All too often, CAR-T cells beat back cancer only to disappear from the bloodstream, allowing cancer to return. CAR-T cells, then, need to be more fervent, more persistent, and more vigilant. To help CAR-T cells deliver cancer cures, and not just temporary remissions, scientists at Dana-Farber Research Institute have developed what they call the CAR-E therapeutic platform. The “E” in CAR-E stands for “Enhancer.”
With this platform, a target antigen is fused with a low-affinity enhancer molecule to enable the precise targeting of the CAR-T molecule. The platform also facilitates the preferential delivery of immune-modulating agents post-infusion.
Details about the new platform appeared in Nature Biotechnology, in an article titled, “Development of a CAR-Enhancer (CAR-E) therapeutic platform to enhance the activity and persistence of CAR-T cells.” For example, the article described how the CAR-E platform was used to create a B-cell maturation antigen (BCMA) CAR-E, that is, a BCMA antigen fused with a low-affinity interleukin-2 (IL-2). A BCMA CAR-E was deemed a suitable object of study, given that BCMA CAR T-cell treatments for multiple myeloma have difficulty achieving durable remission.
“The BCMA CAR-E … selectively binds to CAR-T cells, leading to their proliferation, effective clearance of tumor cells, and promotion of the development of memory CAR-T cells with diverse phenotypes,” the article’s authors wrote. “These memory cells retain the ability to re-expand upon re-stimulation, effectively controlling tumor growth upon rechallenge.”
So, not only does CAR-E help CAR-T cells become more active and persist longer in the body, but it also causes CAR-T cells to form a memory of the cancer cell, so they can spring back into action if the cancer recurs.
CAR-E therapy not only causes CAR-T cells to proliferate but to diversify, the researchers found. “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,” said the study’s senior author, Mohammad Rashidian, PhD, of Dana-Farber.
In laboratory cultures of myeloma cells and in animal models of the disease, CAR-E therapy brought about the complete clearance of tumor cells. There were other benefits as well. Researchers discovered that the long-lasting CAR-T cells generated by the therapy could be re-stimulated by re-administering CAR-E. This suggests that patients who relapse after CAR-T cell therapy could be effectively treated with additional doses of CAR-E treatment.
“Most of the research addressing [the relapse] 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,” Rashidian noted. “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.”
Instead of trying to alter the inner workings of CAR-T cells, Rashidian and his colleagues developed an approach that works from the outside—by delivering to the cells’ doorstep a molecule that extends their lives and prompts them to form memory. The vehicle for accomplishing this is a fused-together “platform” unlike any other used in medical treatment.
“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 remarked. “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.”
“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,” added the study’s first author Taha Rakhshandehroo, PhD, of Dana-Farber.
“Mechanistic studies revealed the involvement of both CAR and IL-2R endodomains in CAR-E’s mechanism of action; inhibition of either pathway diminishes its impact,” the study’s authors observed. “Notably, this approach enables therapy with lower doses of CAR-T cells. CAR-E can seamlessly integrate with FDA-approved CAR-T cells or newer generations of CAR cells, offering an off-the-shelf, versatile, and promising therapeutic strategy.”
Essentially, CAR-E raises the possibility that patients could be treated with smaller numbers of CAR-T cells than at present. The current practice of allowing CAR-T cells to multiply into the hundreds of millions is a time-consuming, expensive, resource-heavy process that requires patients to wait many weeks before receiving an infusion of the cells. The large quantities are partly responsible for one of the most common side effects of CAR-T cell therapy: cytokine release syndrome, in which an overaggressive immune response results in fever, nausea, rapid heartbeat, neurological problems, or other issues. With CAR-E, it might be possible to skip the expansion process altogether: CAR-T cells would simply be made and infused into patients, followed by treatment with CAR-E.
“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 related. “When we gave them the CAR-E treatment, the CAR-T cells expanded and were able to clear the cancer.”
One of the first goals of a clinical trial of CAR-E therapy will be to ensure safety and to determine the best dose and schedule of administration. Initially, Rashidian and colleagues expect that the treatment would begin about a month after patients are infused with CAR-T cells. Treatment would consist of a weekly dose of CAR-E therapy for three or 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,” Rakhshandehroo says. “It’s such an elegant solution to the problem of CAR-T cell depletion. We’re eager to begin testing it in clinical trials.”
