Since the first FDA approval of chimeric antigen receptor (CAR) T cell therapy in 2017, the use of engineered T cells expressing specific CARs to treat cancer has generated durable cures for many patients. Nevertheless, a significant subset of patients with B cell malignancies relapse following treatment due to lack of CAR T cell persistence and the ability of cancer cells to change with time and evade therapeutic interventions. Autologous T cell therapies also carry significant timeline and cost burdens, making widespread adoption difficult. In this application, we propose a novel allogeneic CAR T cell therapy aimed at improving outcomes for patients with mantle cell lymphoma (MCL) by overcoming deficiencies present in current generation CD19 targeted therapeutics. B cell activating factor (BAFF) provides critical survival signals to both normal and neoplastic B cells through a family of receptors (BAFF receptor, TACI, and BCMA) thus mitigating potential for antigen escape. BAFF and its receptors have remained underexplored in the context of B cell malignancies where strategies have relied overwhelmingly on pan B cell antigens such as CD19 and CD20. Since BAFF binds its receptors with moderate affinity, we believe this will increase the ability of these cells to form memory populations and engage in serial killing. We will leverage this ligand-based CAR design in an allogeneic gamma delta (γδ) T cell platform, as γδ T cells have been shown to have high replicative properties in vitro and do not mediate graft versus host disease in new hosts. We have produced preliminary data that confirms our ability to use the non- viral TcBuster DNA transposon system to generate T cells with BAFF-CAR expression. The overall objective of this proposal is to further develop and evaluate our γδ BAFF-CAR T cell therapy for the treatment of MCL in IND enabling studies. In doing so, our allogeneic BAFF-CAR T cell therapy supports an urgently needed shift in therapeutic development toward new tumor antigens that protect against antigen escape while reducing the manufacturing burden associated with cellular therapies through use of a readily available cell source.
Public Health Relevance Statement: PROJECT NARRATIVE This proposal describes a novel allogeneic chimeric antigen receptor (CAR) T cell therapy that aims to improve outcomes for patients with mantle cell lymphoma. Our approach improves upon current immunotherapies by engineering T cells in a unique way to express a novel CAR against multiple underexplored targets in an allogenic platform. We expect immunotherapeutic delivery of these modified T cells will reduce disease recurrence by preventing antigen escape, improving persistence, and decreasing manufacturing burden.
Project Terms: Adoption; Animals; immunogen; Antigens; B-Lymphocytes; B blood cells; B cell; B cells; B-Cells; B-cell; Biological Assay; Assay; Bioassay; Biologic Assays; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Cell Line; CellLine; Strains Cell Lines; cultured cell line; Cells; Cell Body; Chemistry; DNA; Deoxyribonucleic Acid; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Engineering; Family; Genetic Engineering; Genetic Engineering Biotechnology; Genetic Engineering Molecular Biology; Recombinant DNA Technology; genetically engineered; graft vs host disease; GvHD; Homologous Wasting Disease; Runt Disease; graft versus host disease; graft vs. host disease; Human; Modern Man; Immunotherapy; Immune mediated therapy; Immunologically Directed Therapy; immune therapeutic approach; immune therapeutic interventions; immune therapeutic regimens; immune therapeutic strategy; immune therapy; immune-based therapies; immune-based treatments; immuno therapy; In Vitro; Ligands; Longevity; Length of Life; life span; lifespan; Memory; Methods; Mus; Mice; Mice Mammals; Murine; Patients; Drug Kinetics; Pharmacokinetics; Pharmacology; Production; Quality Control; Recommendation; Relapse; Messenger RNA; mRNA; Running; Safety; Signal Transduction; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; T-Lymphocyte; T-Cells; thymus derived lymphocyte; Testing; Time; Tumor Antigens; Tumor-Associated Antigen; cancer antigens; tumor-specific antigen; Work; Generations; Immunocompromised; Immunocompromised Patient; Immunosuppressed Host; immunosuppressed patient; Immunocompromised Host; B Cell-Activating Factor Receptor; CD124 Antigens; CDw124 Antigen; IL-4 Receptors; IL4 Receptors; Interleukin-4 Receptor Alpha; Interleukin 4 Receptor; timeline; improved; Clinical; Malignant; Malignant - descriptor; Residual; Residual state; Specified; Specific qualifier value; Phase; Evaluation; Technology Transfer; Toxicity Testing; Toxicity Tests; Relapsed Disease; Recurrent disease; Co-culture; Cocultivation; Coculture; Coculture Techniques; cell mediated therapies; cell-based therapeutic; cell-based therapy; cellular therapeutic; cellular therapy; Cell Therapy; Genetic; cancer cell; Malignant Cell; Mantle Cell Lymphoma; Centrocytic Small-Cell Lymphoma; Lymphoma, Lymphocytic, Diffuse, Poorly-Differentiated; Mantle-Zone Lymphoma; Life; Cellular biology; cell biology; Complex; Autologous; Protocols documentation; Protocol; Source; System; Xenograft procedure; Heterograft; Heterologous Transplantation; Xenograft; Xenotransplantation; xeno-transplant; xeno-transplantation; Viral; cytotoxicity; Lytotoxicity; experience; receptor; Receptor Protein; receptor expression; cell killing; DNA Transposons; transposon element; Toxic effect; Toxicities; novel; Benefits and Risks; Positioning Attribute; Position; Therapeutic Intervention; intervention therapy; Property; response; Immunotherapeutic agent; immune drugs; immune-based therapeutics; immunologic therapeutics; immunotherapeutics; immunotherapy agent; Documentation; activated B cells; B-Cell Activation; Molecular Interaction; Binding; preventing; prevent; CD19 gene; CD19; MS4A1 gene; Bp35; CD20; Leu-16; MS4A1; MS4A2; Address; Dose; Affinity; cytotoxic; Data; Mature B-Lymphocyte; Mature B-Cell; Qualifying; Reproducibility; in vivo; Allogenic; Antigen Targeting; Patient-Focused Outcomes; Patient outcome; Patient-Centered Outcomes; patient oriented outcomes; Validation; validations; Process; Development; developmental; safety study; neoplastic; pre-clinical; preclinical; cost; designing; design; determine efficacy; efficacy analysis; efficacy assessment; efficacy determination; efficacy examination; evaluate efficacy; examine efficacy; efficacy evaluation; B cell malignancy; B lymphoid malignancy; tumor xenograft; manufacturing process; cost effective; Population; innovate; innovative; innovation; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; murine model; mouse model; commercialization; tumor; therapeutic agent development; therapeutic development; pre-clinical evaluation; preclinical evaluation; product development; safety testing; good laboratory practice; T cell based therapeutics; T cell based therapy; T cell directed therapies; T cell targeted therapeutics; adoptive T cell transfer; adoptive T-cell therapy; therapeutic T-cell platform; T cell therapy; chimeric antigen T cell receptor; chimeric antigen receptor; targeted drug therapy; targeted drug treatments; targeted therapeutic; targeted therapeutic agents; targeted therapy; targeted treatment; improved outcome; patient subgroups; patient subpopulations; patient subtypes; patient subsets; Gamma-delta T cells; γδT cells; γδ T cells; preservation; in vivo testing; in vivo evaluation; engineered T cells; CAR T cells; CAR modified T cells; CAR-T; CAR-Ts; T cells for CAR; chimeric antigen receptor (CAR) T cells; chimeric antigen receptor fusion protein T-cells; chimeric antigen receptor modified T cells; chimeric antigen receptor T cells; CAR T therapy; chimeric antigen receptor (CAR) T cell therapy; chimeric antigen receptor T cell therapy; CAR T cell therapy; manufacture
