Main
tumor, toxicity, cancer, contributeWe, tumors
MULTIPLE MYELOMA, TUMOR, B-CELL NEOPLASM, CANCER, SOLID TUMORS, TUMORS
Chimeric antigen receptor (CAR)-engineered T cell therapies have shown remarkable results in patients with relapsed/refractory (r/r) B-cell neoplasms and multiple myelomaA key obstacle for CAR-T cell approaches in solid tumors is the lack of highly cancer-specific cell-surface targets for efficient tumor eradication without on-target/off-tumor toxicity. Other common challenges are poor expansion and persistence, to which lack of antigenic stimulation due to inaccessibility of the target antigen in the periphery and an immunosuppressive tumor microenvironment may contributeWe have previously identified the primitive tight junction protein claudin 6 (CLDN6) as a potentially ideal immunotherapy targetWe have designed a highly sensitive, strictly CLDN6-specific second generation CAR with fusion of a CLDN6-specific single-chain variable fragment, the CD8α hinge and transmembrane region and 4-1BB and CD3ζ signaling moieties, which mediates rapid rejection of CLDN6-positive tumors by engineered T cells in xenograft and syngeneic mouse modelsBased on this work, we initiated a phase 1/2 first-in-human clinical trial to evaluate CLDN6 CAR-T cells alone and in combination with CARVac in patients with relapsed or refractory (r/r) CLDN6-positive solid tumors in a dose escalation part followed by cancer type-specific dose expansion cohorts. The manufacturing process of the CAR-T product is being developed in parallel to its clinical testing to implement a mature process with favorable product characteristics to facilitate a transition from manual to automated manufacturing before starting potentially pivotal trials.Here we present a non-prespecified interim analysis of 22 patients treated at two dose levels in the phase 1 dose escalation part of this trial, comprising the complete set of data obtained with the manual version of the manufacturing process. These data provide insights into the feasibility, safety and antitumor activity of the first-in-human concept of targeting the CLDN6 with a CAR-T therapy and combining with a CAR-amplifying vaccine.