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



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.



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.



κ.CART infusion is feasible and safe and can lead to complete clinical responses.



ClinicalTrials.gov NCT00881920.



National Cancer Institute (NCI) grants 3P50CA126752 and 5P30CA125123 and Leukemia and Lymphoma Society (LLS) Specialized Centers of Research (SCOR) grant 7018.
Carlos A
CA
Ramos
Barbara
B
Savoldo
Vicky
V
Torrano
Brandon
B
Ballard
Huimin
H
Zhang
Olga
O
Dakhova
Enli
E
Liu
George
G
Carrum
Rammurti T
RT
Kamble
Adrian P
AP
Gee
Zhuyong
Z
Mei
Meng-Fen
MF
Wu
Hao
H
Liu
Bambi
B
Grilley
Cliona M
CM
Rooney
Malcolm K
MK
Brenner
Helen E
HE
Heslop
Gianpietro
G
Dotti
D019264:Adoptive Transfer; D000328:Adult; D000368:Aged; D018941:Antigens, CD19 / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007145:Immunoglobulin kappa-Chains / Q000276:immunology*; D016130:Immunophenotyping; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000628:therapy*; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D012074:Remission Induction; D012190:Retroviridae / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D016896:Treatment Outcome
D018941:Antigens, CD19; C000605956:CD19-specific chimeric antigen receptor; D007145:Immunoglobulin kappa-Chains; D011948:Receptors, Antigen, T-Cell