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Principal Investigator: Yicheng Wang
Organization: IMMUNOVA THERAPEUTICS, LLC
Fiscal Year: 2024
Award: $1,001,029
Funding agency: National Cancer Institute
Abstract
Breast cancer is a leading cause of cancer-related deaths of women in the United States and worldwide.
Immunotherapy is a promising approach, but has not proven successful yet in metastatic breast cancer,
particularly in triple-negative breast cancer (TNBC). TNBC is the most aggressive subtype among all breast cancer
subtypes, with little treatment options available. First-line treatment with pembrolizumab–chemotherapy results in
better overall survival than chemotherapy alone among patients with advanced TNBC. Sacituzumab Govitecan is
offered as an option for the second line of treatment. Despite these significant progresses, most patients eventually
collapse and die without further treatment option. Thus, TNBC remains an unmet medical need for urgent
development of novel therapeutics. The rationale for this application is that clinical responses to immune
checkpoint therapy rely on the presence of tumor-infiltrating and antigen-specific T cells. Thus, development of
tumor-specific TCR-T cell immunotherapy is key to the success of immunotherapy in breast cancer. Immunova
Therapeutics is a startup company with the mission to further develop TCR-T cell immunotherapy for the treatment
of solid cancers, including TNBC. Due to the nature of tumor heterogeneity, antigen loss or negative tumor variants
represents a key mechanism to develop resistance to immunotherapy. This IMT-422 product is an HLA-DR13-
restricted KK-LC-1-specific TCR-engineered CD4+ T cells, and has been demonstrated to completely inhibit or
even eliminate TNBC in a mouse model. Our finding is also supported by recent studies showing that CD4+ T cells
could eliminate antigen-positive and -negative tumor cells. To further improve the therapeutic potential, we
engineered TCR with three key technologies to increase the pools of stem-like memory T cells and resistance to
T cell exhaustion and immune suppression. We named the final IMT-422 product as CD4 TCR-STEM T cells,
which could completely reject breast cancer growth in a mouse model. Based on these solid data, we propose to
generate GMP grade Master Cell Bank (MCB) and viral particles of TCR-STEM required for Chemistry,
Manufacturing and Controls (CMC) (Aim 1); and determine the pharmacokinetics, biodistribution and
pharmacological toxicity of the IMT-422 (CD4 TCR-STEM T cells) product (Aim 2). Upon completion of the
proposed studies, we are well positioned to initiate and file an investigator-initiated new drug (IND) application for
a future phase I clinical trial, thus accelerating the development of new breast cancer immunotherapy.
Terms: <70 kDa zeta-associated protein><Acceleration><Address><Antigenic Determinants><Antigens><B7-H1><B7H1><Binding Determinants><Biodistribution><Breast Cancer><CD274><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Cancer Cause><Cancer Etiology><Cancers><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Chemistry><Clinical><Constant Region><Contract Services><Cytolysis><Data><Development><Drug Kinetics><Drugs><EGF Receptor><EGFR><ERBB Protein><Early-Stage Clinical Trials><Engineering><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Epitopes><Estrogen Receptors><Future><Generalized Growth><Goals><Growth><HER1><HLA-DR13><HLA-DR13 antigen><Human><IRB><IRBs><Ig Constant Region><Immune><Immune mediated therapy><Immunes><Immunoglobulin Constant Region><Immunologically Directed Therapy><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><Indiana><Infiltration><Institutional Review Boards><Intracellular Communication and Signaling><Intratumoral heterogeneity><Investigational Drugs><Investigational New Drugs><Investigators><Keytruda><Kinases><Lysis><MHC Receptor><Major Histocompatibility Complex Receptor><Malignant Breast Neoplasm><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Mediating><Medical><Medication><Memory><Metastatic breast cancer><Mice><Mice Mammals><Mission><Modern Man><Murine><Mus><Names><Nature><Normal Tissue><Normal tissue morphology><Outcome><PD 1><PD-1><PD-L1><PD1><PDL-1><PDL1><Patients><Pharmaceutical Preparations><Pharmacokinetics><Phase><Phase 1 Clinical Trials><Phase I Clinical Trials><Phosphotransferase Gene><Phosphotransferases><Population><Position><Positioning Attribute><Process><Production><Progesterone Receptors><Progestin Receptors><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Protein Tyrosine Kinase Zap70><Protocol><Protocols documentation><Pulmonary Cancer><Pulmonary malignant Neoplasm><Receptor Signaling><Reporting><Research Personnel><Researchers><Resistance><Resistance development><Resistant development><SBIR><SRK><Safety><Signal Transduction><Signal Transduction Systems><Signaling><Site><Small Business Innovation Research><Small Business Innovation Research Grant><Solid><Specificity><Syk-related tyrosine kinase><T memory cell><T-Cell Antigen Receptors><T-Cell Receptor><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><TGF-alpha Receptor><TNBC><Technology><Testicles><Testing><Testis><Therapeutic><Tissue Growth><Toxic effect><Toxicities><Transforming Growth Factor alpha Receptor><Transphosphorylases><Tumor Antigens><Tumor Cell><Tumor Immunity><Tumor-Associated Antigen><United States><Universities><Urogastrone Receptor><Variant><Variation><Viral><Women's mortality><Work><ZAP-70><ZAP-70 Gene><ZAP-70 Kinase><ZAP-70 protein><ZAP70><Zeta-Chain Associated Protein Kinase><anti-cancer immunotherapy><anti-tumor immunity><anticancer immunotherapy><antigen-specific T cells><antitumor immunity><biological signal transduction><c-erbB-1><c-erbB-1 Protein><cancer antigens><cancer immunity><cancer immunotherapy><cancer microenvironment><cancer sub-types><cancer subtypes><cancer/testis antigen><cell bank><check point blockade><check point immunotherapy><check point inhibitor therapy><check point inhibitory therapy><check point therapy><checkpoint blockade><checkpoint immunotherapy><checkpoint inhibitor therapy><checkpoint inhibitory therapy><checkpoint therapy><chemotherapy><cross reactivity><cytokine><death among females><death among women><death in females><death in women><death rate among women><death rate in women><developing resistance><developmental><drug/agent><engineered T cells><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><exhaustion><female death><female mortality><genetically engineered T-cells><heterogeneity in tumors><immune check point blockade><immune check point therapy><immune checkpoint blockade><immune checkpoint therapy><immune suppression><immune suppressive activity><immune suppressive function><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunosuppressive activity><immunosuppressive function><immunosuppressive response><immunotherapy for cancer><immunotherapy of cancer><improved><innovate><innovation><innovative><intra-tumoral heterogeneity><intratumor heterogeneity><knock-down><knockdown><lung cancer><malignancy><malignant breast tumor><manufacture><memory T lymphocyte><mortality among females><mortality among women><mortality in females><mortality in women><mouse model><murine model><name><named><naming><neoplasm/cancer><neoplastic cell><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutics><novel therapy><ontogeny><particle><pembrolizumab><pharmacologic><phase 2 study><phase I protocol><phase II study><product development><programmed cell death 1><programmed cell death ligand 1><programmed cell death protein 1><programmed cell death protein ligand 1><programmed death 1><protein death-ligand 1><proto-oncogene protein c-erbB-1><resistant><response><scale up><shRNA><short hairpin RNA><sle2><small hairpin RNA><stem><success><systemic lupus erythematosus susceptibility 2><therapeutic agent development><therapeutic development><thymus derived lymphocyte><transgenic T- cells><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor heterogeneity><tumor microenvironment><tumor-specific antigen><women's death><women's death rate>