Phase I Amount
$1,000,000
The overall goal of this Phase II SBIR grant proposal is to research and develop the GMP manufacturing process for next-generation tumor infiltrating lymphocyte (TIL) cancer therapeutic for solid tumors. In clinical trials, TIL-based immunotherapies have demonstrated tumor regression and increased survival rates against different cancer types. Despite these encouraging clinical results, durable antitumor responses are typically observed in a subset of patients with advanced cancers like melanoma. This stresses the need to develop more effective TIL-based strategies and to expand efficacy against different cancer types. TIL therapies are hindered in part by low TIL accumulation into tumors, low persistence, weak T cell receptor (TCR) affinity and/or avidity as well as the low expression of tumor antigens on the cell's surface. Additionally, the presence of suppressive signals on T cells such as Lag3, Tim3, CD39, pose a major obstacle to generating effective and long-lived antitumor T cell responses. In our published and preliminary studies, activating MyD88 signaling in human or mouse T cells, increases antitumor activity and prolongs T cell survival. By fusing the high affinity CD8a (extracellular) to MyD88 (intracellular; CD8a:MyD88) we have developed a novel and universal platform that activates MyD88 signaling strictly upon the engagement of the TCR with the MHC-antigen on tumor cells. CD8a:MyD88 expression in TILs cells substantially increases responses to weak and suboptimal levels of tumor antigens including neoantigens, and in preliminary studies has demonstrated the extraordinary property of reducing the T cells entry into an "exhausted state'. Importantly, the use of the CD8a co-receptor represents a "universal' approach to enhancing T cell responses, and can be used in patients regardless of the patient's HLA type. Through this SBIR Phase II application, we propose the following aims. Aim 1 will research, develop, and manufacture GMP grade g-retroviral vectors. Here, we will generate high virus titer-producing CD8a:MyD88-EGFRt PG-13 cell lines, accompanying analytical assays, and manufacture the GMP CD8a:MyD88-EGFRt g-retroviral vectors. For this aim, we are partnering with a commercial contract development manufacturing organization (CDMO), Vigene Biosciences to generate GMP viral vectors. In Aim 2, we propose to develop and manufacture GMP CD8a:MYD88 engineered TILs (coR8:AMPTM TILs). In collaboration with the Gates Manufacturing Facility (GBF) at the University of Colorado Anschutz Medical Campus (UCAMC) we will conduct process & analytical assay, QC release assay, develop and manufacture of GMP grade coR8:AMPTM TILs. The successful completion of these aims will lead to the pre-IND and IND filings with the FDA for a Phase I clinical trial in patients with immune refractory solid tumors. This activity will be conducted in collaboration with the UCAMC's Cell Therapy Operations Program (CTOP), Gates Biomanufacturing Facility, and our team members who have extensive experience in cell therapy drug development.
Public Health Relevance Statement: Project Narrative T cell-based immunotherapies such as tumor infiltrating lymphocytes (TILs) have revolutionized the treatment of a number of different cancers including advanced melanoma. However, most patients still do not benefit from this form of therapy because few immune cells penetrate the tumor and show transient antitumor activity. We have developed a novel, genetically engineered TIL therapy that overcomes multiple impediments to conventional TIL therapy.
Project Terms: Attention; Australia; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Sciences; Biologic Sciences; Bioscience; Life Sciences; Canada; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Cell Line; CellLine; Strains Cell Lines; cultured cell line; Cell Survival; Cell Viability; Cells; Cell Body; Clinical Trials; Colorado; Eligibility Determination; Eligibility; Protocol Screening; Engineering; Europe; Future; Genetic Engineering; Genetic Engineering Biotechnology; Genetic Engineering Molecular Biology; Recombinant DNA Technology; genetically engineered; Goals; Recording of previous events; History; 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; Interleukin-2; Co-Stimulator; Costimulator; Epidermal Thymocyte Activating Factor; IL-2; IL2 Protein; Interleukin 2; Interleukin 2 Precursor; Interleukin II; Interleukine 2; Interleukine 2 Precursor; Interleukine II; Lymphocyte Mitogenic Factor; Mitogenic Factor; T cell growth factor; T-Cell Growth Factor; T-Cell Stimulating Factor; Thymocyte Stimulating Factor; Japan; Laboratories; Lead; Pb element; heavy metal Pb; heavy metal lead; melanoma; Malignant Melanoma; Methods; Mus; Mice; Mice Mammals; Murine; Patents; Legal patent; Patients; Publishing; MHC Receptor; Major Histocompatibility Complex Receptor; T-Cell Antigen Receptors; T-Cell Receptor; Recurrent; Recurrence; Research; Safety; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Signal Transduction; Stress; Survival Rate; T-Cells; thymus derived lymphocyte; T-Lymphocyte; Cell-Mediated Lympholytic Cells; Cytolytic T-Cell; Cytotoxic T Cell; killer T cell; Cytotoxic T-Lymphocytes; Technology; Tumor Antigens; Tumor-Associated Antigen; cancer antigens; tumor-specific antigen; Universities; Virus; Tumor-Infiltrating Lymphocytes; base; exhaust; Solid; Clinical; Refractory; Phase; Medical; Cytokine Receptors; Licensing; Solid Tumor; Solid Neoplasm; TIL therapy; tumor infiltrating lymphocyte therapy; Collaborations; Intellectual Property; TLR signal adaptor protein MyD88; MyD88 protein; Engraftment; cell mediated therapies; cell-based therapeutic; cell-based therapy; cellular therapy; Cell Therapy; Therapeutic; Contracting Opportunities; Contracts; Deposit; Deposition; adoptive cell therapy; adoptive cellular therapy; Adoptive Cell Transfers; programs; exhaustion; Chemotherapy Protocol; Chemotherapy Regimen; Combination Chemotherapy Regimen; Quimioterapia; cancer chemotherapy; Chemotherapy-Oncologic Procedure; Immunes; Immune; Head and Neck; Head and neck structure; extracellular; interest; Infusion; Infusion procedures; experience; Tumor Cell; neoplastic cell; Receptor Protein; receptor; MHC antigen; Toxicities; Toxic effect; novel; member; Cell surface; Modeling; Property; response; assay development; drug development; immunogenic; Advanced Cancer; Advanced Malignant Neoplasm; Phase I Clinical Trials; Early-Stage Clinical Trials; Phase 1 Clinical Trials; phase I protocol; cancer therapy; Cancer Treatment; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; anti-cancer therapy; anticancer therapy; cancer-directed therapy; gene delivery system; Adaptor Protein; Adaptor Protein Gene; Adaptor Signaling Protein Gene; adapter protein; Adaptor Signaling Protein; Malignant Soft Tissue Neoplasm; malignant soft tissue tumor; sarcoma; Address; Dose; Affinity; Avidity; cytotoxic; Grant Proposals; Applications Grants; Retrovirus Vector; Retroviral Vector; Antigen Targeting; Antitumor Response; anti-tumor response; Engineered Gene; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Tumor-Derived; Tumor Immunity; anti-tumor immunity; antitumor immunity; cancer immunity; Viral Vector; Process; Development; developmental; pre-clinical; preclinical; next generation; conditioning; manufacturing process; manufacturing facility; cancer type; Autologous Tumor-Infiltrating Lymphocyte; viral gene delivery; Homing; Biomanufacturing; chemotherapy; mouse model; murine model; therapy development; develop therapy; intervention development; treatment development; tumor; Regimen; T cell response; operation; chimeric antigen receptor; chimeric antigen T cell receptor; Therapy trial; cancer clinical trial; oncology clinical trial; patient subsets; patient subgroups; patient subpopulations; patient subtypes; experimental study; experiment; experimental research; Cellular immunotherapy; cell-based immunotherapy; immune cell therapy; neoantigens; neo-antigen; neo-epitopes; neoepitopes; Tumor-infiltrating immune cells; Immune infiltrates; T cell infiltration; T cell tumor trafficking; immune cell infiltrate; immune infiltration; intratumoral immune cell; tumor immune cell; first-in-human; first in man; safety assessment; engineered T cells
