Novel chimeric antigen receptors (CARs) with different configurations of the natural ligand APRIL for BCMA and TACI antigens delivered fast anti-tumor responses but did not protect from tumor recurrence, similar to CAR T cell therapies using antibody fragments for BCMA binding. The Arber Lab identifies potential mechanisms of resistance shared by different CAR T cell types targeting BCMA.
Standard-of-care CAR T cell therapy targeting B cell maturation antigen (BCMA) in relapsed/ refractory multiple myeloma (MM) produces fast responses in most patients, but tumors frequently recur. Mechanisms of resistance are still poorly understood. Alternative CAR designs simultaneously targeting two antigens on myeloma are evaluated.
Researchers led by Caroline Arber designed and characterized dual antigen targeted CAR T cells using different configurations of A proliferation inducing ligand (APRIL), the natural ligand for two antigens expressed on myeloma: BCMA and transmembrane activator and calcium modulating ligand (CAML) interactor (TACI). Results published in the Journal for ImmunoTherapy of Cancer show that APRIL-CAR T cells in a trimeric ligand binding conformation and a short linker conferred fast anti-tumor responses, but again, those responses were not sustained. Thus, Caroline Arber’s group investigated mechanisms of resistance comparing three different BCMA-binding moieties: the newly designed APRIL CARs, a clinically used single-chain-variable-fragment based CAR, and a heavy-chain-only based CAR. Various methods were used to investigate the CAR T cell – myeloma cell interactions, including a new protocol for live cell imaging specifically developed to study this interaction. The group found that BCMA was rapidly downmodulated on myeloma cells after contact with CAR T cells independently of the binding moiety used. CAR T cells acquired BCMA by trogocytosis, and BCMA on MM cells was rapidly internalized. Since BCMA can be re-expressed during tumor progression and persisting CAR T cells may not protect patients from relapse, we investigated whether non-functional CAR T cells play a role in tumor progression. While CAR T cell – MM cell interactions activated BCMA pathway, we did not find enhanced tumor growth in vitro or in vivo.
Researchers concluded that anti-tumor responses with APRIL-CAR T cells were fast but not sustained, similar to CAR T cells targeting BCMA alone. Rapid BCMA downmodulation occurred independently of the binding moiety used. BCMA internalization mostly contributed to this effect, but trogocytosis by CAR T cells was also observed. The study sheds light on the mechanisms underlying CAR T cell failure in multiple myeloma when targeting BCMA and can inform the development of improved treatment strategies.
This research*was conducted in collaboration with the SIB Swiss Institute of Bioinformatics.
The project was supported by the Stiftung für Krebsbekämpfung and the Fondation Dr Henri Dubois-Ferrière Dinu Lipatti.
*Both APRIL and antibody-fragment-based CAR T cells for myeloma induce BCMA downmodulation by trogocytosis and internalization