Expanded T cells isolated from tumor infiltrating lymphocytes (TILs) have achieved remarkable clinical efficacy for the treatment of metastatic melanoma. TILs are composed of a polyclonal mix of tumor-reactive T cell receptors (TCRs), and several pioneering groups have isolated individual therapeutic TCRs targeting public tumor-associated antigens from TILs. The anti-tumor TCRs within the TIL population are able to target the many intracellular and patient-specific neoantigen targets not previously druggable. However, ex vivo expansion of TILs is labor intensive, time consuming, and may result in cellular phenotypic changes that could reduce efficacy. Isolating TCRs from pre-expanded "young" TIL populations would alleviate these issues and could be converted into a recombinant anti-tumor therapy. Leaders in the field have proposed that primary T cells engineered with polyclonal anti-tumor TCRs could be an ideal therapeutic approach. However, conventional T cell discovery relies on low-throughput methods and requires subsequent cloning of individual reactive TCRs. Generating a true "recombinant TIL" therapy requires a technology that can capture millions of T cells per hour and produce polyclonal libraries of TIL TCRs with native TCRa/b pairing. Previously, we developed GigaLink, a world-leading technology for generating recombinant TCR repertoires from primary T cell samples. We have used this technology to make expression libraries of natively paired TCRs from five clinically-validated malignant melanoma TILs. The Specific Aim of this Phase I SBIR project is to generate pre-clinical efficacy data in mouse models for a recombinant TIL T-cell therapeutic approach for the personalized treatment of cancer. We will achieve the Specific Aim by applying our GigaLink technology to patient derived xenograft (PDX) tumor models in mice.
Public Health Relevance Statement: PROJECT NARRATIVE Project Title: Recombinant TIL Cell Therapy for Salvage Solid Tumor Patients Organization: GigaMune Inc. PI: Matthew J Spindler, Ph.D. Cancer remains an intractable disease, but doctors have been achieving incredible results with new therapies that rely on genetic engineering of T cells. We are using microfluidics and DNA sequencing to capture disease- modulating T cells from patients. Anti-tumor genes from these T cells are then engineered into healthy T cells to create a patient-specific engineered T cell therapy.
Project Terms: Antigens; immunogen; ATGN; B-Lymphocytes; Bursa-Equivalent Lymphocyte; Bursa-Dependent Lymphocytes; B-cell; B-Cells; B cells; B cell; B blood cells; Bone Marrow Transplantation; Marrow Transplantation; Bone Marrow Transplant; Bone Marrow Grafting; Malignant Neoplasms; neoplasm/cancer; malignancy; Malignant Tumor; Cancers; Cloning; Cessation of life; Death; Disease; Disorder; Engineering; Genes; Genetic Engineering; genetically engineered; Recombinant DNA Technology; Genetic Engineering Molecular Biology; Genetic Engineering Biotechnology; Genotype; Human; Modern Man; Immunotherapy; immuno therapy; immune-based treatments; immune-based therapies; immune therapy; immune therapeutic interventions; Immunologically Directed Therapy; In Vitro; Libraries; melanoma; Malignant Melanoma; Methods; Mus; Murine; Mice Mammals; Mice; Patients; Phenotype; T-Cell Receptor; Receptors, Antigen, T-Cell; Major Histocompatibility Complex Receptor; MHC Receptor; Safety; Students; T-Lymphocyte; thymus derived lymphocyte; Thymus-Dependent Lymphocytes; T-Cells; Technology; Time; Tumor Antigens; tumor-specific antigen; cancer antigens; Tumor-Associated Antigen; Tumor-Infiltrating Lymphocytes; Salvage Therapy; Salvage-Tx; Immunology; Clinical; Phase; cardiomyocyte; Heart myocyte; Heart Muscle Cells; Cardiocyte; Cardiac Muscle Cells; Cardiac Myocytes; Individual; Licensing; Metastatic Melanoma; Solid Tumor; Solid Neoplasm; TIL therapy; tumor infiltrating lymphocyte therapy; Cell Therapy; cell-based therapy; cell mediated therapies; Therapeutic; cancer cell; Malignant Cell; Adoptive Cell Transfers; adoptive cellular therapy; adoptive cell therapy; Hour; Tumor Volume; Postdoctoral Fellow; post-doctoral; post-doc; Research Associate; Postdoc; neoplastic cell; Tumor Cell; drug efficacy; cell killing; Toxic effect; Toxicities; Cell surface; Modeling; Sampling; cellular engineering; cell engineering; Microfluidics; Microfluidic; Incubated; Dose; Data; Doctor of Philosophy; PhD; Ph.D.; Recombinants; in vivo; Expression Library; Small Business Innovation Research; SBIR; Small Business Innovation Research Grant; Tumor Expansion; Xenograft Model; stem cell differentiation; clinical efficacy; tumor xenograft; therapy efficacy; therapeutically effective; therapeutic efficacy; intervention efficacy; Treatment Efficacy; Population; translational study; novel therapy; novel drugs; novel drug treatments; next generation therapeutics; new therapy; new therapeutics; new drugs; new drug treatments; novel therapeutics; murine model; mouse model; tumor; FDA approved; pre-clinical efficacy; preclinical efficacy; adoptive T-cell therapy; adoptive T cell transfer; T cell based therapy; CAR T-cell therapy; T cell therapy; chimeric antigen receptors; Chimeric antigen T-cell receptor; chimeric antigen receptor; targeted therapy; targeted therapeutic agents; targeted therapeutic; targeted drug treatments; targeted drug therapy; targeted treatment; personalized cancer treatment; individualized cancer therapy; personalized cancer therapy; tailored approach; precision approach; individualized approach; Personalized medical approach; personalized approach; intratumor heterogeneity; intra-tumoral heterogeneity; heterogeneity in tumors; Intratumoral heterogeneity; tumor heterogeneity; DNAseq; DNA seq; DNA sequencing; neoepitopes; neo-epitopes; neo-antigen; neoantigens; TCR repertoire; T-cell receptor repertoire
