Document text
Principal Investigator: Marc Ladanyi
Organization: SLOAN-KETTERING INST CAN RESEARCH
Fiscal Year: 2024
Award: $436,396
Funding agency: National Cancer Institute
RP3: Identifying Targetable Epigenetic and Immuno-Oncologic Vulnerabilities in Synovial Sarcoma
ABSTRACT
Synovial sarcoma (SS) is driven by SS18::SSX-dependent chromatin dysregulation, suggesting that elucidating
key aspects of this deregulation might point to therapeutic epigenetic vulnerabilities. At the same time, driver
fusions such as SS18::SSX may generate a unique class of shared, or public, neoantigens because they create
novel peptide sequences that diverge significantly from self-proteins. Specifically, the junctional amino acid
sequence of the chimeric SS18::SSX proteins is unique to SS cells. In addition, there is evidence that epigenetic
modulation may potentiate immunotherapy approaches. Thus, our overall goal is to identify epigenetic and
immuno-oncologic vulnerabilities in SS and potential synergies between them towards an overall goal of long-
term responses in metastatic SS. To accomplish this, our multidisciplinary research team of experts in cancer
genomics and epigenetics, T cell immunobiology and immune-peptidomics, and clinical trials in pediatric and
young adult sarcomas will pursue 3 specific aims. Aim 1 is to decipher H3K36 methylation-dependent crosstalk
and vulnerabilities in SS, on the basis of our clinical genomic profiling data on SS identifying recurrent loss of
function in histone 3 lysine 36 (H3K36) methyltransferases (e.g. SETD2) in ~10% of cases. In isogenic cell lines,
we will determine how decreased H3K36me3 affects the genomic localization of SS18::SSX and fusion protein-
dependent transcriptional programs and establish the key determinants of DNA methylation and polycomb-
mediated chromatin domains. We will validate these observations in prospectively collected patient-derived
tissues and xenografts (PDXs). Finally, we will identify SETD2-/--specific dependencies in SS using a chemical
probe approach; resulting hits will be studied mechanistically and validated in both PDXs and isogenic SETD2-/-
models. Because epigenetic mechanisms are important tumor-intrinsic mediators of immune escape, we will
also explore whether SETD2 loss affects SS immunogenicity. Aim 2 is to measure the immunogenicity of an
SS18::SSX public neoantigen and test the antitumor efficacy of T cells genetically engineered with a T cell
receptor recognizing it. Specifically, we will define the HLA-restricted immunogenic peptides resulting from the
SS18::SSX fusion protein, retrieve the TCR α/β gene sequences associated with SS patient-derived T cells that
recognize such peptides, and validate that cloned TCRs confer fusion-derived reactivity and tumor regression in
vivo when retrovirally transduced into a polyclonal T cell population. In Aim 3, we will determine the tolerability,
immunogenicity, and antitumor efficacy of a multivalent mRNA vaccine encoding the SS18::SSX(1/2) junction
sequence and multiple cancer-testis antigens (CTAs) highly expressed in SS, in combination with an anti-PD-L1
antibody, via a phase I/II clinical trial in collaboration with Moderna and TRACON. Correlative analyses
associated with the trial will measure how the vaccine affects the T cell response to polypeptides containing the
above sequences and resolve the HLA restriction and TCR clonotypes for T cells responding to the SS18::SSX
fusion and CTA sequences.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Affect><Amino Acid Sequence><Anti-Cancer Agents><Antibodies><Antigenic Determinants><Antigens><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Binding Determinants><Biological Response Modifiers><Biomodulators><Body Tissues><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8><CD8B><CD8B1><CD8B1 gene><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 virus><COVID-19 years><COVID19 virus><CTAG><CTAG1><CTAG1 gene><CTAG1B><CTAG1B Gene><Cancer Drug><Cell Body><Cell Line><CellLine><Cells><Chemicals><Childhood><Chimera Protein><Chimeric Proteins><Chromatin><Clinical><Clinical Trials><Clonal Expansion><CoV-2><CoV2><Collaborations><DNA Methylation><Data><Dependence><Drug Targeting><EC 2.1.1><ERVs><ESO1><Endogenous Retroviruses><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epitopes><Fusion Protein><Gene Transcription><Gene Transfer><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genomics><Goals><HERVs><Haplotypes><Heterograft><Heterologous Transplantation><Histones><Human Endogenous Retroviruses><Immune><Immune Mediators><Immune Mediators/Modulators><Immune Regulators><Immune mediated therapy><Immune response><Immunes><Immunity><Immunization><Immunobiology><Immunological response><Immunologically Directed Therapy><Immunomodulation><Immunophysiology><Immunotherapy><In Vitro><Interdisciplinary Research><Interdisciplinary Study><Interferon Type I><L-Lysine><LAGE2B><LYT3><Libraries><Lysine><MHC Receptor><Major Histocompatibility Complex Receptor><Malignant Soft Tissue Neoplasm><Measures><Mediating><Messenger RNA><Metastatic Synovial Sarcoma><Metastatic/Recurrent><Methylation><Methyltransferase><Mice><Mice Mammals><Modeling><Multidisciplinary Collaboration><Multidisciplinary Research><Murine><Mus><Mutation><NY-ESO-1><Neoplastic Disease Chemotherapeutic Agents><PD-L1 antibody><PDL1 antibody><PRAME><Patients><Peptides><Phase 1/2 Clinical Trial><Phase I/II Clinical Trial><Polycomb><Population><Primary Protein Structure><Proteins><Proteolytic Clipping><Proteolytic Processing><RNA Expression><RNA vaccine><RNA-based vaccine><Recurrence><Recurrent><Resectable><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Safety><Sarcoma><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Soft tissue sarcoma><Strains Cell Lines><Synovioma><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell response><T cell targeted therapeutics><T cell therapy><T-Cell Antigen Receptors><T-Cell Receptor><T-Cell Receptor Genes><T-Cells><T-Lymphocyte><T-cell therapeutics><T-cell transfer therapy><T4 Cells><T4 Lymphocytes><TcR Genes><Testing><Therapeutic><Time><Tissues><Transcription><Tumor-Specific Treatment Agents><Vaccine Design><Vaccines><Wuhan coronavirus><Xenograft><Xenograft procedure><Xenotransplantation><aPD-L1 antibodies><adoptive T cell transfer><adoptive T-cell therapy><adult youth><anti-PD-L1 antibodies><anti-PD-L1 monoclonal antibodies><anti-PDL1 antibodies><anti-cancer drug><cancer genomics><cancer/testis antigen><cohort><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 virus><cultured cell line><derepression><determine efficacy><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><engineered T cells><epigenetic regulation><epigenetic therapy><epigenetically><evaluate efficacy><examine efficacy><experience><genetically engineered T-cells><genome mutation><genome profiling><genomic profiling><hCoV19><host response><hypoimmunity><immune deficiency><immune modulation><immune regulation><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunodeficiency><immunogen><immunogenic><immunogenicity><immunologic reactivity control><immunomodulatory><immunomodulatory biologics><immunoregulation><immunoregulatory><immunoresponse><in vivo><innovate><innovation><innovative><loss of function><mRNA><mRNA vaccine><mRNA-based vaccine><malignant soft tissue tumor><methylase><nCoV2><neo-antigen><neo-epitopes><neoantigens><neoepitopes><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><oncogenomics><pediatric><peptide aminoacid sequence><peptide sequence><polypeptide><preferentially expressed antigen in melanoma><programs><prospective><protein aminoacid sequence><protein sequence><response><retroviral transduction><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><synergism><synovial cell sarcoma><synovial sarcoma><therapeutic T-cell platform><thymus derived lymphocyte><transgenic T- cells><transmethylase><tumor><vaccine platform><xeno-transplant><xeno-transplantation><young adult><young adulthood><αPD-L1 antibodies>