Hotspot TCR-T: A Phase I/Ib Study of Adoptively Transferred T-cell Receptor Gene-engineered T Cells (TCR-T)

Patients will be infused with T cells engineered to express TCRs targeting one to five tumor-specific antigens expressed by their autologous tumor. The number of T cells infused will range from 1e9 to 1e11. Monoclonal antibodies targeting PD-1 (pembrolizumab) and CD40 (CDX-1140, Celldex Therapeutics)43 will be administered, in that order, starting within 24 hours of cell infusion and re-administered at approximately 3 week intervals. Clinic visits will include longitudinal evaluation of toxicities and monitoring of immunological parameters. The presence or absence of replication competent retrovirus (RCR) will be evaluated for the first year following adoptive cell transfer, or longer, if there is evidence of RCR. Tumor Response assessment by RECIST 1.1 is performed every 9-12 weeks. Study treatment continues until progression. Option repeat TCR-T infusion is allowed and in addition may incorporate preconditioning chemotherapy using a de-intensified non-myeloablative (NMA) regimen consisting of a single dose of gemcitabine and a single dose of either cyclophosphamide or epirubicin, designed to elicit immunogenic cell death and transient lymphopenia. The primary objective of this study is to determine the safety of the adoptive transfer of TCR-gene engineered T cells targeting TSA in combination with CD40 and PD-1 immunotherapy. The secondary objective is to determine whether this therapy can mediate objective clinical responses as determined by objective criteria (e.g. RECIST 1.1). The study will also characterize the differentiation and functional state of the TCR-gene modified T cells before and after cell therapy and monitor their persistence in the patient after treatment. Up to 24 patients will be enrolled in this study. Based on published trials treating patients with TCR-transduced T cells, adverse events such as fever, chills, dyspnea, hypotension, fatigue, edema, rash, and rarely acute cytokine release syndrome, may occur. Clinical and immunological data will be analyzed which will determine whether this therapy is safe and effective, and whether there are biomarkers or immunological signatures that correlate to efficacy and/or lack of efficacy. This data will determine whether additional studies are warranted.