Clinical responses with T lymphocytes targeting malignancy-associated κ light chains
Carlos A. Ramos, … , Helen E. Heslop, Gianpietro Dotti
Carlos A. Ramos, … , Helen E. Heslop, Gianpietro Dotti
Published June 6, 2016
Citation Information: J Clin Invest. 2016;126(7):2588-2596. https://doi.org/10.1172/JCI86000.
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Clinical Medicine Oncology

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

Abstract

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 NCT00881920.

FUNDING. National Cancer Institute (NCI) grants 3P50CA126752 and 5P30CA125123 and Leukemia and Lymphoma Society (LLS) Specialized Centers of Research (SCOR) grant 7018.

Authors

Carlos A. Ramos, Barbara Savoldo, Vicky Torrano, Brandon Ballard, Huimin Zhang, Olga Dakhova, Enli Liu, George Carrum, Rammurti T. Kamble, Adrian P. Gee, Zhuyong Mei, Meng-Fen Wu, Hao Liu, Bambi Grilley, Cliona M. Rooney, Malcolm K. Brenner, Helen E. Heslop, Gianpietro Dotti

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Figure 4

Patient 2 achieved a durable CR after 2 infusions of κ.CARTs.

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Patient 2 achieved a durable CR after 2 infusions of κ.CARTs. Patient 2 ...
Patient 2 had transformed follicular lymphoma (FL) with active disease in the neck 4 weeks after receiving 1 dose of bendamustine, as documented in the preinfusion PET/CT scan, which showed a hypermetabolic 7.2 × 3.4-cm left anterior mass (circled) and a hypermetabolic 1.7 × 1-cm left paratracheal lymph node. Six weeks after the first infusion of κ.CARTs, a PET/CT scan showed a PR, with a decrease in the activity and size of the mass (2.4 × 0.8 cm) and lymph node (1.3 × 0.6 cm). Another PET scan obtained after a second infusion was consistent with a CR. This patient has been without evidence of disease for almost 3 years.