CD19-directed chimeric antigen receptor T cell therapy in Waldenström macroglobulinemia: a preclinical model and initial clinical experience.

Waldenström macroglobulinemia (WM) is an incurable disease and, while treatable, can develop resistance to available therapies and be fatal. Chimeric antigen receptor (CAR) T cell therapy directed against the CD19 antigen has demonstrated efficacy in relapsed or refractory B lymphoid malignancies, and is now approved for B cell acute lymphoblastic leukemia and certain B cell lymphomas. However, CAR T therapy has not been evaluated for use in WM. We performed preclinical studies demonstrating CAR T cell activity against WM cells in vitro, and developed an in vivo murine model of WM which demonstrated prolonged survival with use of CAR T therapy. We then report the first three patients with multiply relapsed and refractory WM treated for their disease with CD19-directed CAR T cells on clinical trials. Treatment was well tolerated, and observed toxicities were consistent with those seen in CAR T treatment for other diseases, and no grade 3 or higher cytokine release syndrome or neurotoxicity events occurred. All three patients attained at least a clinical response to treatment, including one minimal residual disease-negative complete response, though all three eventually developed recurrent disease between 3 and 26 months after initial treatment. This report summarizes preclinical and clinical activity of CD19-directed CAR T therapy in WM, demonstrating early tolerability and efficacy in patients with WM, and representing a possible treatment option in patients with heavily pretreated and relapsed or refractory WM. Larger studies evaluating CAR T therapy in WM are warranted, along with further evaluation into mechanisms of resistance to CAR T therapy.

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Competing interests: MLP has received consulting fees from BeiGene, Novartis and Synthekine. An immediate family member of MLP is a Board Member with DKMS, has IP rights with Juno Therapeutics and Seres Therapeutics, and receives consulting fees from Rheos Medicines, Ceramedix, GKS, Priotera, and WindMIL Therapeutics. MR has received consulting fees from Celgene and Physicians’ Education Resource, and consulting fees plus equity interest in Auron Therapeutics. IR has received consulting fees and funding support from Juno Therapeutics, in which she had an equity interest. RJB has licensed intellectual property to and collect royalties from BMS, Caribou and Sanofi. RJB received research funding from BMS. RJB is a consultant to BMS and was a consultant for Gracell Biotechnologies but ended employment in the past 24 months. JHP received consulting fees from Amgen, Allogene, Artiva Biotherapeutics, Autolus, BMS, Curocell, GSK, Incyte, Innate Pharma, Intellia Therapeutics, Kite Pharma, Kura Oncology, Minerva Biotechnologies, Novartis, Pfizer and Servier, and serves as a DSMB member for Affyimmune and Bright Pharmaceuticals. ELS received IP or royalties from BMS, Sanofi, and is a consultant to BMS, Novartis, and Chimeric Therapeutics. DQ, SM, SS, AD, BS, XW, and MS have no conflicts of interest to disclose.