Dual-targeted CAR T-cell Therapy Shows Promising Anti-tumor Response in Mice

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by Alice Melão |

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A preclinical study has shown that a new dual-targeting APRIL CAR T-cell therapy appears to be better at eliminating multiple myeloma cells than conventional CAR T-cell therapies.

The findings were reported in a study titled, “An APRIL based chimeric antigen receptor for dual targeting of BCMA and TACI in multiple myeloma has potent activity in vitro and in vivo,” which appeared in Blood, the journal of the American Society of Hematology.

CAR-T cell therapies are based on the genetic manipulation of a patient’s own T-cells. This reprogramming is designed to make the T-cells specific to certain cancer proteins, making them more efficient at eliminating tumors.

For multiple myeloma, researchers have been developing CAR T-cells targeting the B-cell maturation antigen (BCMA), a protein found in nearly all myeloma cells. While this strategy has shown promise in the clinic, cases of relapse — caused by cells that evade treatment — have been reported.

The biopharmaceutical company Autolus has been developing a new CAR T-cell strategy that targets two myeloma proteins — BCMA and the transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI) — rather than one.

The approach makes the T-cells produce a truncated form of the proliferation-inducing ligand (APRIL), which naturally binds to both BCMA and TACI.

Because the T-cells recognize two target proteins, each myeloma cell has more proteins that can be targeted, making it harder to miss.

“Emerging evidence shows that the level of available antigen on the surface of cancer cells may be an important factor in determining the efficacy of CAR T-cells,” Jesus G. Berdeja, MD, director of myeloma research and senior investigator at Sarah Cannon Research Institute’s hematologic malignancies department, said in a press release.

“Treatment of multiple myeloma with its low antigen expression may benefit from a dual targeting approach, potentially impacting both initial response and reducing relapse,” Berdeja added.

In mouse models of myeloma, researchers showed that APRIL CAR T-cells are better at eliminating myeloma cells than CAR T-cells targeting BCMA alone, where relapses of BCMA-negative tumors were seen.

The approach also targeted cancer cells that had either lost or reduced the amount of BCMA. This suggests that APRIL CAR T-cells may prevent myeloma cells from evading therapy, reducing the risk of relapse.

“This publication illustrates an example of our approach to address defence mechanisms used by cancers cells to evade CAR-T treatment,” said Christian Itin, PhD, CEO of Autolus. “Dual targeting CAR-T approaches may maximize initial treatment effect and minimize the risk of relapse.”

Autolus is currently conducting a Phase 1/2 trial (NCT03287804) exploring the safety and effectiveness of an APRIL CAR T-cell therapy, AUTO2, in patients with relapsed or refractory multiple myeloma.