Novel CAR-E Platform Enhances CAR T-Cell Functionality in Cancer Treatment

Researchers at Dana-Farber Cancer Institute have unveiled a new technique to address a significant limitation of chimeric antigen receptor (CAR) T-cell therapy: the high rate of relapse in patients whose cancer initially goes into remission. Detailed in a recent paper published in Nature Biotechnology, this approach aims to extend the persistence and effectiveness of CAR T cells in the body to help address this challenge.^1,2

CAR T-cell therapy, which involves modifying a patient's T cells to produce CARs that target and destroy cancer cells, has shown to be a promising treatment for certain cancers. Despite initial success, however, many patients experience relapse within 1 to 2 years.

"In myeloma, for example, virtually 100% of patients have an excellent response to CAR T-cell therapies initially, but almost all relapse, half of them within 1 to 2 years of treatment. Relapse coincides with the disappearance of CAR T cells in the bloodstream," said Mohammad Rashidian, PhD, the study's senior author, in a statement.²

"The most exciting part of this therapy is how easily it can be integrated into the care of patients receiving CAR T-cell therapies," says the study's first author, Taha Rakshandehroo, PhD, Dana-Farber. | Image Credit: Alpha Tauri 3D-stock.adobe.com

To tackle this challenge, the researchers developed an antigen-based CAR-enhancer (CAR-E) therapeutic platform. Instead of modifying the CAR T cells themselves, CAR-E works externally by delivering a molecule that extends the life and memory of CAR T cells. This platform involves a novel fusion of a weakened form of interleukin-2 (IL-2) with the antigen that the CAR is designed to target, specifically the B-cell maturation antigen (BCMA) in multiple myeloma.² Although IL-2 strongly affects T cells by activating them and causing them to proliferate, it can also be highly toxic to patients. Because of this, a very weak form of IL-2 was used in the CAR-E platform.

The results from laboratory experiments and animal models have shown that CAR-E therapy not only boosts the proliferation of CAR T cells but also enhances their diversity.

"It generated not only effector T cells, which most patients already have, but also stem cell–like memory T cells, central memory T cells, effector memory T cells—a complete repertoire of the kinds of T cells needed for an effective immune response to cancer," explained Rashidian.

The benefits of CAR-E therapy extend beyond just enhancing the initial attack on cancer cells. The long-lasting CAR T cells created by this therapy can be restimulated with additional doses of CAR-E, suggesting that patients who relapse could be treated effectively without needing a new batch of CAR T cells. This approach could also allow for the use of smaller numbers of CAR T cells, reducing the time, cost, and potential adverse effects associated with their expansion.

The next goal includes clinical trials to ensure safety and determine CAR-E therapy's optimal dosing and administration schedule. The researchers expect treatment would start about a month after CAR T-cell infusion, with weekly doses of CAR-E for 3 to 4 weeks.

First author Taha Rakshandehroo, PhD, added, "The most exciting part of this therapy is how easily it can be integrated into the care of patients receiving CAR T-cell therapies. It's such an elegant solution to the problem of CAR T-cell depletion. We're eager to begin testing it in clinical trials."

References

1. Rakhshandehroo T, Mantri SR, Moravej H, et al. A CAR enhancer increases the activity and persistence of CAR T cells. Nat Biotechnol. Published online July 30, 2024. doi:10.1038/s41587-024-02339-4

2. Researchers devise novel solution to preventing relapse after CAR T-cell therapy. News release. Dana-Farber Cancer Institute. July 30, 2024. August 6, 2024. https://www.dana-farber.org/newsroom/news-releases/2024/researchers-devise-novel-solution-to-preventing-relapse-after-car-t-cell-therapy#:~:text=Researchers%20discovered%20that%20the%20long,doses%20of%20CAR%2DE%20treatment