The use of engineered T cells to destroy cancer cells has been successful in treating some types of cancer, such as leukemia and lymphoma. However, adoptive cell therapy using chimeric antigen receptor (CAR) T cells hasn’t worked as well for solid tumors. One reason for this lack of success is that the T cells target only one tumor antigen, and if some of the tumor cells don’t express that antigen, they can escape the T cell attack.

MIT researchers have now found a way to overcome this obstacle, using a vaccine that boosts the response of CAR T cells, and also helps the immune system to generate new T cells that target other tumor antigens. In studies in mice, the researchers found that this approach made it much more likely that tumors could be eradicated.

“This vaccine boosting appears to drive a process called antigen spreading, wherein your own immune system collaborates with engineered CAR T cells to reject tumors in which not all of the cells express the antigen targeted by the CAR T cells,” said Darrell Irvine, PhD, the Underwood-Prescott Professor with appointments in MIT’s departments of Biological Engineering and of Materials Science and Engineering, and a member of MIT’s Koch Institute for Integrative Cancer Research and the Ragon Institute of MGH, MIT, and Harvard.

Irvine is senior author of the team’s study, which is published in Cell and titled “Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity.” The lead author of the paper is Leyuan Ma, PhD, a former postdoc at the Koch Institute and currently an assistant professor of pathology and laboratory medicine at the University of Pennsylvania School of Medicine.

FDA has approved several types of T cell therapies for blood cancers. These treatments are based on CAR T cells, which are engineered to display receptors that can recognize a specific antigen found on cancer cells. “Adoptive cell therapy (ACT) using chimeric antigen receptor (CAR) T cells has revolutionized the treatment of relapsed/refractory CD19+ B cell acute lymphoblastic leukemia and lymphomas,” the team noted. However, the investigators further pointed out, CAR T cell therapy has been “less successful” against solid tumors.

When trying to adapt this kind of treatment to the brain cancer glioblastoma, researchers designed CAR T cells that target a mutated version of the EGFR receptor. However, not all glioblastoma cells express this antigen, and when attacked by CAR T cells, some glioblastoma cells respond by halting production of the target antigen. The two main challenges in treating solid tumors with CAR T cells are that not all tumors express the antigen targeted by the CAR, while antigen loss can occur during treatment, the authors suggested.

In a 2019 study, Irvine and his colleagues enhanced the effectiveness of CAR T cells against glioblastoma by delivering a vaccine to mice shortly after the engineered T cells were administered. This vaccine, which carries the same antigen targeted by the CAR T cells, is taken up by immune cells in the lymph nodes, where the CAR T cells are exposed to it.

In that study the researchers found that the vaccine boost not only helped the engineered CAR T cells attack tumors, but it had another, unexpected effect, in that it helped to generate host T cells that target other tumor antigens. This phenomenon, known as antigen spreading (AS), is desirable because it creates populations of T cells that, working together, can fully eradicate tumors and prevent tumor regrowth.

“That would be exactly the kind of thing that could help you deal with the antigen heterogeneity of solid tumors, because if you primed host T cells to attack other antigens, they may be able to come in and kill the tumor cells that your CAR T cells cannot,” Irvine said. In their current published paper, the team stated, “In the setting of ACT, strategies to target one surface-expressed antigen using CAR T cells while inducing endogenous T cell responses against additional tumor antigens would be an attractive option to overcome tumor heterogeneity and antigen-loss-mediated escape.”

For this newly reported study the researchers wanted to explore how that additional T cell response becomes activated. They used the same type of CAR T cells from their 2019 study, which are engineered to target mutant EGFR, and the same vaccine. Treated mice were given two doses of the vaccine, one week apart.

The researchers found that in these boosted mice, metabolic changes occurred in the CAR T cells that increased their production of interferon gamma (IFN-γ), a cytokine that helps stimulate a strong immune response. This helps the T cells to overcome the immunosuppressive environment of the tumor, which normally shuts down any T cells in the vicinity.

As the CAR T cells killed tumor cells expressing the target antigen, host T cells (not the engineered CAR T cells) encountered other antigens from those tumor cells, stimulating those host T cells to target those antigens and help destroy tumor cells. The researchers found that without the host T cell response tumors would regrow even if the CAR T cells destroyed most of the original tumor cells. This happened because tumor cells treated with CAR T cells often stop producing the antigen targeted by the engineered cells, allowing them to evade those cells.

“Mechanistically, we found that the enhanced production of IFN-γ by vaccine-boosted CAR T cells was a major contributor to AS” the team noted. “Vaccine-boosted CAR T promoted dendritic cell (DC) recruitment to tumors, increased tumor antigen uptake by DCs, and elicited the priming of endogenous anti-tumor T cells.” The activated DCs in the tumor in turn secrete IL-12 that, together with the autocrine effect of IFN-γ, enhanced CAR T cell anti-tumor activity, “leading to pronounced endogenous T cell priming and induction of enhanced effector programs in endogenous T cells that infiltrate tumors.”

The researchers tested their approach in mice with tumors that had different levels of the target antigen. They found that even in tumors where only 50% of the tumor cells expressed the target antigen, about 25 percent of the tumors could still be eradicated, by a combination of CAR T cells and host T cells.

The success rate was higher for tumors with greater levels of the target antigen. When 80 percent of the tumor cells expressed the antigen targeted by CAR T cells, tumors were eliminated in about 80% of the mice. Commenting on their overall findings, the team stated, “IFN-γ sustained high levels of cytotoxicity and effector cytokine expression in vaccine-boosted CAR T cells in a cell-intrinsic manner. These enhanced CAR T cell effector functions in turn, which correlated with the increased expression of DC-recruiting chemokines in tumors, increased DC infiltration, tumor antigen uptake, and the activation of intratumoral DCs.”

In their reported study the researchers focused on glioblastoma and melanoma, but they believe the technology could potentially be used to combat other types of cancer as well. “In principle, this should apply to any solid tumor where you have generated a CAR T cell that could target it,” Irvine said. The authors commented, “… CAR-T-cell-derived IFN-γ plays a critical role in promoting AS, and vaccine boosting provides a clinically translatable strategy to drive such responses against solid tumors … Notably, vaccines for CAR T cells are already being explored clinically, suggesting that this approach can be readily translated to CAR T cell clinical trials.”

The researchers are also working on ways to adapt CAR T cell therapy so that it can be used to attack tumors for which no targetable antigens have been identified. The technology has been licensed to Elicio Therapeutics, which is working on developing it for potential testing in patients.

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