Anti-TACI single and dual-targeting CAR T cells overcome BCMA antigen loss in multiple myeloma

Rebecca C. Larson, Michael C. Kann, Charlotte Graham, Christopher W. Mount, Ana P. Castano, Won-Ho Lee, Amanda A. Bouffard, Hana N. Takei, Antonio J. Almazan, Irene Scarfó, Trisha R. Berger, Andrea Schmidts, Matthew J. Frigault, Kathleen M. E. Gallagher and Marcela V. Maus ()
Additional contact information
Rebecca C. Larson: Massachusetts General Hospital
Michael C. Kann: Massachusetts General Hospital
Charlotte Graham: Massachusetts General Hospital
Christopher W. Mount: Massachusetts General Hospital and Harvard Medical School
Ana P. Castano: Massachusetts General Hospital
Won-Ho Lee: Massachusetts General Hospital
Amanda A. Bouffard: Massachusetts General Hospital
Hana N. Takei: Massachusetts General Hospital
Antonio J. Almazan: Massachusetts General Hospital
Irene Scarfó: Massachusetts General Hospital
Trisha R. Berger: Massachusetts General Hospital
Andrea Schmidts: Massachusetts General Hospital
Matthew J. Frigault: Massachusetts General Hospital
Kathleen M. E. Gallagher: Massachusetts General Hospital
Marcela V. Maus: Massachusetts General Hospital

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Chimeric Antigen Receptor (CAR) T cells directed to B cell maturation antigen (BCMA) mediate profound responses in patients with multiple myeloma, but most patients do not achieve long-term complete remissions. In addition, recent evidence suggests that high-affinity binding to BCMA can result in on-target, off-tumor activity in the basal ganglia and can lead to fatal Parkinsonian-like disease. Here we develop CAR T cells against multiple myeloma using a binder to targeting transmembrane activator and CAML interactor (TACI) in mono and dual-specific formats with anti-BCMA. These CARs have robust, antigen-specific activity in vitro and in vivo. We also show that TACI RNA expression is limited in the basal ganglia, which may circumvent some of the toxicities recently reported with BCMA CARs. Thus, single-targeting TACI CARs may have a safer toxicity profile, whereas dual-specific BCMA-TACI CAR T cells have potential to avoid the antigen escape that can occur with single-antigen targeting.

Date: 2023
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DOI: 10.1038/s41467-023-43416-7

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