Next Generation Preclinical Advancement of CAR-T Therapy: Improved Function and Efficacy in Multiple Myeloma

Next Generation Trimeric CAR-T Immunotherapies: Improvement Over Monospecific CAR-T Cell Therapy

CAR-T therapies are gaining in number and success, with B-cell maturation antigen (BCMA) as the third top target for CAR-T therapy products. There are currently 24 active therapies with this target (see chart), and while CAR-T cell therapies targeting BCMA have demonstrated success in treating B cell malignancies, including relapsed/refractory multiple myeloma (MM), due to BCMA escape, this may not be a curative treatment for many patients. Therefore, the need for improved CAR-T therapies continues. IsoPlexis’ single-cell metric, PSI, was used to address this challenge in a recent study that demonstrated a novel trimeric proliferation-inducing ligand (APRIL)-based CAR that can efficiently target both BCMA+ and BCMA MM.

Advancing Treatments Against Multiple Myeloma

IsoPlexis is excited to be a part of next generation and complex cell therapy development work that is advancing treatments against Multiple Myeloma (MM) with potential of preventing and treating BCMA antigen escape, which demonstrates the continued correlative power of PSI. IsoPlexis’ polyfunctionality metrics continue to accelerate decision making through discovering deep potency data within critical therapeutic candidates.

This data was recently published in Blood Advances in an article titled, “Rational design of a trimeric APRIL-based CAR-binding domain enables efficient targeting of multiple myeloma.

Publication Highlights

  • Positive association of Polyfunctional Strength Index (PSITM) to the functional enhancement of trimeric APRIL (TriPRIL) CAR-T cells. PSI correlated with tumor killing activity against in vitro and in vivo human and mouse models.
  • Demonstration of functional improvement difference of TriPRIL CAR-T cells versus APRIL and conventional BCMA CAR-T cells.
  • Identification of highly upregulated polyfunctionality in TriPRIL CAR-T cell products targeting both BCMA and transmembrane activator and CAML interactor (TACI).
  • Superiority of BCMA/TACI-specific polyfunctional response of TriPRIL CAR-T cells revealed, compared to the cell products with a monomeric APRIL format.
  • Demonstration of the impact of polyfunctional metrics by single-cell functional proteomics IsoCode Chip in precisely profiled dual-specific TriPRIL CAR-T cells for the prevention and treatment of patients with relapsed/refractory MM.

Increased Polyfunctionality and Improved binding and efficacy of next generation trimeric CAR-T construct

This novel construct targets BCMA and TACI with a human APRIL-based CAR product that would retain its trimeric conformation and lead to improved binding and efficacy against MM cells as well as decrease immunogenicity from the use of human sequences. The study found that “TriPRIL CAR-Ts were sufficient to eliminate myeloma cells in vivo, despite the absence of BCMA expression.” They also observed that the enhanced binding to BCMA and TACI, as well as CAR-T activity, occurred with a trimeric APRIL format over a monomeric one against in vitro and in vivo MM. The type of construct in this study proves to be a “promising therapeutic approach for MM” with the potential to prevent as well as treat BCMA escape.

polyfunctional cells

IsoPlexis’ single-cell functional biology was able to provide the data to help researchers determine functional differences between this unique CAR construct and other CARs. As mentioned above, this new TriPRIL showed increased number of polyfunctional cells as well as the highest PSI of the cell products tested. This helped to verify that this novel construct holds promise for the treatment of MM.

Read the full Blood Advances article here and contact a single-cell functional proteomics expert to learn more about how IsoPlexis’ technology can help you in your next cell therapy project.

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