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
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
DOI: 10.1172/jci86000
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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