Eradication of Escaped Variant Tumor Cells for Cancer Immunotherapy

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Principal Investigator: Yong  Lu
Organization: METHODIST HOSPITAL RESEARCH INSTITUTE
Fiscal Year: 2024
Award: $369,383
Funding agency: National Cancer Institute

Project Summary
Recently, we discovered that adoptive transfer of CD39KO tumor-specific (mixed CD4+ and CD8+) T cells,
resulted in long-term survival of mice bearing large established tumors. Unexpectedly, we found that these T
cells promoted killing of antigen-loss-variants (ALVs) in vivo and prevented tumor recurrence. Moreover,
transfer of CD39KO, but not control KO, tumor-specific T cells eradicated large chimeric tumors that contained
10% of ALVs and resulted in long-term tumor-free survival and protection against rechallenge with ALV tumor
cells. Based on these novel findings, we hypothesize that transfer of tumor-specific CD39KO T cells will
eradicate large established tumors and prevent recurrence of ALV tumors, due to their ability to directly kill the
tumor cells and induce anti-ALV responses. Aim 1 will determine the contribution of type I IFN production at
the tumor site in preventing recurrence of ALV tumors. Aim 2 will determine the role of CD39KO T cells in the
recruitment of inflammatory myeloid cells and the induction of type I IFN production for tumor clearance. Aim 3
will determine whether human tumor-specific CD39KO T cells are also endowed with these abilities to
effectively eradicate human tumors in humanized mice. These innovative and mechanistic studies will shed
light on the mechanisms underlying CD39KO T cell-mediated antitumor immunity and will thus establish a
foundation for translating this discovery into more effective immunotherapies using tumor-specific T-cell
subsets in human cancers.

Terms: <5,6-dihydroxyindole-2-carboxylic acid oxidase><Adenosine><Adoptive Cell Transfers><Adoptive Transfer><Antigens><Antitumor Response><B Cell Antigen CD19><B blood cells><B cell><B cells><B-Cell Antigen CD22><B-Cells><B-Lymphocyte Antigen CD19><B-Lymphocyte Surface Antigen B4><B-Lymphocytes><B-cell><B3 antigen><Blood leukocyte><Blood monocyte><Bp35><CAR T cells><CAR modified T cells><CAR-T><CAR-Ts><CD19><CD19 Antigens><CD19 gene><CD19 molecule><CD20><CD22><CD22 antigen><CD22 gene><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><Cancers><Cell Body><Cell Lineage><Cells><Cellular injury><Clinical Research><Clinical Study><Clinical Trials><Color><DHI2C oxidase><DHICA oxidase><Darkness><Data><Differentiation Antigen CD19><Disease remission><Down-Regulation><Endowment><Extracellular Space><Foundations><Future><Generalized Growth><Genetic Alteration><Genetic Change><Genetic defect><Germinoblastic Sarcoma><Germinoblastoma><Glioblastoma><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Growth><Human><IFN><Immune><Immune mediated therapy><Immune response><Immunes><Immunological response><Immunologically Directed Therapy><Immunotherapy><Inflammatory><Intercellular Space><Interferons><Knock-out><Knockout><LYT3><Leu 12><Leu-16><Leukocytes><Leukocytes Reticuloendothelial System><Lymphoma><MS4A1><MS4A1 gene><MS4A2><Malignant Cell><Malignant Lymphoma><Malignant Melanoma><Malignant Neoplasms><Malignant Tumor><Marrow leukocyte><Marrow monocyte><Mediating><Melanins><Melanoma><Mice><Mice Mammals><Modeling><Modern Man><Multiple Myeloma><Murine><Mus><Mutation><Myeloid Cells><Pathway interactions><Patients><Plasma-Cell Myeloma><Production><Purine Receptors><Purinergic Receptors><Purinoceptor><Recurrence><Recurrent><Recurrent Neoplasm><Recurrent tumor><Relapse><Remission><Resistance><Reticulolymphosarcoma><Role><SIGLEC2><Sialic Acid-Binding Immunoglobulin-Like Lectin 2><Site><Solid Neoplasm><Solid Tumor><Stress><Surface><T cells for CAR><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Subsets><T8 Cells><T8 Lymphocytes><Testing><Tissue Growth><Toxic effect><Toxicities><Translating><Tumor Cell><Tumor Immunity><Tumor Tissue><Tyrosinase related protein-1><Variant><Variation><White Blood Cells><White Cell><Work><adoptive cell therapy><adoptive cellular therapy><anti-cancer immunotherapy><anti-tumor effect><anti-tumor immune response><anti-tumor immunity><anti-tumor response><anticancer immunotherapy><antitumor effect><antitumor immunity><cancer cell><cancer immunity><cancer immunotherapy><cell damage><cell injury><cellular damage><chimeric antigen T cell receptor><chimeric antigen receptor (CAR) T cells><chimeric antigen receptor T cells><chimeric antigen receptor fusion protein T-cells><chimeric antigen receptor modified T cells><cost><damage to cells><determine efficacy><dihydroxyindole-carboxylic acid oxidase><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><experience><extracellular><genome mutation><glioblastoma multiforme><host response><humanized mice><humanized mouse><immune system response><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><immunogenic><immunoresponse><immunotherapy for cancer><immunotherapy of cancer><in vivo><injury to cells><innovate><innovation><innovative><leukemia><malignancy><monocyte><mouse model><murine model><myeloma><myelomatosis><neoplasm recurrence><neoplasm/cancer><neoplastic cell><novel><ontogeny><pathway><pre-clinical><preclinical><prevent><preventing><recruit><resistant><response><social role><spongioblastoma multiforme><thymus derived lymphocyte><tumor><tumor eradication><tyrosinase-related TRP-1 protein><tyrosinase-related TRP1 protein><tyrosinase-related protein><white blood cell><white blood corpuscle>