Clinical responses with T lymphocytes targeting malignancy-associated κ light chains
| Autor: | Enli Liu, Zhuyong Mei, Hao Liu, Rammurti T. Kamble, Bambi Grilley, Barbara Savoldo, Helen E. Heslop, Malcolm K. Brenner, Brandon Ballard, Huimin Zhang, Gianpietro Dotti, Olga Dakhova, Adrian P. Gee, George Carrum, Meng Fen Wu, Cliona M. Rooney, Vicky Torrano, Carlos A. Ramos |
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| Rok vydání: | 2016 |
| Předmět: |
Adult
Male 0301 basic medicine Adoptive cell transfer Cyclophosphamide T-Lymphocytes T cell Chronic lymphocytic leukemia Antigens CD19 Receptors Antigen T-Cell Enzyme-Linked Immunosorbent Assay CD19 Immunophenotyping Immunoglobulin kappa-Chains 03 medical and health sciences 0302 clinical medicine Antigen immune system diseases hemic and lymphatic diseases medicine Humans B cell Aged biology business.industry Lymphoma Non-Hodgkin Remission Induction General Medicine Middle Aged medicine.disease Adoptive Transfer Leukemia Lymphocytic Chronic B-Cell 3. Good health Retroviridae Treatment Outcome 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Immunology Cancer research biology.protein Feasibility Studies Female Clinical Medicine business medicine.drug |
| Zdroj: | Journal of Clinical Investigation. 126:2588-2596 |
| ISSN: | 1558-8238 0021-9738 |
| Popis: | BACKGROUND. 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. METHODS. 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. RESULTS. 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. CONCLUSION. κ.CART infusion is feasible and safe and can lead to complete clinical responses. TRIAL REGISTRATION. ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00881920","term_id":"NCT00881920"}}NCT00881920. FUNDING. National Cancer Institute (NCI) grants 3P50CA126752 and 5P30CA125123 and Leukemia and Lymphoma Society (LLS) Specialized Centers of Research (SCOR) grant 7018. |
| Databáze: | OpenAIRE |
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