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- Title
Clinical responses with T lymphocytes targeting malignancy-associated κ light chains.
- Authors
Ramos, Carlos A.; Savoldo, Barbara; Torrano, Vicky; Ballard, Brandon; Huimin Zhang; Dakhova, Olga; Enli Liu; Carrum, George; Kamble, Rammurti T.; Gee, Adrian P.; Zhuyong Mei; Meng-Fen Wu; Hao Liu; Grilley, Bambi; Rooney, Cliona M.; Brenner, Malcolm K.; Heslop, Helen E.; Dotti, Gianpietro; Zhang, Huimin; Liu, Enli
- Abstract
<bold>Background: </bold>Treatment of B cell malignancies with adoptive transfer of T cells with a CD19-specific chimeric antigen receptor (CAR) shows remarkable clinical efficacy. However, long-term persistence of T cells targeting CD19, a pan-B cell marker, also depletes normal B cells and causes severe hypogammaglobulinemia. Here, we developed a strategy to target B cell malignancies more selectively by taking advantage of B cell light Ig chain restriction. We generated a CAR that is specific for the κ light chain (κ.CAR) and therefore recognizes κ-restricted cells and spares the normal B cells expressing the nontargeted λ light chain, thus potentially minimizing humoral immunity impairment.<bold>Methods: </bold>We conducted a phase 1 clinical trial and treated 16 patients with relapsed or refractory κ+ non-Hodgkin lymphoma/chronic lymphocytic leukemia (NHL/CLL) or multiple myeloma (MM) with autologous T cells genetically modified to express κ.CAR (κ.CARTs). Other treatments were discontinued in 11 of the 16 patients at least 4 weeks prior to T cell infusion. Six patients without lymphopenia received 12.5 mg/kg cyclophosphamide 4 days before κ.CART infusion (0.2 × 108 to 2 × 108 κ.CARTs/m2). No other lymphodepletion was used.<bold>Results: </bold>κ.CART expansion peaked 1-2 weeks after infusion, and cells remained detectable for more than 6 weeks. Of 9 patients with relapsed NHL or CLL, 2 entered complete remission after 2 and 3 infusions of κ.CARTs, and 1 had a partial response. Of 7 patients with MM, 4 had stable disease lasting 2-17 months. No toxicities attributable to κ.CARTs were observed.<bold>Conclusion: </bold>κ.CART infusion is feasible and safe and can lead to complete clinical responses.<bold>Trial Registration: </bold>ClinicalTrials.gov NCT00881920.<bold>Funding: </bold>National Cancer Institute (NCI) grants 3P50CA126752 and 5P30CA125123 and Leukemia and Lymphoma Society (LLS) Specialized Centers of Research (SCOR) grant 7018.
- Subjects
LYMPHOCYTES; B cell lymphoma; T cells; GAMMA globulins; HODGKIN'S disease; CYCLOPHOSPHAMIDE; CHRONIC lymphocytic leukemia treatment; LYMPHOMA treatment; ANTIGENS; CELL receptors; CHRONIC lymphocytic leukemia; CLINICAL trials; COMPARATIVE studies; ENZYME-linked immunosorbent assay; IMMUNIZATION; IMMUNOGLOBULINS; IMMUNOPHENOTYPING; LYMPHOMAS; RESEARCH methodology; MEDICAL cooperation; RESEARCH; RESEARCH funding; RETROVIRUSES; PILOT projects; EVALUATION research; TREATMENT effectiveness; DISEASE remission
- Publication
Journal of Clinical Investigation, 2016, Vol 126, Issue 7, p2588
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI86000