SBIR-STTR Award

Multiple myeloma (MM) claims over 80,000 lives globally each year. Although several new therapies have been approved over the past decade, virtually all patients relapse and the median survival remains at only 5 years. The depth of therapeutic response correlates with time to relapse, and eradicating tumor cells early in the disease process may be necessary to achieve clinical cure. A potentially curative approach is autologous cell therapy with chimeric antigen receptor (CAR) T-cells redirected to a target antigen. For MM, an attractive target antigen is B cell maturation antigen (BCMA), an antigen marker with extremely high sensitivity and specificity for myeloma and plasma cells. Experiments proposed in this SBIR will define a transiently- expressed anti-BCMA CAR product that will overcome the toxicities generated by permanently modified T- cells. The goals of the Specific Aims are to 1) reduce immunogenicity of transiently-expressed (mRNA) anti- BCMA CAR T-cells to target MM in vitro; 2) optimize T-cell activation domains for the RNA-based CAR construct; 3) optimize translation and degradation of the mRNA transcript in T cells, and 4) demonstrate anti- BCMA CAR T-cell function in two in vivo models of MM. Such transient expression allows for predictable and controllable treatment of myeloma and may enable CAR T-cell therapy to be used in patients with early disease, with vastly improved potential of achieving clinical cure.

Project Terms:
3' Untranslated Regions; 5' Untranslated Regions; advanced disease; Adverse effects; Affinity; antigen binding; Antigen Targeting; Antigens; Area; Autologous; B-Lymphocytes; base; Binding; Biological Assay; Biological Sciences; Biotechnology; Body Weight; CD28 gene; CD3 Antigens; Cell Maturation; Cell physiology; Cell Therapy; Cellular immunotherapy; chemotherapy; chimeric antigen receptor; Chimeric Proteins; Clinical; clinical effect; Clinical Trials; cytokine release syndrome; Data; Differentiation Antigens; Disease; DNA; Electroporation; Engineering; Evaluation; experimental study; Goals; Government; Half-Life; Human; immunogenicity; improved; In Vitro; in vivo; in vivo Model; Inflammatory Response; Lead; Legal patent; Length; Licensing; Malignant Neoplasms; meetings; Messenger RNA; Modification; Monoclonal Antibody Therapy; mRNA Transcript Degradation; Multiple Myeloma; Mus; neoplastic cell; next generation; novel therapeutics; Parents; Patients; Persons; Phase; Phase I Clinical Trials; Plasma Cells; Plasmacytoma; Poly(A) Tail; prevent; Process; Production; Refractory Disease; Relapse; relapse patients; Research; response; RNA; Safety; Secure; Sensitivity and Specificity; Severe Adverse Event; Signal Transduction; Small Business Innovation Research Grant; Specificity; T cell therapy; T-Cell Activation; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Toxic effect; Transcript; Translations; treatment response; tumor; Tumor Antigens; tumor eradication; tumor growth; Untranslated Regions; Untranslated RNA; Viral Physiology; virtual; Xenograft Model;

Multiple myeloma (MM) claims over 80,000 lives globally each year. Although several new therapies have been approved over the past decade, virtually all patients relapse, and the median survival remains at only 5 years. The depth of therapeutic response correlates with time to relapse, and eradicating tumor cells early in the disease process may be necessary to achieve clinical cure. A potentially curative approach is autologous cell therapy with chimeric antigen receptor (CAR) T-cells redirected to a target antigen. For MM, an attractive target antigen is B cell maturation antigen (BCMA), an antigen marker with extremely high sensitivity and specificity for myeloma and plasma cells. Experiments described in this SBIR proposal cover early-stage clinical research (Phase I/II Clinical Trial) of an autologous anti-BCMA CAR T-cell product generated with mRNA (Descartes-11) in order to overcome the toxicities associated with permanently modified CAR T-cells. The goals of the Specific Aims are to 1) determine the safety, tolerability and Maximum Tolerated Dose of Descartes-11 in patients with relapsed/refractory MM; 2) establish preliminary clinical benefit of Descartes-11 at MTD in relapsed/refractory MM; 3) define correlative biomarkers of safety and efficacy in Descartes-11-treated patients. Use of mRNA to generate Descartes-11 enables predictable pharmacokinetics, providing the prospect of controlled CAR T-cell treatment of MM early in the course of the disease.

Public Health Relevance Statement:
NARRATIVE Cellular immunotherapy has shown remarkable responses in patients with certain cancers, including multiple myeloma. In their current form, permanently-modified cell therapies are often toxic, limiting their use to patients with advanced disease. The proposed research will examine safety and potential efficacy in a Clinical Trial of a powerful new cell therapy that is inherently more suited to patients with less advanced multiple myeloma, increasing the possibility of long-term cure.

Project Terms:
Address; advanced disease; Antibodies; Antibody Response; Antigen Targeting; Antigens; authority; Autologous; Autologous Stem Cell Transplantation; B-Lymphocytes; Biological Assay; Biological Markers; Blood; Cell Maturation; Cell Therapy; Cellular immunotherapy; chimeric antigen receptor; chimeric antigen receptor T cells; Clinical; clinical development; Clinical Research; Clinical Trials; Clinical Trials Design; Competence; curative treatments; Cyclic GMP; Cyclophosphamide; cytokine; cytokine release syndrome; cytotoxicity; Data; design; Development; Diagnosis; Differentiation Antigens; Disease; DNA; Dose; Dose-Limiting; Drug Kinetics; European; Evaluation; experimental study; first-in-human; fludarabine; Generations; Goals; Government; Grant; Half-Life; immunogenicity; Immunology; Immunophenotyping; improved; In complete remission; In Vitro; in vivo; Inflammatory Response; Infusion procedures; innovation; Malignant Neoplasms; Maximum Tolerated Dose; Measures; meetings; Messenger RNA; Molecular Biology; Multiple Myeloma; neoplastic cell; neurotoxicity; next generation; novel therapeutics; operation; Patients; Persons; Phase; Phase I Clinical Trials; Phase I/II Clinical Trial; Plasma Cells; Population; Pre-Clinical Model; preclinical development; preconditioning; Process; Production; Proliferating; Refractory; Relapse; relapse patients; Research; response; Risk; S Phase; Safety; safety assessment; senescence; Sensitivity and Specificity; Serum; Small Business Innovation Research Grant; T memory cell; T-Lymphocyte; Testing; Therapeutic; Time; Toxic effect; treatment effect; treatment response; tumor; virtual