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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 Research and Public Health Oncology Article has an altmetric score of 42

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

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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 5

Patient 9 achieved a transient CR after 3 infusions of κ.CARTs.

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Patient 9 achieved a transient CR after 3 infusions of κ.CARTs.
Patient ...
Patient 9 had transformed FL with active disease in the retroperitoneum and pelvis, including a 2.1 × 1.2-cm left external iliac lymph node near the anterior aspect of the left acetabulum, with a standard uptake value (SUV) of 8.5 (bottom row) and a 1 × 1-cm posterior left common iliac chain lymph node, with an SUV of 4.4 (top row). Six weeks after the first infusion of κ.CARTs, a repeat PET/CT scan showed interval improvement in uptake and, to a lesser degree, in the size of multiple lymph nodes, including mild interval improvement in uptake (SUV 5.5) and size (2 × 0.9-cm) in the external iliac lymph node and improved uptake (SUV 3.4) and a slight decrease in the size of the common iliac lymph node. Six weeks after the second infusion of κ.CARTs, we observed a significant response with what appeared to be residual disease within the left pelvic lymph nodes, with the external iliac lymph node that had remained stable in size but had decreased to an SUV of 2.9 and the common iliac lymph node with an SUV of 2.2. Six weeks after the third infusion of κ.CARTs, there was a decrease in the size (the external iliac lymph node was 1.7 × 0.9 cm) and resolution of the previous uptake within the left pelvic lymph nodes and normal uptake elsewhere, consistent with a CR.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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