive rapcabtagene autoleucel treatment, the participant must meet eligibility criteria for rapcabtagene autoleucel infusion, as defined in the inclusion and exclusion criteria. Participants who switch to rapcabtagene autoleucel will be considered as non-responders at all time points after switching.

[0279] Progression of ILD, compared with baseline, is defined as: PAT059852-PCT-SEC01

[0280] 1. Worsening respiratory symptoms AND

[0281] 2. Absolute decline in FVC% predicted of >5% within 1 year of follow-up.

[0282] Study Population

[0283] The study population consists of participants with severe refractory idiopathic inflammatory myopathies including refractory DM, ASyS or IMNM with or without secondary Interstitial Lung Disease (ILD) (defined as per inclusion criteria). Participants must be positive for MSA based on an historical result or for any of the MSAs listed below, based on the central laboratory result during Screening. MSAs are as follows:

[0284] • ASyS: anti-histidyl-ribonucleic acid [tRNA] synthetase (Jo-1), anti-threonyl-tRNA synthetase (PL7), anti-alanyl-tRNA synthetase (PL12), anti-isoleucyl-tRNA synthetase (OJ), anti-glycyl-tRNA synthetase (EJ) antibodies, OR

[0285] • DM: anti-Mi-2 (Mi-2 / nucleosome remodeling and deacetylase [NuRD] complex), antitranscription intermediary factor 1 -Gamma (UFl-y), anti-nuclear matrix protein 2 (NXP-2), anti-small ubiquitin-like modifier- 1 activating enzyme (SAE-1), anti- antimelanoma differentiation-associated gene 5 (MDA-5) antibodies, OR

[0286] • IMNM: anti-signal recognition particle (SRP), anti-3-hydroxy-3-methylglutaryl- coenzyme A reductase (HMGCR) antibodies.

[0287] If the participant is MSA-negative, then the participant must fit in one of the following two categories: a) IIM diagnosis must be definite according to ACR / EULAR 2017 criteria OR b) diagnosed with probable IIM and at least muscle biopsy and / or classical DM skin rash criteria are part of the total score of the ACR / EULAR classification criteria (since IMNM is not part of the current classification criteria, a muscle biopsy that shows necrosis of muscle fibers is acceptable).

[0288] Participants who had inadequate response to high-dose GC at a dose of at least 0.75 mg / kg / day oral prednisone (or equivalent), unless there are safety concerns regarding use of high-dose GC due to comorbidities. Additionally, participants must have had inadequate response to treatment with two therapeutic agents, with at least one of them from the list of therapeutic agents below; each agent must have been received for a minimum of 3 months (sequential or combined) prior to Screening. The list of therapeutic agents to treat severe IIM includes: my cophenolate mofetil, tacrolimus, cyclosporine, abatacept, IVIG, subcutaneous PAT059852-PCT-SEC01 immunoglobulin (SCIG), rituximab, cyclophosphamide or repository corticotropin injection. Inadequate response is defined as a lack of sufficient response to most recent therapy and presence of ongoing muscle weakness, DM rashes, dysphagia, progressive dyspnea despite treatment, and based on the Investigator opinion, one or more of these symptoms are due to active disease. Intolerance or contraindication to use is not considered inadequate response. Intolerance or contraindication to use is not considered inadequate response, except for high- dose GC in cases with comorbidities which prevent high dose corticosteroid use (see above).

[0289] Study Treatment

[0290] Eligible participants undergo the following sequence of events prior to rapcabtagene autoleucel administration: (1) leukapheresis, (2) pre-lymphodepletion evaluation, (3) lymphodepletion, (4) premedication, (5) Rapcabtagene autoleucel pre-treatment evaluation, and (6) rapcabtagene autoleucel injection at a target dose of 12.5 x 106CAR-positive viable T cells.

[0291] Lymphodepleting therapy starts within one week before rapcabtagene autoleucel injection, which means that rapcabtagene autoleucel is injected 2 to 6 days after lymphodepleting therapy is completed. Lymphodepleting therapy may be repeated in the case rapcabtagene autoleucel has been delayed by more than 2 weeks. The lymphodepleting therapy regime is as follows: (1) fludarabine administered 25 mg / m2intravenously [i.v.] daily for 3 doses (for participants with renal impairment, the dose may be reduced as per local approved labels of fludarabine), and (2) cyclophosphamide administered 250 mg / m2i.v. daily for 3 doses starting with the first dose of fludarabine.

[0292] All participants are pre-medicated with acetaminophen / paracetamol (500-1000 mg, orally and diphenhydramine (25-50 mg, i.v. or orally) or another Hl antihistamine approximately 30 to 60 minutes prior to injection. These medications can be repeated every 6 hours as needed. Nonsteroidal anti-inflammatory medication may be prescribed if the participant continues to have fever not relieved with acetaminophen (paracetamol).

[0293] Before randomization, the Investigator will choose the most appropriate treatment option for each participant based on the participant’s medical history as well as IIM-related medical history and treatment history. The Investigator should not choose a treatment option with a lack of response in the participant’s treatment history. The Investigator may choose one treatment regimen from 4 options below: PAT059852-PCT-SEC01

[0294] 1) Rituximab (RTX) i.v. at dose according to local label and practice (e.g., 375 mg / m2 weekly for 4 doses) starting on Day 1

[0295] 2) Cyclophosphamide (CYC) i.v. at dose according to local label and practice (e.g., 500 ~1000mg / m2 every 4 weeks, or 750 to 1000 mg every 4 weeks for 6 months) starting on Day 1

[0296] 3) MMF or MPA orally at dose according to local label and practice starting on Day 1

[0297] 4) Tacrolimus (TAC) orally at dose according to local label and practice starting on Day 1 (e.g., initial dose at 0.075 mg / kg / day divided into two doses, subsequently adjusted to maintain trough levels between 5 and 10 ng / ml and to keep total daily doses <0.3 mg / kg)

[0298] Glucocorticoid Tapering

[0299] All participants entering the study with background GC therapy will initiate a predefined, guided GC taper regimen. Guidance for participants in rapcabtagene autoleucel arm can be found in Table 1. All participants should have their GC tapered down to 5 mg of prednisone (or equivalent) or less by Week 24. The Investigator will decide whether to continue the taper after reaching 5 mg / day of prednisone (or equivalent).

[0300] Table 1 Guidance for GC taper in rapcabtagene autoleucel arm [mg prednisone / day (or equivalent)]

[0301] Acute corticosteroid administration prior to Week 38 may occur for purposes other than the treatment of IIM disease activity, such as short-acting hydrocortisone dosed peri-operatively in participants with suppressed hypothalamic-pituitary-adrenal axis, an asthma or chronic PAT059852-PCT-SEC01 obstructive pulmonary disease (COPD) exacerbation, a contact dermatitis flare, etc. Such dosing should not exceed a cumulative dose of 150 mg of prednisone or equivalent if used between Week 24 to 38. Use after Week 38 is prohibited. A participant will be classified as a nonresponder with respect to the primary endpoint if: • For treatment of IIM, the participant could not be tapered to 5 mg prednisone per day (or equivalent) by Week 24

[0302] • For treatment of IIM, the GC dose needs to be increased above 5 mg prednisone per day (or equivalent) after Week 24

[0303] • For treating conditions other than IIM after Week 38, any use of systemic GC.

[0304] Safety, Pharmacokinetic (PK) and Efficacy Assessments

[0305] Objectives and related endpoints are summarized in Table 2

[0306] Table 2 Objectives and related endpoints

[0307] Objective(s) Endpoint(s)

[0308] Primary objective(s) Endpoint(s) for primary objective(s)

[0309] • To demonstrate the superiority of rapcabtagene • Achieving at least moderate autoleucel at a target dose of 12.5 x 106CAR-positive improvement in TIS (TIS > 40) at viable T cells, as a single infusion, over comparator Week 52 (Yes / No)

[0310] (Investigator choice of treatment defined in

[0311] Section 6.1 2.2) with respect to achieving at least a moderate improvement in the Total Improvement Score (TIS) at Week 52 for MSA-positive participants.

[0312] Secondary objective(s) Endpoint(s) for secondary objective(s)

[0313] • To demonstrate the superiority of rapcabtagene autoleucel • achieving at least moderate over comparator with respect to: improvement in TIS (> 40)

[0314] • achieving at least moderate improvement (TIS > 40) at Week 52 (Yes / No), as

[0315] Week 52 for participants regardless of MSA status defined for primary endpoint

[0316] • reducing cumulative use of glucocorticoids from * Adjusted annual cumulative baseline to Week 52 for MSA-positive participantsGC dose up t0 Week 52

[0317] • improving pulmonary function at Week 52 in MSA- * change from baseline in positive participants with secondary 7 ILD. P®rc;®nt pred / ctt™ Vital Capacity (FVC%)eat

[0318] • achieving major improvement (TIS > 60) at Week 52 Week 52 for MSA-positive participants . . .

[0319] • achieving major

[0320] • reducing fatigue at Week 52 for MSA-positive improvement in TIS (> 60) participants at Week 52 (Yes / No), as

[0321] • reducing cumulative use of glucocorticoids from defined for primary endpoint baseline to Week 52 regardless of MSA status Pel with greater improvement required PAT059852-PCT-SEC01

[0322] Objective(s) Endpoint(s)

[0323] • improving pulmonary function at Week 52 in • change from baseline in participants with secondary ILD regardless of MSA Patient-Reported Outcome status. Measurement Information

[0324] • achieving major improvement (TIS > 60) at Week 52 System (PROMIS)-Fatigue for participants regardless of MSA status 7a at Week 52

[0325] • reducing fatigue at Week 52 for participants regardless of MSA status

[0326] • To evaluate the overall safety and tolerability of • Safety parameters include vital rapcabtagene autoleucel. signs, adverse events, laboratory parameters and ECG evaluation

[0327] The primary clinical endpoint is whether at least moderate improvement in TIS at Week 52 (Yes / No) is achieved as defined as meeting each of the following three criteria:

[0328] 1. TIS > 40 at the Week 52 assessment as per the 2016 ACR / EULAR response criteria, corresponding to moderate improvement (US > 40 and <60) or major improvement (TIS > 60).

[0329] 2. No confirmed deterioration up to Week 52, where confirmed deterioration is defined as deterioration on two or more consecutive visits, at least 4 weeks apart, any time after Week 12. Deterioration is defined as:

[0330] • Physician's global assessment of worsening of > 2 cm on the Visual Analogue Scale (VAS) and worsening of > 20% on the Manual Muscle Testing-8 (MMT-8) score, OR

[0331] • Extramuscular Global Assessment worsening of > 2 cm on the Myositis Disease Activity Assessment Tool (MDAAT) VAS, OR

[0332] • Any 3 of 5 CSM worsening by > 30% (excluding the enzymes CSM).

[0333] 3. No treatment failure any time after Week 12 and up to Week 52. Treatment failure is defined as:

[0334] • Use of rescue medication, OR

[0335] • Major deviation in GC taper

[0336] Secondary clinical endpoints of interest include a determination of whether rapcabtagene autoleucel is superior to comparator with respect to the primary clinical endpoint using the same evaluation criteria. Additional secondary clinical endpoints include:

[0337] • Demonstrate the superiority of rapcabtagene autoleucel over comparator with respect to the reduction in cumulative use of glucocorticoids from baseline for myositis specific antibodies (MSA) positive participants PAT059852-PCT-SEC01

[0338] • Demonstrate the superiority of rapcabtagene autoleucel over comparator with respect to improving pulmonary function from baseline for MSA-positive participants with secondary ILD

[0339] • Demonstrate the superiority of rapcabtagene autoleucel over comparator with respect to achieving major improvement in TIS in MSA-positive patients

[0340] • Demonstrate the superiority of rapcabtagene autoleucel over comparator with respect to reducing fatigue from baseline for MSA-positive participants

[0341] • Demonstrate the superiority of rapcabtagene autoleucel over comparator with respect to reducing cumulative GC from baseline regardless of MSA status

[0342] • Demonstrate the superiority of rapcabtagene autoleucel over comparator with respect to improving pulmonary function from baseline in participants with secondary ILD regardless of baseline MSA

[0343] • Demonstrate the superiority of rapcabtagene autoleucel over comparator with respect to achieving major clinical improvement regardless of MSA status

[0344] • Demonstrate the superiority of rapcabtagene autoleucel over comparator with respect to reducing fatigue from baseline regardless of MSA status.

[0345] To assess the effects of rapcabtagene autoleucel on disease activity in patients with systemic sclerosis, the following assessments are performed at various time points:

[0346] Percent Predicted Forced Vital Capacity in Participants with ILD

[0347] Forced vital capacity (FVC) is a total volume that can be forcefully expired from a maximum inspiratory effort (in Liters). The result is then compared to predicted value based on healthy standards and expressed as FVC% predicted. FVC measurements will be conducted in participants with pre-existing ILD as per the study Spirometry Manual, which is based on the American Thoracic Society / European Respiratory Society (ATS / ERS) Consensus Statement (Graham et al 2019). To calculate FVC% predicted, this study will utilize the Global Lung Function 2012 Equations published by (Quanjer et al 2012) or Japanese Respiratory Society reference values for Japanese patients (Kubota et al 2014).

[0348] Total Improvement Score (TIS)

[0349] The International Myositis Assessment and Clinical Studies Group (IMACS) (Disease Activity Core Set Measures (nih.gov)) has developed a consensus on a set of six Core Set Domains and Measures for the assessment of disease activity which are thought to be reversible PAT059852-PCT-SEC01 and result directly from the inflammatory process. These criteria are Physician Global Activity (PhGA) - Visual Analog Scale, Patient Global Activity (PaGA) - Visual Analog Scale, Muscle Strength Testing - Manual Muscle Testing (MMT-8), Functional Assessment Tool - HAQ-DI, Laboratory - Muscle Enzymes, and Extramuscular Assessment - Myositis Disease Activity Assessment Tool (MDAAT) - Visual Analog Scale. The criteria use the 6 core set measures (CSM), combining the absolute percentage change criteria in each with varying weights to obtain a TIS on a scale of 0-100 which corresponds to the degree of improvement, with higher scores corresponding to a greater degree of improvement. TIS threshold of 20 or higher is defined as minimal improvement, 40 or higher as moderate improvement and 60 or higher as major improvement. These criteria, which have now been accepted by the American College of Rheumatology and European League Against Rheumatism, are recommended for use as primary endpoints in myositis therapeutic trials (Final Response Criteria (nih.gov)).

[0350] Physician Global Activities (PhGA) - Visual Analog Scale

[0351] This tool measures the global evaluation by the blinded assessor of the overall disease activity of the participant at the time of assessment using a 10 cm visual analogue scale (Rider et al 1997).

[0352] Patient Global Activity (PaGA)- Visual Analogue Scale

[0353] This tool measures the global evaluation by the participant of the participant's overall disease activity at the time of assessment using a 10 cm visual analogue scale (Rider et al 1997).

[0354] Muscle Strength Testing - Manual Muscle Testing (MMT-8)

[0355] MMT-8 is a tool to assess muscle strength using 8 proximal, distal, and axial muscles. The designated proximal and distal muscles will be tested bilaterally using a 0 - 10 point scale for each muscle (potential score 0-140). Axial (neck flexors) will also be tested (potential score 0-10) to arrive at a maximum MMT-8 score of 150 (Rider et al 2003).

[0356] Laboratory - Muscle Enzymes

[0357] This tool measures the serum activities of at least 2 of the 4 muscle-associated enzymes including creatine phosphokinase (CK), the transaminases (ALT, AST), lactate dehydrogenase (LD) and aldolase (Rider et al 2003, Volochayev et al 2012).

[0358] Extramuscular Assessment - Myositis Disease Activity Assessment Tool (MDAAT) This tool measures the blinded assessor's assessment of disease activity of various organ systems (extra-muscular and muscle) using a visual analog scale (VAS) (Isenberg et al 2004, PAT059852-PCT-SEC01

[0359] Sultan et al 2008). Each organ system is assessed for presence of clinical features or symptoms within the previous 4 weeks that are due to active disease. The Extramuscular Global Assessment which is the overall evaluation for the disease activity in all extramuscular systems (excluding muscle disease activity) is the IMACS' CSM.

[0360] Functional Assessment Tool -HAQ-DI

[0361] The Health Assessment Questionnaire (HAQ) Disability Index (DI) is a tool to assess physical function. The HAQ-DI consists of 20 questions referring to eight component domains related to measuring difficulty in performing daily activities: dressing / grooming, arising, eating, walking, hygiene, reach, grip, and activities (Cole et al 2006). Each question is rated on a 0-3 scale, where 0 indicates “without difficulty” and 3 indicates “unable to do,” and additional points can be added if aids or devices are needed for specific activities. For each of these categories, participants report the amount of difficulty they have in performing two or three specific activities. The highest score reported by the participant for any component question of the eight categories determines the score for that category. The total score indicates the patient’s selfassessed level of disability. A negative change from baseline indicates improvement.

[0362] Patient-Reported Outcome Measurement Information System Fatigue Short Form 7a (PROMIS F-SF)

[0363] Fatigue is a frequently experienced symptom of IIM, and the Patient-Reported Outcome Measurement Information System® Fatigue Short Form 7a (PROMIS F-SF) will be used to assess the study treatment's effect on fatigue. The PROMIS F-SF is a 7-item form with a recall period of the past seven days that assess a range of self-reported symptoms, from mild feelings of tiredness to an overwhelming, debilitating, and sustained sense of exhaustion that likely decreases one’s ability to execute daily activities and function normally in family or social roles (Celia et al 2010). Fatigue is divided into the experience of fatigue (frequency, duration, and intensity) and the impact of fatigue on physical, mental, and social activities. Scores can range from 7 to 35, with higher scores indicating greater fatigue.

[0364] Appropriateness of Efficacy Assessments

[0365] FIS was selected as a primary endpoint since it is a validated endpoint developed by the International Myositis Assessment and Clinical Studies Group (IMACS). In order to determine how myositis changes over time, information is collected from both physicians and participants in a standardized way. Disease activity assesses the manifestations of myositis which are thought PAT059852-PCT-SEC01 to be reversible that result directly from the inflammatory process and IMACS has developed a consensus on a set of Core Set Domains and Measures for the assessment of disease activity which are being assessed in this study.

[0366] The secondary endpoint efficacy assessments were selected because they address important aspects of IIM: fatigue and FVC in participants with ILD. Fatigue is a key symptom for this patient population and will be assessed via a well-established instrument (PROMIS- Fatigue 7a) and a Symptom Diary which includes questions regarding fatigue. Percent predicted FVC was selected as an important assessment of lung function in participants with ILD.

[0367] Additional Assessments

[0368] Additional clinical outcome and patient reported assessments may also be evaluated during this trial.

[0369] Myositis Function Index (FI-3)

[0370] The Myositis Function Index FI-3 (Ernste et al 2021), a performance outcome measure, is a reliable and valid method for the functional assessment of IIM patients for muscle impairment of the major muscle groups in the neck and upper and lower extremities in patients at various stages of disease. Three tasks will be performed unilaterally on the dominant side: shoulder flexion, neck flexion and hip flexion and a total score will be calculated. Scoring is based on the number of correctly performed repetitions varying from 0 to 60 repetitions for shoulder flexion, 0 to 60 for hip flexion and 0 to 30 for neck flexion for a total number of repetitions of 150 at the completion of the test which reflects normal muscle endurance. The total score of the FI-3 is then calculated by dividing the total number of repetitions by 3.

[0371] Myositis Damage Index (MDI)

[0372] This tool assesses the degree of disease damage due to IIM of all organ systems. It is composed of a series of organ- specific questions relating to the presence or absence of a given sign or symptom or problem to measure the extent of damage, and an overall rating of the disease damage of each system using a 10 cm visual analogue scale to measure the severity of damage (Rider et al 2009, Isenberg et al 2004).

[0373] Modified Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) in participants with DM

[0374] Modified CDASI (CDASI ver02) is an instrument designed to capture the extent of cutaneous disease in DM. It is a one-page validated, quantitative outcome measure that has three PAT059852-PCT-SEC01 activities (erythema, scale, and presence of erosion / ulceration) and two damage measures (presence of poikiloderma and / or calcinosis) assessed over 15 anatomical sites. Separately, it also measures three specific areas: Gottron's hands, periungual and alopecia. The total score of the modified CDASI ranges from 0 to 132 and the activity and damage sub-scores range from 0 to 100 and 0 to 32, respectively Yassaee et al 2010. A study by Anyanwu et al 2015 showed that CDASI activity scores of 19 or less characterize mild disease however, the actual cut-off may fall between 14 and 19 points. Activity scores above this cut-off value indicated moderate to severe disease.

[0375] SF-36

[0376] The Medical Outcome Short Form Health Survey (SF-36) Version 2 (Acute Form) is a survey evaluating individual participant's health status, which also monitors and compares participant's disease burden. It consists of eight subscales that can be scored individually: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health (Ware et al 1993). Two overall summary scores, the Physical Component Summary (PCS) and the Mental Component Summary (MCS) also can be computed (Ware et al 1994). The SF-36 has proven useful in monitoring general and specific populations, comparing the relative burden of different disease, differentiating the health benefits produced by different treatments, and in screening individual participants. The purpose of the SF-36 in this study is to assess the effects of the study treatment on HRQoL. Given the acute nature of this disease, version 2, with a one-week recall period, will be used in this study.

[0377] L-PF for Participants with pre-existing ILD

[0378] The Living with Pulmonary Fibrosis (L-PF) questionnaire is a 44-item questionnaire with two modules: Symptoms (23 items) and Impacts (21 items) intended for use in patients with all forms of progressive fibrosing ILD. The Symptoms module assesses shortness of breath, cough and fatigue in the past 24 hours. The Impacts module assesses multiple aspects of HRQoL with a recall period of 1 week. Items in both modules have response options on a five-option numeric rating score with an anchor of 0 “Not at all” to 4 “Extremely”. Domain and total scores range from 0 to 100, with higher scores indicating greater impairment (Swigris et al 2022). In this study, it will be assessed in participants with pre-existing ILD.

[0379] Pharmacokinetic and Immunogenicity PAT059852-PCT-SEC01

[0380] For pharmacokinetic (PK) analysis, serial blood samples are collected at different time points to measure rapcabtagene autoleucel transgene concentrations in peripheral blood by quantitative polymerase chain reaction (qPCR). Levels of rapcabtagene autoleucel transduced cells will be measured by flow cytometry of CD3 -positive, rapcabtagene autoleucel -positive cells. The absolute number of CD 19+ B cells in the peripheral blood is measured by flow cytometry and used as the pharmacodynamics (PD) marker. The flow cytometry analysis can be performed using a validated panel that also includes the analysis of T cells and NK cells (TBNK).

[0381] Pre-existing and treatment- induced immunogenicity (cellular, humoral, neutralizing antibodies) of rapcabtagene autoleucel is assessed by one or more of the following: (1) humoral immunogenicity (anti-drug antibodies, ADA) measured by flow cytometry analysis of ADA binding to ARM-CD19 CAR-expressing cells, (2) presence of neutralizing antibodies measured by a reporter gene assay, (3) cellular immunogenicity measured by flow cytometry analysis of T cell interferon-gamma expression. Analytical methods for PK and immunogenicity assessments are listed in Table 2.

[0382] Table 2. Analytical methods associated with the PK and immunogenicity assessments PAT059852-PCT-SEC01

[0383] Results

[0384] An open-label, controlled study in refractory (inadequate response to >2 prior systemic therapies) idiopathic inflammatory myopathy includes two cohorts. Cohort 1 (Lead-In Cohort) comprises a single-arm safety cohort to assess safety and tolerability of rapcabtagene autoleucel, followed by Cohort 2 (Randomized Cohort). In Cohort 1, 6 eligible IIM participants received protocol-defined lymphodepleting chemotherapy (fludarabine and cyclophosphamide), followed by a single intravenous infusion of rapcabtagene autoleucel. The first 3 participants were dosed sequentially with a 28-day observation period between each participant; subsequent participants were dosed in parallel following safety review. Patient baseline characteristics are set forth in Table 3.

[0385] Table 3

[0386] PAT059852-PCT-SEC01

[0387] All participants were hospitalized for >14 days post-infusion and monitored closely for adverse events. Rapcabtagene autoleucel was well-tolerated as summarized in Table 4. All cases of cytokine release syndrome were resolved without sequelae; no instances of immune effector PAT059852-PCT-SEC01 cell-associated neurotoxicity syndrome were observed. Adverse events were manageable and aligned with the established safety profile of CAR-T cell therapies.

[0388] Table 4

[0389] ‘Considered SAE due to prolongation of protocol mandated hospitalization period. tPrior to rapcabtagene autoleucel infusion.

[0390] Patients treated with rapcabtagene autoleucel in Cohort 1 demonstrated rapid and profound B cell depletion. All 3 IIM patients with >12 weeks of follow-up showed moderate to major improvement in Total Improvement Score within 12 weeks post-infusion, including a first- ever major response noted in an immune-mediated necrotizing myopathy patient treated with autologous CD 19 CAR-T therapy. (FIG. 3). In three patients with >3 months of follow-up circulating CD19 B cells reappeared 90 days post- infusion. All patients were able to discontinue all immunosuppressive therapies. In sum, preliminary data suggest administration of rapcabtagene autoleucel is effective in treating idiopathic inflammatory myopathies.

[0391] EQUIVALENTS

[0392] The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this invention has been disclosed with reference to certain embodiments, it is apparent that further embodiments and variations of this invention may be devised by others skilled in the art without departing PAT059852-PCT-SEC01 from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

Claims

1. PAT059852-PCT-SEC01What is claimed:

1. A method of treating idiopathic inflammatory myopathy in a subject comprising administering rapcabtagene autoleucel in an effective amount to treat the idiopathic inflammatory myopathy, wherein the rapcabtagene autoleucel is administered at a dose of 12.5xlOA6 CAR-positive viable cells.

2. The method of claim 1, wherein the Total Improvement Score (US) of the subject is increased by at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 points from baseline.

3. The method of claim 2, wherein the improvement in TIS score is achieved within 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months following administration of rapcabtagene autoleucel.

4. The method of claim 2, wherein the improvement in TIS score is sustained for at least 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months.

5. The method of claim 2, wherein the subject shows an increase in US score of at least 40 points, 50 points, 60 points, 70 points, 80 points, 90 points, or 100 points after no more than 52 weeks.

6. The method of claim 1 , wherein My ostitis Damage Index (MDI) score of the subject improves by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% from baseline.

7. The method of claim 6, wherein the improvement in MDI score is achieved within 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months following administration of rapcabtagene autoleucel.

8. The method of claim 6, wherein the improvement in MDI score is sustained for at least 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months.

9. The method of claim 1, wherein the modified CDASI score of the subject improves.

10. The method of claim 9, wherein the modified CDASI score of the subject decreases by at least 4 points, 6 points, 8 points, 10 points, 15 points, 20 points, 25 points, 30 points, 35 points, 40 points, 45 points, 50 points, 55 points, 60 points, 65 points, 70 points, 75PAT059852-PCT-SEC01 points, 80 points, 85 points, 90 points, 95 points, 100 points, 105 points, 110 points, 115 points, 120 points, 125 points, or 130 points from baseline.

11. The method of claim 9 wherein the overall CDASI score of the subject improves to below 40 points, 35 points, 30 points, 25 points, 20 points, 15 points, 10 points, or 5 points.

12. The method of claim 9, wherein the improvement in the modified CDASI score is achieved within 3 months, 6 months, 9 months, or 12 months following administration of rapcabtagene autoleucel.

13. The method of claim 9, wherein the improvement in modified CDASI score is sustained for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months following administration of rapcabtagene autoleucel.

14. The method of claim 1, wherein myositis disease activity assessment tool (MDAAT) score of the subject improves by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50 %, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% from baseline.

15. The method of claim 14, wherein the improvement in MDAAT score is achieved within 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months following administration of rapcabtagene autoleucel.

16. The method of claim 14, wherein the improvement in MDAAT score is sustained for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, or at least 24 months following administration of rapcabtagene autoleucel.

17. The method of claim 1, wherein the forced vital capacity (FVC) of the subject improves.

18. The method of claim 17, wherein the improvement in FVC is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at leat 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

19. The method of claim 17, wherein the improvement in FVC is achieved within 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months following administration of rapcabtagene autoleucel.PAT059852-PCT-SEC0120. The method of claim 17, wherein the improvement in FVC is sustained for least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, or at least 24 months following administration of rapcabtagene autoleucel.

21. The method of claim 1, wherein the Health Assessment Questionnaire - Disability Index (HAQ-DI) score of the subject is lowered.

22. The method of claim 21, wherein the HAQ-DI score is lowered by at least 0.2 points, at least 0.25 points, at least 0.3 points, at least 0.35 points, at least 0.4 points, at least 0.45 points, at least 0.5 points, at least 0.55 points, at least 0.6 points, at least 0.65 points, at least 0.7 points, at least 0.75 points, at least 0.8 points, at least 0.85 points, at least 0.9 points, at least 0.95 points, at least 1.0 points, at least 1.1 points, at least 1.15 points, at least 1.2 points, at least 1.25 points, at least 1.3 points, at least 1.35 points, at least 1.4 points, at least 1.45 points, at least 1.5 points, at least 1.55 points, at least 1.6 points, at least 1.65 points, at least 1.7 points, at least 1.75 points, at least 1.8 points, at least 1.85 points, at least 1.9 points, at least 1.95 points, at least 2.0 points, at least 2.1 points, at least 2.15 points, at least 2.2 points, at least 2.25 points, at least 2.3 points, at least 2.35 points, at least 2.4 points, at least 2.45 points, at least 2.5 points, at least 2.55 points, at least 2.6 points, at least 2.65 points, at least 2.7 points, at least 2.75 points, at least 2.8 points, at least 2.85 points, at least 2.9 points, at least 2.95 points, or at least 3.0 points.

23. The method of claim 21, wherein the HAQ-DI score decrease is achieved within 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months following administration of rapcabtagene autoleucel.

24. The method of claim 21, wherein the HAQ-DI score decrease is sustained for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, or at least 24 months following administration of rapcabtagene autoleucel.

25. The method of claim 1, wherein the manual muscle testing (MMT-8) score of the subject improves by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% from baseline.

26. The method of claim 25, wherein the improvement in MMT-8 score is achieved within 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months following administration of rapcabtagene autoleucel.PAT059852-PCT-SEC0127. The method of claim 25, wherein the improvement in MMT-8 score is sustained for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, or at least 24 months following administration of rapcabtagene autoleucel.

28. The method of claim 1, wherein myositis function index (FI-3) score of the subject improves by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% from baseline.

29. The method of claim 28, wherein the improvement in FI-3 score is achieved within 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months following administration of rapcabtagene autoleucel.

30. The method of claim 28, wherein the improvement in FI-3 score is sustained for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, or at least 24 months following administration of rapcabtagene autoleucel.

31. The method of claim 1, wherein the patient global activity (PGA) score of the subject improves by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% from baseline.

32. The method of claim 31 , wherein the improvement in PGA score is achieved within 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months following administration of rapcabtagene autoleucel.

33. The method of claim 31, wherein the improvement in PGA score is sustained for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, or at least 24 months following administration of rapcabtagene autoleucel.

34. The method of claim 1, wherein the physician global activity (PhGA) score of the subject improves by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50 %, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% from baseline.

35. The method of claim 34, wherein the improvement in PhGA score is achieved within 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months following administration of rapcabtagene autoleucel.

36. The method of claim 34, wherein the improvement in PhGA score is sustained for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, or at least 24 months following administration of rapcabtagene autoleucel.PAT059852-PCT-SEC0137. The method of claim 1, wherein the Patient Reported Outcome MeasurementInformation System Fatigue Short Form 7a (PROMIS F-SF) score of the subject decreases by at least 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, 8 points, 9 points, 10 points, 11 points, 12 points, 13 points, 14 points, 15 points, 16 points, 17 points, 18 points, 19 points, 20 points, 21 points, 22 points, 23 points, 24 points, 25 points, 26 points, 27 points, or 28 points from baseline.

38. The method of claim 37, wherein the decrease in PROMIS F-SF score is achieved within 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months following administration of rapcabtagene autoleucel.

39. The method of claim 37, wherein the decrease in PROMIS F-SF score is sustained for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, or at least 24 months following administration of rapcabtagene autoleucel.

40. The method of claim 1, wherein the 36 item short form survey (SF-36) score of the patient improves by an increase of at least 5 points, 10 points, 15 points, 20 points, 25 points, 30 points, 35 points, 40 points, 45 points, or 50 points from baseline.

41. The method of claim 40, wherein the increase in SF-36 score is achieved within 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months following administration of rapcabtagene autoleucel.

42. The method of claim 40, wherein the increase in SF-36 score is sustained for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, or at least 24 months following administration of rapcabtagene autoleucel.

43. The method of claim 1, wherein the Living with Pulmonary Fibrosis (L-PF) score of the subject decreases by at least 5 points, 10 points, 15 points, 20 points, 25 points, 30 points, 35 points, 40 points, 45 points, 50 points, 55 points, 60 points, 65 points, 70 points, 75 points, 80 points, 85 points, 90 points, 95 points, or 100 points from baseline.

44. The method of claim 1, wherein the muscle enzymes of the subject are reduced.

45. The method of claim 44, wherein the muscle enzymes are selected from the group consisting of creatine phosphokinase (CK), lactate dehydrogenase (LD), aspartate transaminase (AST) and alanine transaminase (ALT), and aldolase.PAT059852-PCT-SEC0146. The method of claim 44, wherein the subject’s muscle enzymes are reduced by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50 %, 55%, 60%, 65%, 70%, 75%, 80%,85%, 90%, 95%, or 100% from baseline.

47. The method of claim 44, wherein the reduction in muscle enzymes score is achieved within 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months following administration of rapcabtagene autoleucel.

48. The method of claim 44, wherein the reduction in muscle enzymes is sustained for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, or at least 24 months following administration of rapcabtagene autoleucel.

49. Rapcabtagene autoleucel for use in a method of treating a subject having idiopathic inflammatory myopathy, said method comprising administering to the subject rapcabtagene autoleucel at a dose of 12.5 x 10A6 cells.

50. A pharmaceutical composition comprising the rapcabtagene autoleucel of claim 49 and a pharmaceutically acceptable carrier.

51. A method of treating a subject with idiopathic inflammatory myopathy (IMM) comprising administering to the subject rapcabtagene autoleucel, wherein the rapcabtagene autoleucel is made by a method comprising: a) contacting a population of T-cells derived from the subject with IMM with an agent that stimulates a CD3 / TCR complex; b) contacting the population of T-cells with a nucleic acid molecule encoding a CD 19 CAR, thereby providing a population T cells comprising the CD 19 CAR c) harvesting the population of T-cells for storage or administration, wherein i. step (ii) is performed together with step (i) or no later than 20 hours after the beginning of step (i) and step (iii) is performed no later than 30 hours after the beginning of step (i); ii. step (ii) is performed together with step (i) or no later than 20 hours after the beginning of step (i) and step (iii) is performed no later than 30 hours after the beginning of step (ii); or, iii. the population of cells from step (iii) are not expanded as assessed by the number of living cells compared to the population of cells at the beginning of stepPAT059852-PCT-SEC0152. The method of claim 51, wherein:(a) the percentage of naive cells, for example, naive T cells, for example, CD45RA+ CD45RO- CCR7+ T cells, in the population of cells from step (iii) is the same as or differs by no more than 5 or 10% from the percentage of naive cells, for example, naive T cells, for example, CD45RA+ CD45RO- CCR7+ cells, in the population of cells at the beginning of step (i);(b) the percentage of naive cells, for example, naive T cells, for example, CD45RA+ CD45RO- CCR7+ T cells, in the population of cells from step (iii) is increased by, for example, at least 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, or 3-fold, as compared to the percentage of naive cells, for example, naive T cells, for example, CD45RA+ CD45RO- CCR7+ cells, in the population of cells at the beginning of step (i);(c) the percentage of CAR-expressing naive T cells, for example, CAR-expressing CD45RA+ CD45RO- CCR7+ T cells in the population of cells increases during the duration of step (ii), for example, increases by, for example, at least 30, 35, 40, 45, 50, 55, or 60%, between 18-24 hours after the beginning of step (ii); or(d) the percentage of naive cells, for example, naive T cells, for example, CD45RA+ CD45RO- CCR7+ T cells, in the population of cells from step (iii) does not decrease, or decreases by no more than 5 or 10%, as compared to the percentage of naive cells, for example, naive T cells, for example, CD45RA+ CD45RO- CCR7+ cells, in the population of cells at the beginning of step (i).

53. The method of claim 52, wherein:(a) the population of cells from step (iii) shows a higher percentage of naive cells, for example, naive T cells, for example, CD45RA+ CD45RO- CCR7+ T cells (for example, at least 10, 20, 30, or 40% higher), compared with cells made by an otherwise similar method in which step (iii) is performed more than 26 hours after the beginning ofPAT059852-PCT-SEC01 step (i), for example, more than 5, 6, 7, 8, 9, 10, 11, or 12 days after the beginning of step (i);(b) the percentage of naive cells, for example, naive T cells, for example, CD45RA+ CD45RO- CCR7+ T cells, in the population of cells from step (iii) is higher (for example, at least 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, or 3-fold higher) than the percentage of naive cells, for example, naive T cells, for example, CD45RA+ CD45RO- CCR7+ T cells, in cells made by an otherwise similar method in which step (iii) is performed more than 26 hours after the beginning of step (i), for example, more than 5, 6, 7, 8, 9, 10, 11, or 12 days after the beginning of step (i);(c) the percentage of CAR-expressing naive T cells, for example, CAR-expressing CD45RA+ CD45RO- CCR7+ T cells, in the population of cells from step (iii) is higher (for example, at least 4, 6, 8, 10, or 12-fold higher) than the percentage of CAR- expressing naive T cells, for example, CAR-expressing CD45RA+ CD45RO- CCR7+ T cells, in cells made by an otherwise similar method in which step (iii) is performed more than 26 hours after the beginning of step (i), for example, more than 5, 6, 7, 8, 9, 10, 11, or 12 days after the beginning of step (i);(d) the population of cells from step (iii) shows a higher percentage of naive cells, for example, naive T cells, for example, CD45RA+ CD45RO- CCR7+ T cells (for example, at least 10, 20, 30, or 40% higher), compared with cells made by an otherwise similar method which further comprises, after step (ii) and prior to step (iii), expanding the population of cells (for example, T cells) in vitro for more than 3 days, for example, for 5, 6, 7, 8 or 9 days;(e) the percentage of naive cells, for example, naive T cells, for example, CD45RA+ CD45RO- CCR7+ T cells, in the population of cells from step (iii) is higher (for example, at least 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, or 3-fold higher) than the percentage of naive cells, for example, naive T cells, for example, CD45RA+ CD45RO- CCR7+ T cells, in cells made by an otherwise similar method which further comprises, after step (ii) and prior to step (iii), expanding the population of cells (for example, T cells) in vitro for more than 3 days, for example, for 5, 6, 7, 8 or 9 days; orPAT059852-PCT-SEC01(f) the percentage of CAR-expressing naive T cells, for example, CAR-expressing CD45RA+ CD45RO- CCR7+ T cells, in the population of cells from step (iii) is higher (for example, at least 4, 6, 8, 10, or 12-fold higher) than the percentage of CAR- expressing naive T cells, for example, CAR-expressing CD45RA+ CD45RO- CCR7+ T cells, in cells made by an otherwise similar method which further comprises, after step (ii) and prior to step (iii), expanding the population of cells (for example, T cells) in vitro for more than 3 days, for example, for 5, 6, 7, 8 or 9 days.

54. The method of claim 53, wherein:(a) the percentage of central memory cells, for example, central memory T cells, for example, CD95+ central memory T cells, in the population of cells from step (iii) is the same as or differs by no more than 5 or 10% from the percentage of central memory cells, for example, central memory T cells, for example, CD95+ central memory T cells, in the population of cells at the beginning of step (i);(b) the percentage of central memory cells, for example, central memory T cells, for example, CCR7+CD45RO+ T cells, in the population of cells from step (iii) is reduced by at least 20, 25, 30, 35, 40, 45, or 50%, as compared to the percentage of central memory cells, for example, central memory T cells, for example, CCR7+CD45RO+ T cells, in the population of cells at the beginning of step (i);(c) the percentage of CAR-expressing central memory T cells, for example, CAR- expressing CCR7+CD45RO+ cells, decreases during the duration of step (ii), for example, decreases by, for example, at least 8, 10, 12, 14, 16, 18, or 20%, between 18-24 hours after the beginning of step (ii); or(d) the percentage of central memory cells, for example, central memory T cells, for example, CCR7+CD45RO+ T cells, in the population of cells from step (iii) does not increase, or increases by no more than 5 or 10%, as compared to the percentage of central memory cells, for example, central memory T cells, for example, CCR7+CD45RO+ T cells, in the population of cells at the beginning of step (i).PAT059852-PCT-SEC0155. The method of claim 53, wherein:(a) the population of cells from step (iii) shows a lower percentage of central memory cells, for example, central memory T cells, for example, CD95+ central memory T cells (for example, at least 10, 20, 30, or 40% lower), compared with cells made by an otherwise similar method in which step (iii) is performed more than 26 hours after the beginning of step (i), for example, more than 5, 6, 7, 8, 9, 10, 11, or 12 days after the beginning of step (i);(b) the percentage of central memory cells, for example, central memory T cells, for example, CCR7+CD45RO+ T cells in the population of cells from step (iii) is lower (for example, at least 20, 30, 40, or 50% lower) than the percentage of central memory cells, for example, central memory T cells, for example, CCR7+CD45RO+ T cells, in cells made by an otherwise similar method in which step (iii) is performed more than 26 hours after the beginning of step (i), for example, more than 5, 6, 7, 8, 9, 10, 11, or 12 days after the beginning of step (i);(c) the percentage of CAR-expressing central memory T cells, for example, CAR- expressing CCR7+CD45RO+ T cells in the population of cells from step (iii) is lower (for example, at least 10, 20, 30, or 40% lower) than the percentage of CAR-expressing central memory T cells, for example, CAR-expressing CCR7+CD45RO+ T cells, in cells made by an otherwise similar method in which step (iii) is performed more than 26 hours after the beginning of step (i), for example, more than 5, 6, 7, 8, 9, 10, 11, or 12 days after the beginning of step (i);(d) the population of cells from step (iii) shows a lower percentage of central memory cells, for example, central memory T cells, for example, CD95+ central memory T cells (for example, at least 10, 20, 30, or 40% lower), compared with cells made by an otherwise similar method which further comprises, after step (ii) and prior to step (iii), expanding the population of cells (for example, T cells) in vitro for more than 3 days, for example, for 5, 6, 7, 8 or 9 days;PAT059852-PCT-SEC01(e) the percentage of central memory cells, for example, central memory T cells, for example, CCR7+CD45RO+ T cells in the population of cells from step (iii) is lower (for example, at least 20, 30, 40, or 50% lower) than the percentage of central memory cells, for example, central memory T cells, for example, CCR7+CD45RO+ T cells, in cells made by an otherwise similar method which further comprises, after step (ii) and prior to step (iii), expanding the population of cells (for example, T cells) in vitro for more than 3 days, for example, for 5, 6, 7, 8 or 9 days; or(f) the percentage of CAR-expressing central memory T cells, for example, CAR- expressing CCR7+CD45RO+ T cells in the population of cells from step (iii) is lower (for example, at least 10, 20, 30, or 40% lower) than the percentage of CAR-expressing central memory T cells, for example, CAR-expressing CCR7+CD45RO+ T cells, in cells made by an otherwise similar method which further comprises, after step (ii) and prior to step (iii), expanding the population of cells (for example, T cells) in vitro for more than 3 days, for example, for 5, 6, 7, 8 or 9 days.

56. The method of claim 53, wherein:(a) the percentage of stem memory T cells, for example, CD45RA+CD95+IL-2 receptor P+CCR7+CD62L+ T cells, in the population of cells from step (iii) is increased, as compared to the percentage of stem memory T cells, for example, CD45RA+CD95+IL-2 receptor P+CCR7+CD62L+ T cells, in the population of cells at the beginning of step (i);(b) the percentage of CAR-expressing stem memory T cells, for example, CAR-expressing CD45RA+CD95+IL-2 receptor P+CCR7+CD62L+ T cells, in the population of cells from step (iii) is increased, as compared to the percentage of CAR- expressing stem memory T cells, for example, CAR-expressing CD45RA+CD95+IL-2 receptor P+CCR7+CD62L+ T cells, in the population of cells at the beginning of step (i);(c) the percentage of stem memory T cells, for example, CD45RA+CD95+IL-2 receptor P+CCR7+CD62L+ T cells, in the population of cellsPAT059852-PCT-SEC01 from step (iii) is higher than the percentage of stem memory T cells, for example, CD45RA+CD95+IL-2 receptor P+CCR7+CD62L+ T cells, in cells made by an otherwise similar method in which step (iii) is performed more than 26 hours after the beginning of step (i), for example, more than 5, 6, 7, 8, 9, 10, 11, or 12 days after the beginning of step (i); or(d) the percentage of CAR-expressing stem memory T cells, for example, CAR-expressing CD45RA+CD95+IL-2 receptor P+CCR7+CD62L+ T cells, in the population of cells from step (iii) is higher than the percentage of CAR-expressing stem memory T cells, for example, CAR-expressing CD45RA+CD95+IL-2 receptor P+CCR7+CD62L+ T cells, in cells made by an otherwise similar method in which step (iii) is performed more than 26 hours after the beginning of step (i), for example, more than 5, 6, 7, 8, 9, 10, 11, or 12 days after the beginning of step (i);(e) the percentage of stem memory T cells, for example, CD45RA+CD95+IL-2 receptor P+CCR7+CD62L+ T cells, in the population of cells from step (iii) is higher than the percentage of stem memory T cells, for example, CD45RA+CD95+IL-2 receptor P+CCR7+CD62L+ T cells, in cells made by an otherwise similar method which further comprises, after step (ii) and prior to step (iii), expanding the population of cells (for example, T cells) in vitro for more than 3 days, for example, for 5, 6, 7, 8 or 9 days; or(f) the percentage of CAR-expressing stem memory T cells, for example, CAR-expressing CD45RA+CD95+IL-2 receptor P+CCR7+CD62L+ T cells, in the population of cells from step (iii) is higher than the percentage of CAR-expressing stem memory T cells, for example, CAR-expressing CD45RA+CD95+IL-2 receptor P+CCR7+CD62L+ T cells, in cells made by an otherwise similar method which further comprises, after step (ii) and prior to step (iii), expanding the population of cells (for example, T cells) in vitro for more than 3 days, for example, for 5, 6, 7, 8 or 9 days.

57. A method of treating idiopathic inflammatory myopathy in a subject comprising administering a population of cells expressing a CD 19 chimeric antigen receptor (CAR) in an effective amount to treat the idiopathic inflammatory myopathy.PAT059852-PCT-SEC0158. The method of claim 57, wherein the effective amount comprises about 0.5 x 106viable CAR-expressing cells to about 1.25 x 109viable CAR-expressing cells.

59. The method of claim 58, wherein the Total Improvement Score (US) of the subject is increased by at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 points from baseline.

60. The method of claim 58, wherein the improvement in US score is achieved within 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months following administration of the CAR-expressing cells.

61. The method of claim 58, wherein the improvement in US score is sustained for at least 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months.

62. The method of claim 58, wherein the subject shows an increase in TIS score of at least 40 points, 50 points, 60 points, 70 points, 80 points, 90 points, or 100 points after no more than 52 weeks.

63. The method of claim 58, wherein Myostitis Damage Index (MDI) score of the subject improves by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% from baseline.

64. The method of claim 58, wherein the improvement in MDI score is achieved within 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months following administration of the CAR-expressing cells.

65. The method of claim 58, wherein the improvement in MDI score is sustained for at least 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months.

66. The method of claim 58, wherein the modified CDASI score of the subject improves.

67. The method of claim 58, wherein the modified CDASI score of the subject decreases by at least 4 points, 6 points, 8 points, 10 points, 15 points, 20 points, 25 points, 30 points, 35 points, 40 points, 45 points, 50 points, 55 points, 60 points, 65 points, 70 points, 75 points, 80 points, 85 points, 90 points, 95 points, 100 points, 105 points, 110 points, 115 points, 120 points, 125 points, or 130 points from baseline.

68. The method of claim 58, wherein the overall CDASI score of the subject improves to below 40 points, 35 points, 30 points, 25 points, 20 points, 15 points, 10 points, or 5 points.PAT059852-PCT-SEC0169. The method of claim 58, wherein the improvement in the modified CDASI score is achieved within 3 months, 6 months, 9 months, or 12 months following administration of the CAR-expressing cells.

70. The method of claim 58, wherein the improvement in modified CDASI score is sustained for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months following administration of the CAR- expressing cells.

71. The method of claim 58, wherein myositis disease activity assessment tool (MDAAT) score of the subject improves by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50 %, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% from baseline.

72. The method of claim 58, wherein the improvement in MDAAT score is achieved within 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months following administration of the CAR-expressing cells.

73. The method of claim 58, wherein the improvement in MDAAT score is sustained for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, or at least 24 months following administration of the CAR-expressing cells.

74. The method of claim 58, wherein the forced vital capacity (FVC) of the subject improves.

75. The method of claim 58, wherein the improvement in FVC is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at leat 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

76. The method of claim 58, wherein the improvement in FVC is achieved within 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months following administration of the CAR-expressing cells.

77. The method of claim 58, wherein the improvement in FVC is sustained for least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, or at least 24 months following administration of the CAR-expressing cells.

78. The method of claim 58, wherein the Health Assessment Questionnaire - Disability Index (HAQ-DI) score of the subject is lowered.PAT059852-PCT-SEC0179. The method of claim 58, wherein the HAQ-DI score is lowered by at least 0.2 points, at least 0.25 points, at least 0.3 points, at least 0.35 points, at least 0.4 points, at least 0.45 points, at least 0.5 points, at least 0.55 points, at least 0.6 points, at least 0.65 points, at least 0.7 points, at least 0.75 points, at least 0.8 points, at least 0.85 points, at least 0.9 points, at least 0.95 points, at least 1.0 points, at least 1.1 points, at least 1.15 points, at least 1.2 points, at least 1.25 points, at least 1.3 points, at least 1.35 points, at least 1.4 points, at least 1.45 points, at least 1.5 points, at least 1.55 points, at least 1.6 points, at least 1.65 points, at least 1.7 points, at least 1.75 points, at least 1.8 points, at least 1.85 points, at least 1.9 points, at least 1.95 points, at least 2.0 points, at least 2.1 points, at least 2.15 points, at least 2.2 points, at least 2.25 points, at least 2.3 points, at least 2.35 points, at least 2.4 points, at least 2.45 points, at least 2.5 points, at least 2.55 points, at least 2.6 points, at least 2.65 points, at least 2.7 points, at least 2.75 points, at least 2.8 points, at least 2.85 points, at least 2.9 points, at least 2.95 points, or at least 3.0 points.

80. The method of claim 58, wherein the HAQ-DI score decrease is achieved within 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months following administration of the CAR-expressing cells.

81. The method of claim 58, wherein the HAQ-DI score decrease is sustained for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, or at least 24 months following administration of the CAR-expressing cells.

82. The method of claim 58, wherein the manual muscle testing (MMT-8) score of the subject improves by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% from baseline.

83. The method of claim 58, wherein the improvement in MMT-8 score is achieved within 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months following administration of the CAR-expressing cells.

84. The method of claim 58, wherein the improvement in MMT-8 score is sustained for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, or at least 24 months following administration of the CAR-expressing cells.

85. The method of claim 58, wherein myositis function index (FI-3) score of the subject improves by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% from baseline.PAT059852-PCT-SEC0186. The method of claim 58, wherein the improvement in FI-3 score is achieved within 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months following administration of the CAR-expressing cells.

87. The method of claim 58, wherein the improvement in FI-3 score is sustained for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, or at least 24 months following administration of the CAR-expressing cells.

88. The method of claim 58, wherein the patient global activity (PGA) score of the subject improves by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% from baseline.

89. The method of claim 58, wherein the improvement in PGA score is achieved within 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months following administration of the CAR-expressing cells.

90. The method of claim 58, wherein the improvement in PGA score is sustained for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, or at least 24 months following administration of the CAR-expressing cells.

91. The method of claim 58, wherein the physician global activity (PhGA) score of the subject improves by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50 %, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% from baseline.

92. The method of claim 58, wherein the improvement in PhGA score is achieved within 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months following administration of the CAR-expressing cells.

93. The method of claim 58, wherein the improvement in PhGA score is sustained for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, or at least 24 months following administration of the CAR-expressing cells.

94. The method of claim 58, wherein the Patient Reported Outcome Measurement Information System Fatigue Short Form 7a (PROMIS F-SF) score of the subject decreases by at least 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, 8 points, 9 points, 10 points, 11 points, 12 points, 13 points, 14 points, 15 points, 16 points, 17 points, 18 points, 19 points, 20 points, 21 points, 22 points, 23 points, 24 points, 25 points, 26 points, 27 points, or 28 points from baseline.PAT059852-PCT-SEC0195. The method of claim 58, wherein the decrease in PROMIS F-SF score is achieved within 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months following administration of the CAR-expressing cells.

96. The method of claim 58, wherein the decrease in PROMIS F-SF score is sustained for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, or at least 24 months following administration of the CAR-expressing cells.

97. The method of claim 58, wherein the 36 item short form survey (SF-36) score of the patient improves by an increase of at least 5 points, 10 points, 15 points, 20 points, 25 points, 30 points, 35 points, 40 points, 45 points, or 50 points from baseline.

98. The method of claim 58, wherein the increase in SF-36 score is achieved within 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months following administration of the CAR-expressing cells.

99. The method of claim 58, wherein the increase in SF-36 score is sustained for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, or at least 24 months following administration of the CAR-expressing cells.

100. The method of claim 58, wherein the Living with Pulmonary Fibrosis (L-PF) score of the subject decreases by at least 5 points, 10 points, 15 points, 20 points, 25 points, 30 points, 35 points, 40 points, 45 points, 50 points, 55 points, 60 points, 65 points, 70 points, 75 points, 80 points, 85 points, 90 points, 95 points, or 100 points from baseline.

101. The method of claim 58, wherein the muscle enzymes of the subject are reduced.

102. The method of claim 58, wherein the muscle enzymes are selected from the group consisting of creatine phosphokinase (CK), lactate dehydrogenase (LD), aspartate transaminase (AST) and alanine transaminase (ALT), and aldolase.

103. The method of claim 58, wherein the subject’s muscle enzymes are reduced by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50 %, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% from baseline.

104. The method of claim 58, wherein the reduction in muscle enzymes score is achieved within 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months following administration of the CAR-expressing cellsPAT059852-PCT-SEC01105. The method of claim 58, wherein the reduction in muscle enzymes is sustained for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, or at least 24 months following administration of the CAR-expressing cells.

106. A population of CD 19 expressing chimeric antigen cells for use in a method of treating a subject having idiopathic inflammatory myopathy, said method comprising administering to the subject rapcabtagene autoleucel at a dose of 12.5 x 10A6 cells.

107. A pharmaceutical composition comprising the CD 19 expressing chimeric antigen cells of claim 106 and a pharmaceutically acceptable carrier.

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