Dana-Farber Cancer Institute researchers have developed a novel therapeutic platform called CAR-Enhancer (CAR-E) that could address one of the most significant limitations of CAR-T cell therapy: patient relapse after initial treatment success. The approach, described in Nature Biotechnology, works by extending CAR-T cell persistence and activity, enabling them to maintain their cancer-fighting capabilities until all tumor cells are eliminated.
Addressing CAR-T Cell Therapy's Achilles' Heel
CAR-T cell therapies have revolutionized treatment for certain cancers, with virtually 100 percent of multiple myeloma patients showing excellent initial responses. However, almost all patients eventually relapse, with half experiencing cancer recurrence within one to two years of treatment. This relapse coincides with the disappearance of CAR-T cells from the bloodstream.
"Most of the research to address this challenge has focused on re-engineering the CAR T cell itself – for example, by introducing or eliminating genes to keep the cell active for longer," explains senior author Mohammad Rashidian, PhD, of Dana-Farber. "While these approaches hold great promise, they have yet to show much effectiveness in the clinic. We decided to come at the problem from a completely different perspective."
Novel External Approach
Rather than modifying CAR-T cells internally, the Dana-Farber team developed an external solution that delivers life-extending molecules directly to the cells. The CAR-E platform consists of a weakened form of interleukin-2 (IL-2) fused to the specific antigen that CAR cells are designed to target.
"IL-2 has a strong effect on T cells – activating them and causing them to proliferate – but it can also be highly toxic to patients," Rashidian notes. "For that reason, we used a very weak form of it. On its own, it has no effect on normal T cells but has a stimulatory effect on CAR T cells when targeted specifically to them."
In multiple myeloma CAR-T therapies, the platform fuses weakened IL-2 to B-cell maturation antigen (BCMA), the same target found on myeloma cells. First author Taha Rakhshandehroo, PhD, emphasizes the synergistic effect: "Just like weak IL-2, the BCMA antigen by itself doesn't affect CAR T cells, but, together, they have a synergy whose impact was well beyond our expectations."
Comprehensive Immune Response Generation
CAR-E therapy not only promotes CAR-T cell proliferation but also drives cellular diversification. The treatment generates multiple types of CAR-T cells, including effector T cells, stem cell-like memory T cells, central memory T cells, and effector memory T cells – creating what researchers describe as "a complete repertoire of the kinds of T cells needed for an effective immune response to cancer."
In laboratory studies using myeloma cell cultures and animal disease models, CAR-E therapy achieved complete tumor clearance, eliminating all detectable signs of cancer. The long-lasting CAR-T cells generated by the therapy could also be re-stimulated through additional CAR-E doses, suggesting potential for treating patients who relapse after initial CAR-T cell therapy.
Clinical Implementation Advantages
The platform offers several practical benefits for clinical application. CAR-E therapy could enable treatment with significantly fewer CAR-T cells than current protocols require. The existing practice of expanding CAR-T cells to hundreds of millions is time-consuming, expensive, and resource-intensive, requiring patients to wait weeks before receiving treatment.
"In animal studies, we infused mice with very low numbers of CAR T cells and found that weren't able to clear the cancer," Rashidian explains. "When we gave them the CAR-E treatment, the CAR T cells expanded and were able to clear the cancer."
This approach could also reduce cytokine release syndrome, one of the most common side effects of CAR-T cell therapy, which results from over-aggressive immune responses when large numbers of CAR-T cells are infused.
Path to Clinical Testing
Researchers plan to launch clinical trials in the near future, with initial goals focused on establishing safety profiles and determining optimal dosing schedules. The treatment protocol is expected to begin approximately one month after patients receive CAR-T cell infusions, consisting of weekly CAR-E doses for three to four weeks.
"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 Rakhshandehroo. "It's such an elegant solution to the problem of CAR T-cell depletion. We're eager to begin testing it in clinical trials."
The CAR-E platform represents a fundamentally different approach to enhancing CAR-T cell therapy effectiveness, potentially transforming treatment outcomes for patients with B-cell hematologic cancers including leukemias, lymphomas, and multiple myeloma.
