CD138-directed adoptive immunotherapy of chimeric antigen receptor (CAR)-modified T cells for multiple myeloma

Abstract

Adoptive immunotherapy with T cells expressing a tumor-associated chimeric antigen receptor (CAR) provides a promising approach for tumor therapy. We designed a clinical trial for multiple myeloma (MM) treatment with CAR-modified T cells recognizing CD138 (CART-138). Five patients diagnosed with chemotherapy-refractory MM were enrolled into this trial, although one later advanced to plasma cell leukemia. By intravenous infusions, these patients received CD3 + CART-138 cells in an escalating dose. No intolerable toxicity was observed during this process. CART-138 cells were expanded to a level 1,000 times higher than the initial engraftment level and were maintained in the peripheral blood. In addition, increased CART-138 cells were also detected in the bone marrow. Four of the five patients had stable disease (SD) longer than three months, and one patient with advanced plasma cell leukemia had a reduction of the myeloma cells in her peripheral blood (from 10.5% to <3%). This study suggests that the treatment of CART-138 is safe, feasible, and tolerable and has potential antitumor activity in vivo, warranting further research in MM treatment using CART-138.

Clinical responses with T lymphocytes targeting malignancy-associated κ light chains

“…There are few reported clinical data for MM patients treated with CARTs. A recent report from China describes the outcomes of 5 MM patients treated with CD138.CARTs, 4 of whom achieved up to 7 months of SD (19). We observed modest antimyeloma effects, documented by a reduction of the paraprotein, a selective reduction of free κ light chains, and an improvement of anemia.…”

Chimeric antigen receptor T-cell therapies for multiple myeloma

“…36 After conditioning chemotherapy followed by infusion of anti-CD138 CIK cells, the CAR gene was persistently detectable for at least 4 weeks in the blood of all patients. 36 Toxicities were limited and consistent with CRS; interestingly, epithelial toxicity was not noted. 36,43 The best responses on this trial were SD in 4 patients and PD in 1 patient.…”

“…20,26,[81][82][83] Five patients with relapsed and refractory MM or plasma cell leukemia were treated on a phase 1 clinical trial of anti-CD138 CAR-Ts. 36 All patients had CD138 1 MM present in their bone marrow. 36 Peripheral blood mononuclear cells (PBMCs) were isolated and cultured with IFN-g and IL-2 followed by transduction with a lentivirus encoding an anti-CD138 CAR to produce cytokine-induced killer (CIK) cells.…”

“…6 Most CARs tested in clinical trials to date have used single-chain variable fragments (scFvs) with murine variable regions, which might elicit recipient anti-CAR immune responses. 5,9,21,[30][31][32][33][34][35][36] Strategies to use humanized or fully human antibody variable regions are now under development.…”

“…36 Peripheral blood mononuclear cells (PBMCs) were isolated and cultured with IFN-g and IL-2 followed by transduction with a lentivirus encoding an anti-CD138 CAR to produce cytokine-induced killer (CIK) cells. 36 After conditioning chemotherapy followed by infusion of anti-CD138 CIK cells, the CAR gene was persistently detectable for at least 4 weeks in the blood of all patients. 36 Toxicities were limited and consistent with CRS; interestingly, epithelial toxicity was not noted.…”