Use of Natural Signals and Ambient Dendritic Cells to Culture-Expand Cancer Targeting T-Cells Directly From Unfractionated Peripheral Blood: A Phase 1 T-Cell Dose Escalation Trial Targeting Relapsed and Refractory MUC1-Expressing Multiple Myeloma

简要总结

详细描述

PRIMARY OBJECTIVE: I. To determine the toxicity of in-house, manufactured MUC1-activated T cells in patients with relapsed/refractory MUC1-expressing multiple myeloma. SECONDARY OBJECTIVES: I. Obtain preliminary efficacy associated with MUC1-targeting peripheral blood mononuclear cells (PBMC) derived T cells in conjunction with cyclophosphamide (CTX) in MUC1-expressing multiple myeloma patients. Ia. Assess best objective response observed based on International Myeloma Working Group (IMWG) criteria and duration of any partial or complete responses (partial response \[PR\] or complete response \[CR\]). Ib. Assess progression-free (PFS) and overall (OS) survival. II. Determine feasibility of production and administration of MUC1-targeting PBMC-derived T cells and ability to proceed with T cell dose escalation. IIa. Assess the feasibility of in-house preparation of in vitro-sensitized T cells. III. Evaluate the safety, including all grades of neurotoxicity immune effector cell associated neurotoxicity (ICANS) and cytokine release syndrome (CRS) as determined by American Society of Transplantation and Cell Therapy (ASTCT) criteria, by monitoring adverse events, laboratory abnormalities, vital signs, and other safety parameters. IV. Estimate the incidence of Grade 3 or higher of neurotoxicity and cytokine release syndrome by Grade 3 or higher neurotoxicity (ICANS) or CRS per the ASTCT criteria. V. Assess efficacy of a single dose of MUC1-activated T cells. CORRELATIVE RESEARCH OBJECTIVES: I. Perform analyses of Vbeta usage by T cell receptors (TCR) to see whether culture expansion generated TCR oligoclonality; whether such T cells persist in the circulation following adoptive transfer; and whether such persistence significantly correlates to objective responses. Ia. Levels of Vbeta alleles on CD3+ T cells in blood by antibody staining or deoxyribonucleic acid (DNA) sequencing (Adaptive Biotechnologies). II. Characterize the changes in cytokine levels over time. III. Determine whether T cells recognizing MUC1 in an major histocompatibility complex (MHC)-restricted manner in culture (intracellular IFN-gamma assays) correspond to therapeutic efficacy upon subsequent adoptive transfer. IV. Determine the immune phenotype of the immune cells, the inhibitory profile, and transcription factors using multi-color flow cytometry. V. Assess hospital resource utilization and health economics. OUTLINE: This is a dose-escalation study of MUC1-activated T-cells. LYMPHODEPLETION (LD) CHEMOTHERAPY : Patients receive cyclophosphamide intravenously (IV) over 60 minutes on days -5, -4, -3. AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT): Patients receive MUC1-activated T-cells IV over 10 minutes to 1 hour on day 0. After completion of study treatment, patients are followed up on days 1, 2, 3, 7, 28 and every 90 days for up to 2 years.

主要结局

次要结局

• Overall survival(From registration to death due to any cause, assessed up to 4 years)
• Clinical response(Up to 4 years)
• Progression-free survival(From registration to disease progression or death due to any cause, assessed up to 4 years)