Webinar - Targeting Multiple Myeloma

Rational Design of a Trimeric APRIL-based CAR-binding Domain Enables Efficient Targeting of Multiple Myeloma

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Abstract

Chimeric Antigen Receptor (CAR) T-cells have demonstrated great potential for the treatment of certain B-cell neoplasms, including multiple myeloma (MM). So far, the most promising results for CAR T-cell (CAR-T) therapy of MM have been obtained by targeting the B cell maturation antigen (BCMA). However, most remissions in response to BCMA-directed CAR-T therapy have not been sustained long-term.

Under the selective pressure of monospecific anti-BCMA CART treatment, emergence of BCMA escape variants has been reported. Hence, continuous improvement of CART therapies for MM is an important medical need. We engineered a novel trimeric APRIL (a proliferation-inducing ligand)-based CAR that allows for efficient targeting of both BCMA-positive and BCMA-negative MM. Leveraging the natural ligand-receptor pair, APRIL-based CARs facilitate bispecific targeting of the MM-associated antigens BCMA and transmembrane activator and CAML interactor (TACI). Yet, natural ligands as CAR antigen-binding domains may necessitate further engineering for optimal engagement and multimerization to efficiently translate CAR-binding into T-cell activation. We found that a trimeric from of APRIL rather than a monomeric form as the CAR binding domain increased binding to BCMA and TACI and CART efficiency against MM in vitro and in vivo. Dual-specific, trimeric APRIL-based CAR are a promising therapeutic strategy for MM with potential to prevent and treat BCMA-antigen loss variants.

Key Takeaways

  • A trimeric extracellular moiety of APRIL has enhanced binding to BCMA and TACI compared with monomeric APRIL when incorporated into a CAR
  • Trimeric APRIL-based CAR are efficient against BCMA-negative multiple myeloma
  • T cells transduced with a trimeric APRIL-based CAR are a promising approach for the treatment of multiple myeloma

Speaker

Andrea

Andrea Schmidts

Postdoctoral Research Fellow, MD

Cellular Immunotherapy Program,
MGH Cancer Center and Harvard Medical School