Methods for utilizing commensal polyomavirus for cancer therapy

Abstract

Provided herein are methods for treating a cancer, e.g., a solid tumor and / or a blood cancer, using a polyomavirus in a subject in need thereof. The methods further include treating the cancer with an additional cancer therapy, e.g., surgery, radiation, chemotherapy, and / or immunotherapy. Additionally, provided herein are methods of using polyomavirus for immune system activation for the prevention of cancer.

Description

[0001] METHODS FOR UTILIZING COMMENSAL POLYOMA VIRUS FOR CANCER THERAPY

[0002] CLAIM OF PRIORITY

[0003] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 573.020, filed on April 2. 2024. The entire contents of the foregoing are incorporated herein by reference.

[0004] TECHNICAL FIELD

[0005] The present disclosure related to methods of using commensal polyomavirus in the treatment of cancer.

[0006] BACKGROUND

[0007] The advances in cancer immunotherapy over the last decade have revealed the tremendous potential of the immune system to defend against cancer. Cancer immunotherapy has unique advantages compared with other treatment modalities as it can be applied broadly across cancer types and relapses are less likely to happen [1], However, current cancer immunotherapies do not consistently achieve satisfactory outcomes. The average response rate of cancer patients to immune checkpoint blockade (ICB) therapy is between 20 to 50%, and only 15% to 20% of patients who received immunotherapy have achieved long-lasting remissions [12, 13], Overcoming cancer resistance to the current immunotherapies including ICB therapy has emerged as an urgent unmet need in the field of cancer immunology.

[0008] SUMMARY

[0009] Provided herein are methods for treating cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of live or live-attenuated commensal polyomavirus, or antigenic protein, protein fragment, or peptide thereof, to a subject identified as having a cancer. Also provided herein are methods of inducing an immunogenic response to a cancer cell in a subject in need thereof, the method comprising administering a therapeutically effective amount of live or live-attenuated commensal polyomavirus, or antigenic protein, protein fragment, or peptide thereof, to the subject in need thereof. Also provided herein are methods of vaccinating, or reducing the risk of developing cancer in a subject against a solid tumor, the method comprising administering a therapeutically effective amount of live or live-attenuated commensal polyomavirus, or antigenic protein, protein fragment, or peptide thereof, to the subject in need thereof.

[0010] In some embodiments, the live or live-attenuated commensal polyomavirus, or antigenic protein, protein fragment, or peptide thereof, is selected from MPyV. MCPyV, HPyV7, HPyV6, BKPyV, JCPyV, LPyV, KIPyV, WUPyV, and / or TSPyV polyomavirus strains and / or MPyV, MCPyV, HPyV7, HPyV6, BKPyV, JCPyV, LPyV, KIPyV, WUPyV, and / or TSPyV antigenic proteins, protein fragments, or peptides.

[0011] In some embodiments, the subject is a mammal. In some embodiments, the mammal is immunocompetent. In some embodiments, the subject has an increased risk of developing cancer.

[0012] In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is a breast cancer, a lung cancer, a prostate cancer, a glioma, a melanoma, an ovarian cancer, a liver cancer, a pancreatic cancer, a kidney cancer, a bladder cancer, a thyroid cancer, a sarcoma, a stomach cancer, a head and neck cancer, a cervical cancer, an endometrial cancer, an esophageal cancer, a thymoma, a soft tissue sarcoma, a bone cancer, a testicular cancer, a penile cancer, a gallbladder cancer, a uterine sarcoma, an adrenal gland cancer, an ampullary cancer, a hepatic angiosarcoma, a nasal, or a paranasal sinus cancer.

[0013] In some embodiments, the cancer is a blood cancer. In some embodiments, the blood cancer is a leukemia, a lymphoma, a myeloma, a myelodysplastic syndrome, or a myeloproliferative neoplasm.

[0014] In some embodiments, the administering comprises intravenous, intradermal, subcutaneous, intratumoral, intramuscular, or subcutaneous administration.

[0015] In some embodiments, methods provided herein further comprises administering to the subject an additional cancer therapy. In some embodiments, the additional cancer therapy comprises surgery, radiation, chemotherapy, and / or immunotherapy.

[0016] In some embodiments, the additional cancer therapy comprises immune checkpoint blockade therapy. In some embodiments, the immune checkpoint blockade therapy comprises PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, and / or LAG-3 inhibitors. In some embodiments, the PD-1 and PD-L1 inhibitors comprise nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, INCMGA00012, AMP-224, AMP-514, acrixolimab, KN035, cosibelimab, AUNP12, CA-170, and / or BMS-986189. In some embodiments, the CTLA-4 inhibitors comprise ipilimumab and / or tremelimumab. In some embodiments, the LAG-3 inhibitors comprise relatlimab.

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0018] Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims.

[0019] DESCRIPTION OF DRAWINGS

[0020] FIGS. 1A- IB. Intratumor MPyV inhibits lung cancer progression. C57BL / 6 mice w ere colonized with 2 X 106plaque-forming unit (PFU) MPy V for 2 wee s and then were challenged with 1 X 106Lewis lung cancer (LLC) cells that were previously incubated with either 20 MOI MPyV or VLP for 3 days (n=10). (FIG. 1A) Tumor volume was monitored and (FIG. IB) Kaplan-Meier survival plot was recorded. Tumor volume data were analyzed with two-way ANOVA (FIG. 1A) and survival data were analyzed with log-rank (Mantel-Cox) test (FIG. IB).

[0021] FIGS. 2A- 2B. Intratumor MPyV inhibits breast cancer progression. C57BL / 6 mice were colonized with 2 X 106PFU MPyV for 2 weeks and then were challenged with 1 X 106E0771 cells that were previously incubated with either 20 MOI MPyV or VLP for 3 days (n=10). (FIG. 2A) Tumor volume was monitored and (FIG. 2B) Kaplan-Meier survival plot was recorded. Tumor volume data were analyzed with two-way ANOVA (FIG. 2A) and survival data were analyzed with logrank (Mantel-Cox) test (FIG. 2B).

[0022] FIGS. 3A- 3G. Impact of MPyV infection on lung cancer cell viability and activation. (FIGS. 3A-B) LLC cells were treated with 20 MOI MPyV for 3 days, and subsequent cell death was assessed using the PI and Annexin V kit. (FIG. 3A) Flow cytometry’ analysis showing differences between the VLP-treated cells and the MPyV treated cells. (FIG. 3B) Quantification of cells displaying both PI and Annexin V, indicating apoptosis. (FIGS. 3C-G) After a 24-day infection with 20 MOI MPyV, LLC cells underwent assessments for cell surface markers and gene expression. (FIGS. 3C-D) Flow cytometry analyses revealed the levels of (FIG. 3C) MHC-I and (FIG. 3D) PDL1 on the cell surface. (FIGS. 3E-G) Expression levels of IFN-fi (FIG. 3E) , MX1 (FIG. 3F), and TNF-a (FIG. 3G) were determined using qPCR. Statistical analyses for (FIGS. 3B, F, and G) were conducted using the Mann- Whitney U test.

[0023] FIGS. 4A- 4G. Impact of MPyV infection on breast cancer cell viability and activation. (FIGS. 4A-B) E0771 cells were treated yvith 20 MOI MPyV for 3 days, and subsequent cell death was assessed using the PI and Annexin V kit. (FIG. 4A) Flow cytometry analysis showing differences between the VLP-treated cells and the MPyV treated cells. (FIG. 4B) Quantification of cells displaying both PI and Annexin V, indicating apoptosis. (FIGS. 4C-G) After a 24-hours infection with 20 MOI MPyV. E0771 cells underwent assessments for cell surface markers and gene expression. (FIGS. 4C-D) Flow cytometry analyses revealed the levels of (FIG. 4C) MHC-I and (FIG. 4D) PDL1 on the cell surface. (FIGS. 4E-G) Expression levels of IFN- (FIG. 4E), MX1 (FIG. 4F), and TNF-a (FIG. 4G) were determined using qPCR. Statistical analyses for (FIGS. 4B, F, and G) were conducted using the Mann- Whitney U test.

[0024] FIG. 5. MPyV infection did not affect fibroblast cell growth. Mouse embryonic fibroblast cells were infected with 20 MOI MPyV. Cell proliferation was monitored on day 2, 4, and 6 post-infection. Cells were then fixed with PFA and stained with crystal violet.

[0025] FIG. 6. MPyV -immunized mice resisted tumors expressing MPyV antigen. Mice were first colonized with MPyV before being introduced to MPyV+ E0771 tumors. Upon rejecting these E0771 tumors, the mice were subsequently exposed to the melanoma cell line D4M.3A, which expressed either the MPyV middle T antigen or EGFP. Tumor growth was tracked every' other day for a sample size of six mice. Tumor volume results were analyzed using a two-way ANOVA.

[0026] FIG. 7. Tumor rejection mediated by MPyV is dependent on CD4 and CD8 T Cells. Mice were first colonized with MPyV. Following a 14-day period, they were inoculated with either VLP-E0771 or MPyV-E0771 tumors. The MPy V-E0771 mice cohort was then treated with either anti-CD4 antibodies, anti-CD8 antibodies, or administered an IgG control, with a sample size of ten mice per group. Tumor growth metrics were evaluated using a two-way ANOVA.

[0027] FIG. 8. Absence of P2M negates MPyV -induced tumor suppression. In MPyV-colonized mice, E0771 P2M’ ’ tumor cells were incubated with either VLP or MPyV. followed by injection into the mice. A sample group of ten mice was used. Tumor growth was monitored, and data were evaluated using a two-way ANOVA.

[0028] FIGS. 9A-9B. MPyV -colonized and tumor-rejected mice failed to resist P2M" ' tumor cells. (FIG. 9A) Mice initially colonized with MPyV and having successfully rejected the MPyV-E0771 tumors, were subsequently exposed to naive E0771 tumor cells (n=10). (FIG. 9B) Following MPyV colonization and rejection of both MPyV- E0771 and naive E0771 tumors, mice were rechallenged with E0771 |32M" tumor cells (n= 10). Tumor growth was assessed using a two-way ANOVA.

[0029] FIGS. 10A-10C. MPyV infection facilitated antigen spreading. (FIG. 10A) Schematic representation highlighting polyomavirus's role in the antigen-spreading tumor model. (FIG. 10B) C57BL / 6 mice were colonized with 2 x 106PFU MPyV. By day 14, these mice were exposed to one of the following: MPyV-infected LLC-OVA, uninfected (naive) LLC-OVA, or naive E0771-mCherry-OVA (n=6). (FIG. 10C) On day 36. mice from the MPyV-infected LLC-OVA group that remained tumor-free were rechallenged with either E0771-OVA cells or E0771 cells. Subsequent tumor growth was tracked every other day (n=6).

[0030] FIGS. 11A-11B. Utilizing MPyV in cancer therapy. (FIG. 11A) Schematic representation of the therapeutic role of polyomavirus in the tumor model. (FIG. 11B) Following the formation of E0771 tumors in MPyV -colonized mice, tumors were directly treated with an injection of 2 x 106PFU MPyV. Subsequent changes in tumor volume w ere monitored and analyzed using a tw o-w ay ANOVA.

[0031] FIGS. 12A-12G. MPyV reduces tumor development in MMTV-Her2 mice. (FIG. 12A) Quantification of MPyV large T antigen (LT) RNA levels in various organs of WT C57BL / 6 mice at 3 weeks post-infection with live MPyV (n=4). (FIG. 12B) Time course analysis of MPyV LT RNA levels in WT mice mammary glands up to 12 weeks after infection with MPyV (6 weeks, n=6; 0 and 12 weeks, n=5). (FIG. 12C) Five-week-old MMTV-Her2 mice colonized with MPyV and treated with dimethylbenz[a]anthracene (DMBA) and monitored for spontaneous breast tumor development. (FIG. 12D) MMTV-Her2 tumor outcomes as shown by number of palpable tumors over time. (FIG. 12 E) MMTV-Her2 tumor outcomes as shown by time to tumor onset. (FIG. 12F) MMTV-Her2 tumor outcomes as shown by percentage survival (VLP group, n=6; MPyV group, n=8). (FIG. 12G) Quantification of MPyV LT levels in tumors, mammary glands, and spleens at the endpoint in MPyV -colonized MMTV-Her2 mice (n=6). Two-way ANOVA (FIG. 12D), and Logrank (Mantel-Cox) test (FIG. 12E and 12F).

[0032] DETAILED DESCRIPTION

[0033] Commensal viruses are common, inapparent infections that do not usually cause symptoms or diseases in an immunocompetent host after an infection; most of them will establish long-term latency [3], Whole-genome sequencing data of blood from 8,240 individuals without any clear infectious disease revealed 94 different viruses in 42% of the study participants. They included 19 human DNA viruses, proviruses and RNA viruses (herpesviruses, adenoviruses, papillomaviruses, polyomaviruses, adenovirus. HIV. HTLV. hepatitis B, hepatitis C, parvovirus Bl 9. and influenza virus) [4], Approximately 12% to 20% of human cancers are associated with viral infections

[0016] , Viral infections can induce cellular transformation via the induction of chronic inflammation or the expression of viral oncoproteins

[0017] , The viral antigens increase tumor immunogenicity and enhance host immune response against cancer development

[0018] ,

[0034] The methods herein show that polyomavirus can increase tumor immunogenicity by changing the typical ‘cold’ tumors that lack immune cell infiltration into ‘hot’ immunogenic tumors. A major immune adverse event associated with immunotherapies is cytokine release syndrome, in which large amounts of cytokines are released into the circulation causing multiple organ dysfunction

[0015] , The present methods show that polyomavirus infection does not significantly alter the interferons (IFNs) release, exhibiting its potential as a safer immunotherapy candidate without risking a “cytokine storm”. In addition, the systemic colonization of polyomavirus after local deliver}' highlights a unique potential of this virus in generating a systemic therapeutic effect in patients with metastatic cancer.

[0035] In summary, the present methods demonstrate the role of intratumor polyomavirus in cancer development. The polyomaviruses can impede the progression of lung and breast cancers by increasing the cancer immunogenicity7and inhibiting the tumor growth. Thus, live polyomaviruses can serve as novel therapeutic agents for the treatment of tumors.

[0036] Polyomavirus

[0037] Polyomaviruses are small, nonenveloped double-stranded DNA viruses that are widespread in humans

[0019] , In immunocompetent hosts, these viruses colonize the tissues after primary7infection, which appear to cause little or no symptoms during the lifespan of the immunocompetent host [5], A high seroprevalence of polyomaviruses was observed in healthy adult blood donors, and it was found that the seroprevalence of simian vacuolating virus 40 (SV40) was 9%, human polyomavirus 6 (HPyV6) 88.2%, human polyomavirus 7 (HPyV7) 65.7.2%, BK polyomavirus (BKPyV) 82%, JC polyomavirus (JCPyV) 39%, primate lymphotropic polyomavirus (LPyV) 15%, KI polyomavirus (KIPyV) 55%. WU polyomavirus (WUPyV) 69% and Merkel Cell Polyomavirus (MCPyV) 65% [6, 7], Polyomaviruses DNA is detectable in healthy human blood: MCPyV 3.8%, JCPyV and TS polyomavirus (TSPyV) DNA 0.5%, and HPyV9 0.4%. BKPyV, WUPyV, HPyV6, MWPyV, and LIPyV DNA were detected at 0.1%-0.2% blood samples [8], Human MCPyV, HPyV6, and HPyV7 are considered as cutaneous viruses. MCPyV were found at 40-80% DNA positive in healthy^ individuals [9], HPyV6 and HPy V7 were found in 14-50% and 11% respectively in normal human skin [10, 11], Previous studies have shown high polyomavirus seroprevalence and frequent presence of polyomavirus-specific T cells in healthy adults [6, 7], However, in the elderly population. Merkel cell polyomavirus (MCPyV) integration into host genome is the primary oncogenic event in -80% of Merkel cell carcinoma (MCC) cases while the remaining virus-negative MCC cases are associated with ultraviolet (UV) radiation

[0020] , MCPyV-induced MCCs are highly immunogenic and are associated with prominent intratumoral T and natural killer (NK) cell infiltrates

[0012] , The present disclosure is inclusive of polyomaviruses that can establish persistent infection in humans. The Polyomavirus genome is characterized by a specific organizational structure, featuring a double-stranded DNA (dsDNA) genome containing distinct early and late regions. The early region encodes the T antigens, while the late region encodes structural viral proteins, both situated on opposite strands. These regions are demarcated by a noncoding control region. The genetic distance observed in the large T antigen (LTAg) coding sequence to members of the most closely related species exceeds 15%. When two polyomaviruses exhibit a genetic distance of less than 15%, considerations of biological properties such as host specificity, disease association, tissue tropism, etc., may warrant the establishment of a new species. Provided herein are the genome sequences of select human polyomaviruses: HPyV6 (Accession No. NC_014406), HPyV7 (Accession No. NC_014407), and MCPyV (Accession No.NC_010277).

[0038] Cancer

[0039] Provided herein are methods for treating a cancer in a subject in need thereof, the method including administering a therapeutically effective amount of live or live- attenuated commensal polyomavirus, or antigenic protein, protein fragment, or peptide thereof, to a subject identified as having a cancer.

[0040] In some embodiments, the cancer is a solid tumor. For example, the solid tumor can be a breast cancer, a lung cancer, a prostate cancer, a glioma, a melanoma, a keratinocyte cancer (e.g.. a basal cell carcinoma or a squamous cell carcinoma), an ovarian cancer, a liver cancer, a pancreatic cancer, a kidney cancer, a bladder cancer, a thyroid cancer, a sarcoma, a stomach cancer, a head and neck cancer, a colorectal cancer, an anal cancer, a cervical cancer, an endometrial cancer, an esophageal cancer, a thymoma, a soft tissue sarcoma, a bone cancer, a testicular cancer, a penile cancer, a gallbladder cancer, a uterine sarcoma, an adrenal gland cancer, an ampullary cancer, a hepatic angiosarcoma, a nasal, or a paranasal sinus cancer. In some embodiments, the cancer is a blood cancer. For example, the blood cancer can be a leukemia, a lymphoma, a myeloma, a myelodysplastic syndrome, or a myeloproliferative neoplasm. Pharmaceutical Compositions

[0041] Pharmaceutical compositions typically include a pharmaceutically acceptable carrier. As used herein the language “pharmaceutically acceptable carrier” includes saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Pharmaceutical compositions are typically formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, intratumoral, intramuscular or subcutaneous administration.

[0042] Methods of formulating suitable pharmaceutical compositions are known in the art, see, e.g., Remington: The Science and Practice of Pharmacy, 21st ed., 2005; and the books in the series Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs (Dekker, NY). For example, solutions or suspensions 20 used for parenteral, intradermal, intramuscular, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzy l alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite: chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0043] Pharmaceutical compositions suitable for injectable use can include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.

[0044] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-diying, which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0045] In some embodiments, administering a therapeutically effective amount of live or live-attenuated commensal polyomavirus, or antigenic protein, protein fragment, or peptide thereof, to a subject identified as having a cancer includes intravenous, intradermal, subcutaneous, intratumoral, intramuscular, or subcutaneous administration. Systemic administration of a therapeutic compound as described herein can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

[0046] In one embodiment, the therapeutic compounds are prepared with carriers that will protect the therapeutic compounds against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Such formulations can be prepared using standard techniques, or obtained commercially, e.g., from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to selected cells with monoclonal antibodies to cellular antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811. The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0047] Subjects

[0048] The method described herein can be used to treat cancer in subjects detected with a cancer. In some embodiments, the subjects have an increased risk of developing cancer. For example, the subject may have a family history or a personal history of breast cancer or lung cancer. In some embodiments, the breast cancer is a metastatic breast cancer, AR-positive breast cancer, AR positive refractory breast cancer, HER2 positive breast cancer, HR positive breast cancer, or triple negative breast cancer (TNBC). In some embodiments, the lung cancer is a non-small cell lung cancer or a small cell lung cancer. In some embodiments, the cancer is one of the cancers described. In some embodiments, the subject is a mammal, e.g., an immunocompetent mammal. For example, the mammals can be human or non-human veterinary subjects.

[0049] Method of Treatment

[0050] Provided herein are methods for treating a cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of live or live-attenuated commensal polyomavirus, or antigenic protein, protein fragment, or peptide thereof, to a subject identified as having a cancer. The methods described herein include methods for the treatment of cancer, including any of the cancers disclosed.

[0051] The methods include administering a therapeutically effective amount of live or live-attenuated commensal polyomavirus, or antigenic protein, protein fragment, or peptide thereof, to a subject identified as having a cancer. In some embodiments, the live or live-attenuated commensal polyomavirus, or antigenic protein, protein fragment, or peptide thereof, is selected from MPyV, MCPyV, HPyV7, HPyV6, BKPyV, JCPyV, LPyV, KIPyV, WUPyV, and / or TSPyV polyomavirus strains and / or MPyV, MCPyV, HPyV7, HPyV6, BKPyV, JCPyV, LPyV, KIPyV, WUPyV, and / or TSPyV antigenic proteins, protein fragments, or peptides. In some embodiments, subject is administered two or more live or live-attenuated commensal polyomaviruses, or antigenic proteins, protein fragments, or peptides thereof, selected from MPyV, MCPyV, HPyV7, HPyV6, BKPyV, JCPyV, LPyV, KIPyV, WUPyV, and / or TSPyV polyomavirus strains and / or MPyV, MCPyV, HPyV7, HPyV6, BKPyV, JCPyV. LPyV, KIPyV. WUPyV. and / or TSPyV antigenic proteins, protein fragments, or peptides. In some cases, the antigenic protein, protein fragment, or peptide can be expressed by a vector (e.g., a viral vector, a non-viral vector, a DNA vector, or an RNA vector). For example, the viral vector can be a lentivirus, an adenovirus, an adeno-associated virus, a retrovirus, or a herpes simplex virus. The non-viral vector can be a liposome, an exosome, an extracellular vesicle, a polymer, a nanoparticle, a peptide, or a dendrimer.

[0052] The methods described herein can be used to treat cancer in immunocompetent subjects. In some embodiments, the subjects have an increased risk of developing cancer (e.g.. breast cancer, or lung cancer). For example, the subject may have a family history and / or personal history of cancer. In some embodiments, subjects are mammals. For example, the mammal can be immunocompetent.

[0053] Methods for treating a mammal having cancer (e.g., breast cancer) can include identifying the mammal as having cancer. Examples of methods for identifying the mammal as having cancer include, without limitation, physical examination, laboratory tests (e.g., blood, urine, and / or circulating tumor cells (CTCs)), biopsy, imaging tests (e.g, X-ray, PET / CT, MRI, and / or ultrasound), nuclear medicine scans (e.g., bone scans), endoscopy, genetic tests, or other methods of identifying cancer as known in the art.

[0054] Methods for treating a mammal having cancer using a live or live-attenuated commensal polyomavirus, or antigenic protein, protein fragment, or peptide thereof (e.g., a HPyV7) provided herein can be effective to reduce the number of cancer cells in the mammal. In some cases, treating a mammal having cancer using a live or live- atenuated commensal polyomavirus, or antigenic protein, protein fragment, or peptide thereof provided herein can be effective to eliminate the cancer cells in the mammal.

[0055] The methods can also include administration of one or more other treatments known in the art for cancer, e.g., in subjects who have breast cancer, or treatment to reduce the risk of developing breast cancer. For example, a combination treatment with the methods described herein can include surgery, radiation, chemotherapy, targeted and / or immunotherapy. Non-limiting examples of chemotherapy includes alkylating agents (e.g., nitrogen mustards such as mechlorethamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide and busulfan; nitrosoureas such as N-Nitroso-N-methylurea (MNU), carmustine (BCNU), lomustine (CCNU) and semustine (MeCCNU), fotemustine and streptozotocin; tetrazines such as dacarbazine, mitozolomide and temozolomide; aziridines such as thiotepa, mytomycin and diaziquone (AZQ); cisplatins and derivatives such as cisplatin, carboplatin and oxaliplatin; and non-classical alkylating agents such as procarbazine and hexamethylmelamine), anti-metabolites (e.g., anti-folates such as methotrexate and pemetrexed; fluoropyrimidines such as fluorouracil and capecitabine; deoxynucleoside analogues such as cytarabine, gemcitabine, decitabine, Vidaza, fludarabine, nelarabine, cladribine, clofarabine and pentostatin; and thiopurines such as thioguanine and mercaptopurine), anti-microtubule agents (e.g., vinca alkaloids such as vincristine, vinblastine, vinorelbine, vindesine, and vinflunine; and taxanes such as paclitaxel, docetaxel, and cabazitaxel; podophyllotoxin; etoposide; and teniposide), topoisomerase inhibitors (e.g., topoisomerase I inhibitors such as irinotecan and topotecan; and topoisomerase II inhibitors such as etoposide, doxorubicin, mitoxantrone, teniposide, novobiocin, merbarone, and aclarubicin), and cytotoxic antibiotics (e.g., anthracy clines such as doxorubicin, daunorubicin, epirubicin, idarubicin, pirarubicin, aclarubicin, and mitoxantrone; bleomycins; mitomycin C; mitoxantrone; and actinomycin).

[0056] In some embodiments wherein the additional cancer therapy comprises immune checkpoint blockade therapy. For example, the immune checkpoint blockade therapy can include PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, and / or LAG-3 inhibitors. The PD-1 and PD-L1 inhibitors can include nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, cemiplimab, dostarlimab. retifanlimab, toripalimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, INCMGA00012. AMP-224, AMP-514, acrixolimab, KN035, cosibelimab, AUNP12, CA-170, and / or BMS-986189. The CTLA-4 inhibitors can include ipilimumab and / or tremelimumab. The LAG-3 inhibitors can include relatlimab.

[0057] In cases where a live or live-attenuated commensal polyomavirus, or antigenic protein, protein fragment, or peptide thereof provided herein and one or more additional cancer treatments are provided separately, the administration of a live or live-attenuated commensal polyomavirus, or antigenic protein, protein fragment, or peptide thereof provided herein can be in any order relative to the administration of one or more additional cancer treatments. For example, a live or live-attenuated commensal polyomavirus, or antigenic protein, protein fragment, or peptide thereof provided herein can be administered to a mammal prior to, concurrent with, or following administration of one or more additional cancer treatments to the mammal.

[0058] Also, provided herein are methods of inducing an immunogenic response to a cancer cell in a subject (e.g., mammal) in need thereof, the method comprising administering a therapeutically effective amount of live or live-attenuated commensal polyomavirus, or antigenic protein, protein fragment, or peptide thereof, to the subject in need thereof. For example, inducing an immunogenic response can include enhancing T cell response. T cell number and / or T cell infiltration into the tumor and / or around the tumor margin, thereby reducing the risk that the subject will develop cancer.

[0059] Also provided herein are methods of vaccinating or reducing the risk of developing cancer in a subject against a solid tumor, the method comprising administering a therapeutically effective amount of live or live-attenuated commensal polyomavirus, or antigenic protein, protein fragment, or peptide thereof, to the subject in need thereof.

[0060] The live or live-attenuated commensal polyomavirus, or antigenic protein, protein fragment, or peptide thereof are administered in a therapeutically effective amount. A "‘therapeutically effective amount” is an amount sufficient to effect beneficial or desired results. For example, an effective amount is one that achieves a desired therapeutic effect, e.g.. an amount necessary to treat a disease, or to reduce risk of development of disease or disease symptoms (also referred to as a prophylactically effective amount). An effective amount can be administered in one or more administrations, applications, or dosages. A therapeutically effective amount of a therapeutic compound (i.e., an effective dosage) depends on the therapeutic compounds selected. For example, a therapeutically effective amount of live or live- attenuated commensal polyomavirus, or antigenic protein, protein fragment, or peptide thereof provided herein can be effective to reduce the number of and / or eliminate cancer cells in a mammal (e.g, human). The live or live-attenuated commensal polyomavirus, or antigenic protein, protein fragment, or peptide thereof can be administered one or more times per day to one or more times per week; including once every other day. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and / or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of the therapeutic compounds described herein can include a single treatment or a series of treatments. Various factors can influence the actual amount used for a particular application. For example, the frequency of administration, duration of treatment, combination of other agents, site of administration, stage of disease (if present), and the anatomical configuration of the treated area may require an increase or decrease in the actual amount administered.

[0061] The frequency of administration of live or live-attenuated commensal polyomavirus (e.g., HPyV7) provided herein can be any frequency. For example, the frequency of administration can be from about four times a day to about once a month, or more specifically, from about twice a day to about once a week. In addition, the frequency of administration can remain constant or can be variable during the duration of treatment. As with the amount administered, various factors can influence the actual frequency of administration used for a particular application. For example, the amount (dose), duration of treatment, combination of agents, site of administration, stage of disease (if present), and the anatomical configuration of the treated area may require an increase or decrease in administration frequency. For example, the methods can include administering a first dose, followed by one or more additional doses at a later time (e.g., a “booster’" dose), e.g., 1, 2, 3, 4. 5, 6, or 7 days from a previously administered dose. For example, administration can include administering two, three, four, or five doses, administered 1, 2, 3, 4, 5, 6, or 7 days apart. The length of time between multiple doses can be the same (e.g., 2 days between each dose, 3 days between each dose, 4 days between each dose, etc.), or the length of time between multiple doses can be different between each dose (e.g., 4 days between the first and second dose, 3 days between the second and third dose, and 2 days between the third and fourth dose).

[0062] Dosage, toxicity and therapeutic efficacy of the therapeutic compositions can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50. Compositions that exhibit high therapeutic indices are preferred. While compositions that exhibit toxic side effects may be used, care should be taken to minimize and reduce side effects. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compositions used in the methods described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models. Such information can be used to more accurately determine useful doses in humans.

[0063] EXAMPLES

[0064] The disclosure is further described in the following examples, which do not limit the scope of the claims. The methods described here were used to generate the examples described herein.

[0065] Methods

[0066] Human polyomavirus virions were generated in vitro by transfecting 293T cells with polyomavirus genomic DNA using the Lipofectamine 3000. After a 7-day incubation period, virions were harvested from the cells. Quantitative polymerase chain reaction (qPCR) was used to quantify the viral genome equivalents (VGE) in the resulting virus stocks. For treatment purposes, a formulation consisting of live or live-attenuated commensal polyomavirus, or antigenic protein, protein fragment, or peptide, was combined with adjuvants such as Alum, Poly(I:C), or CPG-ODN. This formulation is then administered via intratumoral injection (for virotherapy) and via intradermal injection (for vaccination), ensuring effective delivery' and immune activation at the site of injection.

[0067] Example 1: MPyV inhibits the progression of lung and breast cancer

[0068] To test the effects of MPyV on lung cancer progression, mice were exposed to 2 X 106plaque forming units (PFU) MPyV for 2 weeks, followed by a challenge with 1 X 106Lewis lung carcinoma (LLC) cells that were previously incubated with either 20 multiplicity of infection (MOI) MPyV or virus-like particles (VLP) for 3 days.

[0069] Parallelly, the effects of MPyV were also tested in breast cancer progression. Mice were exposed to 2 X 106PFU MPyV for 2 weeks and then were challenged with 1 X 106E0771 (breast cancer) cells pre-incubated with either 20 MOI MPyV or VLP for 3 days.

[0070] In both lung cancer and breast cancer models, tumor volumes were measured, and Kaplan-Meier survival plot was generated. The study showed that in both lung cancer and breast cancer models, mice colonized or previously exposed to MPyV rejected the tumors infected with MPyV (FIGS. 1A and 2A). Mice colonized with VLP when challenged with either LLC cells or E0771 cells showed tumor growth. Furthermore, it was show n that compared to the mice colonized w i th VLP, the mice colonized with MPyV when challenged with LLC cells infected with MPyV or E0771 cells infected with MPyV had significantly better survival (FIGS. IB and 2B)

[0071] Example 2: MPyV neither induces tumor cell death nor affects cell proliferation

[0072] To investigate the effects of MPyV on tumor cell death and proliferation, LLC cells and E0771 cells were exposed to either 20 MOI MPyV or VLP. After 3 days post infection, cell death was analyzed by staining for propidium iodide (PI) and Annexin. In both lung cancer and breast cancer models. MPyV did not show significant difference in the percentage of cell death or apoptosis compared to VLP (FIGS. 4A-B and FIGS. 5A-B). During viral infections, host cells respond by increasing the expression of major histocompatibility complex class I (MHC-I) molecules. This upregulation is crucial for presenting viral antigens on the cell surface, thereby enabling the immune system to recognize and target infected cells for destruction. Viral infection can induce the expression of PD-L1 on infected cells as part of an immunomodulatory mechanism. PD-L1 interacts with programmed cell death protein 1 (PD-1) on T cells, leading to T cell exhaustion or inhibition of T cell function. Testing MHC-I and PD-L1 expression post-viral infection provides valuable information regarding the host immune response, the potential for immunotherapy interventions, and disease progression. To evaluate the effects of MPyV on inducing immune responses, post 24-hours of infection with MPyV, expression levels of MHC- I and PD-L1 on the cell surfaces were analyzed using flow cytometry (FIGS. 3C-3D and FIGS. 4C-4D), and the expression levels of IFN-P, MX1, and TNF-a were quantified using qPCR. The upregulation of MHC-I expression and interferon- stimulated genes (ISGs) indicate an activated immune response in the virus-infected cells. The infected cells can also produce Tumor Necrosis Factor-alpha (TNF-a) as part of the immune response to the infection. These results show that the MPyV did not affect the tumor cell innate immune activation (FIGS. 3E-3G and FIGS. 4E-4G).

[0073] Also, to test the effects of MPyV on cell proliferation, mouse embryonic fibroblast (MEF) cells were infected with 20 MOI MPyV and sham control, and cells were monitored for 6 days. After day 6, cells were fixed with PFA and stained with crystal violet. This study demonstrated that MPyV infection does not affect cell proliferation (FIG. 5).

[0074] Example 3: MPyV enhances tumor immunogenicity

[0075] To test whether MPyV immunized mice resist tumors expressing MPyV antigens, mice were initially colonized with MPyV and later challenged with MPyV- E0771 cells. It was observed that these mice rejected the MPyV-E0771 tumor grow th. Upon rejection, these mice were subsequently challenged with melanoma cell line D4M.3A which expressed either the MPyV middle T antigen (MT) or EGFP. Tumor volume was measured every other day. The result showed that MPyV colonized mice that rejected MPyV-E0771 tumor growth also rejected other tumor cells (MT- D4M.3A) that express MT antigen from polyomavirus (FIG. 6).

[0076] Example 4: MPyV promotes T cell mediated tumor rejection

[0077] Mice were initially colonized with MPyV and after 14 days, these mice were challenged with either VLP-E0771 cells or MPyV-E0771 cells. The MPyV-E0771 inoculated mice were then treated with anti-CD4 antibodies, or anti-CD8 antibodies, or an IgG control. Depleting the CD4 and CD8 T cells nullified the tumor rejecting capability of the mice colonized with MPyV, showing that the tumor rejection induced by MPyV is dependent upon T cells (FIG. 7).

[0078] Furthermore, MPyV -colonized mice when challenged with E0771-p2M' / _cells, tumor growth were observed after treatment with either VLP or MPyV. This demonstrates that absence of P2M negates the MPyV -induced tumor suppression (FIG. 8)

[0079] Example 5: MPyV-colonized and tumor-rejected mice fail to resist / I2M ' tumor cells.

[0080] MPyV colonized mice after successfully rejecting the MPyV-E0771 tumors were inoculated with naive E0771 tumor cells and showed no tumor growth (FIG. 9 A). However, when these mice were subsequently rechallenged with E0771-P2M' ‘ cells, tumor growth was observed. This shows that the MPyV colonized mice fails to resist the p2M / _tumor growth (FIG. 9B).

[0081] Example 6: MPyV inf ection facilitates antigen spreading

[0082] MPyV colonized mice when treated with MPyV-infected LLC-OVA tumor cells showed no tumor growth (FIGS. 10A-10B). Subsequently, the tumor free mice from the MPyV-infected LLC-OVA cohort were rechallenged with E0771 cells, or E0771 -OVA cells, or E0771 cells. No tumor growth was observed in mice treated with either E0771-OVA cells or E0771 cells, suggesting antigen-spreading activity in MPyV-infected tumors. Moreover, when colonized mice were administered MPyV- infected tumor cells, they developed anti-tumor immunity (FIG. IOC).

[0083] Example 7: Utilizing MPyV in cancer therapy

[0084] To investigate the therapeutic role of polyomavirus in a tumor model. MPyV- colonized mice were inoculated with naive E0771 cells (FIG. 11A). Following the tumor growth, the mice were administered MPyV intratumorally. Direct intratumoral delivery' of MPyV inhibited tumor growth (FIG. 11B).

[0085] Example 8: MPyV colonization reduces spontaneous breast cancer development in oncogene-driven mouse model of breast cancer MMTV-Her2 is a mouse model of spontaneous mammary cancers. MMTV- Her2 mice were colonized with MPyV, treated with dimethylbenz[a] anthracene (DMBA) and monitored for spontaneous breast tumor development (FIG. 12C). MMTV-HER2 mice treated with MPyV developed fewer palpable tumors (FIG. 12D), demonstrated increased time to tumor onset (FIG. 12E), and increased percentage of survival (FIG. 12F). These results demonstrate that MPyV colonization reduces spontaneous breast cancer development.

[0086] References

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[0097] 11. Foulongne, V., et al., Merkel cell polyomavirus DNA detection in lesional and nonlesional skin from patients with Merkel cell carcinoma or other skin diseases. Br J Dermatol, 2010. 162(1): p. 59-63.

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[0107] OTHER EMBODIMENTS

[0108] It is to be understood that while the disclosure has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the disclosure, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method for treating a cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of live or live-attenuated commensal polyomavirus, or antigenic protein, protein fragment, or peptide thereof, to a subject identified as having a cancer.

2. The method of claim 1, wherein the live or live-attenuated commensal polyomavirus, or antigenic protein, protein fragment, or peptide thereof, are selected from MPy V, MCPy V, HPy V7. HPy V6, BKPy V, JCPy V, LPyV, KIPyV, WUPyV, and / or TSPyV polyomavirus strains and / or MPyV, MCPyV, HPyV7, HPyV6, BKPyV, JCPy V, LPyV, KIPyV, WUPyV, and / or TSPyV antigenic proteins, protein fragments, or peptides.

3. The method of claim 2. wherein the subject is a mammal.

4. The method of claim 3, wherein the mammal is immunocompetent.

5. The method of any of claims 1 to 4, wherein the subject has an increased nsk of developing cancer.

6. The method of any of claims 1 to 5, wherein the cancer is a solid tumor.

7. The method of any of claims 1 to 6, wherein the solid tumor is a breast cancer, a lung cancer, a prostate cancer, a glioma, a melanoma, a keratinocyte cancer, an ovarian cancer, a liver cancer, a pancreatic cancer, a kidney cancer, a bladder cancer, a thyroid cancer, a sarcoma, a stomach cancer, a head and neck cancer, a cervical cancer, an endometrial cancer, an esophageal cancer, a thymoma, a soft tissue sarcoma, a bone cancer, a testicular cancer, a penile cancer, a gallbladder cancer, a uterine sarcoma, an adrenal gland cancer, an ampullary cancer, a hepatic angiosarcoma, a nasal, or a paranasal sinus cancer.

8. The method of any of claims 1 to 7, wherein the cancer is a blood cancer.

9. The method of any of claims 1 to 8, wherein the blood cancer is a leukemia, a lymphoma, a myeloma, a myelodysplastic syndrome, or a myeloproliferative neoplasm.

10. The method of any of claims 1 to 9, wherein the administering comprises intravenous, intradermal, subcutaneous, intratumoral, intramuscular, or subcutaneous administration.

11. The method of any of claims 1 to 10. further comprising administering to the subject an additional cancer therapy.

12. The method of any of claims 1 to 11, wherein the additional cancer therapy comprises surgery, radiation, chemotherapy, and / or immunotherapy.

13. The method of any of claims 1 to 12, wherein the additional cancer therapy comprises immune checkpoint blockade therapy.

14. The method of any of claims 1 to 13. wherein the immune checkpoint blockade therapy comprises PD-1 inhibitors. PD-L1 inhibitors, CTLA-4 inhibitors, and / or LAG-3 inhibitors.

15. The method of any of claims 1 to 14, wherein the PD-1 and PD-L1 inhibitors comprise nivolumab, pembrolizumab, atezolizumab, avelumab. durvalumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, INCMGA00012, AMP-224, AMP-514, acrixolimab, KN035, cosibelimab, AUNP12. CA-170, and / or BMS-986189.

16. The method of any of claims 1 to 15, wherein the CTLA-4 inhibitors comprise ipilimumab and / or tremelimumab.

17. The method of any of claims 1 to 16, wherein the LAG-3 inhibitors comprise relatlimab.

18. A method of inducing an immunogenic response to a cancer cell in a subject in need thereof, the method comprising administering a therapeutically effective amount of live or live-attenuated commensal polyomavirus, or antigenic protein, protein fragment, or peptide thereof, to the subject in need thereof.

19. A method of vaccinating, or reducing the risk of developing cancer in a subject against a solid tumor, the method comprising administering a therapeutically effective amount of live or live-attenuated commensal polyomavirus, or antigenic protein, protein fragment, or peptide thereof, to the subject in need thereof.

20. The method of either claim 18 or 19, wherein the subject is a mammal.

21. The method of any of claims 18 through 20, wherein the mammal is immunocompetent.

22. The method of any of claims 18 to 21 , wherein the subject has an increased risk of developing cancer.

23. The method of any of claims claim 18 through 22. wherein the cancer is a solid tumor.

24. The method of any of claims 18 through 23, wherein the solid tumor is a breast cancer, a lung cancer, a prostate cancer, a glioma, a melanoma, an ovarian cancer, a liver cancer, a pancreatic cancer, a kidney cancer, a bladder cancer, a thyroid cancer, a sarcoma, a stomach cancer, a head and neck cancer, a cervical cancer, an endometrial cancer, an esophageal cancer, a thymoma, a soft tissue sarcoma, a bone cancer, a testicular cancer, a penile cancer, a gallbladder cancer, a uterine sarcoma, an adrenalgland cancer, an ampullary cancer, a hepatic angiosarcoma, a nasal, or a paranasal sinus cancer.

25. The method of any of claims 18 through 24, wherein the cancer is a blood cancer.

26. The method of any of claims 18 through 25, wherein the blood cancer is a leukemia, a lymphoma, a myeloma, a myelodysplastic syndrome, or a myeloproliferative neoplasm.

27. The method of any of claims 18 through 26, wherein the administering comprises intravenous, intradermal, subcutaneous, intratumoral, intramuscular, or subcutaneous administration.

28. The method of any of claims 18 through 27, further comprising administering to the subject an additional cancer therapy.

29. The method of any of claims 18 through 28, wherein the additional cancer therapy comprises surgery, radiation, chemotherapy, and / or immunotherapy.

30. The method of any of claims 18 through 29, wherein the additional cancer therapy comprises immune checkpoint blockade therapy.

31. The method of any of claims 18 through 30, wherein the immune checkpoint blockade therapy comprises PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, and / or LAG-3 inhibitors.

32. The method of any of claims 18 through 31, wherein the PD-1 and PD-L1 inhibitors comprise nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, vopratelimab. spartalizumab, camrelizumab, sintilimab, tislelizumab,INCMGA00012, AMP-224, AMP-514, acrixolimab, KN035, cosibelimab, AUNP12. CA-170. and / or BMS-986189.

33. The method of any of claims 18 through 32, wherein the CTLA-4 inhibitors comprise ipilimumab and / or tremelimumab.

34. The method of any of claims 18 through 33, wherein the LAG-3 inhibitors comprise relatlimab.

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