Powering up cancer immunotherapy by improving protein signaling

January 10, 2021
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Personalized CAR-T therapies, checkpoint inhibitors and bispecific antibodies are examples of recently developed cancer therapies that target the immune system’s T cells. These treatments have high success rates in several cancer types, but many patients eventually relapse.

Researchers at Mount Sinai School of Medicine believe they’ve found a way to prevent relapse after immuno-oncology treatment, and it involves controlling a protein called FAS.

The team discovered that non-Hodgkin lymphoma patients with significantly high levels of FAS in their tumors had durable responses to CAR-T treatments in a clinical trial. When they used small-molecule drugs in lab experiments to dial up FAS signaling in tumor cells, that improved the ability of immune cells to attack the cancer, they reported in the journal Cancer Discovery.

Immunotherapies like CAR-T cells target antigens on the tumor cells such as CD19. But some cancer cells don’t have CD19 on their surface at all, while others evolve so they can escape immunotherapies by no longer expressing the antigen.

The Mount Sinai team discovered that immuno-oncology treatments that rely on immune cells like T cells don’t just kill their targets, they often also attack adjacent cancer cells with the help of FAS. That occurs even if those adjacent cells don’t express the target antigen.

To better understand this process, the researchers analyzed tumor samples from non-Hodgkin lymphoma patients who participated in the ZUMA-1 trial of Gilead’s CAR-T therapy Yescarta. They found patients with the most durable responses to the CAR-T treatment had significantly higher FAS expression in their tumors than other study participants did, despite the fact that their levels of CD19 were similar.

The researchers also tested CD19-directed CAR-T therapies in several mouse models, including some with “heterogenous” tumors that included a small percentage of CD19-negative cells. In the mice with heterogenous tumors, blocking FAS resulted in significantly worse survival than it did in animals with 100% CD19-positive cells, the researchers reported.

Those results suggest FAS signaling is critical for CAR-T cells to be able to target the CD19-negative cells that may be to blame for cancer relapse, they added.

It’s the latest study examining the role of protein signaling in immuno-oncology. Over the summer, researchers in China showed in mouse models that if they combined an experimental drug from Merck that inhibits protein kinase B (AKT) with a PD-1 inhibitor, they could interrupt a cell-signaling pathway and slow down the growth of glioblastoma. A team in Spain discovered that if they blocked a specific non-coding RNA, they could amp up protein signals that recruit cancer-killing immune cells to lung tumors in mice.

The Mount Sinai researchers tested small-molecule drugs that increase FAS signaling as part of their study. They reported that in lab studies, the drugs increased the killing of both targeted and adjacent tumor cells by T cells, CAR-Ts and bispecific antibodies. The drugs they used are already being tested in clinical trials in cancer, they reported.

“We propose that investigating combinations of these clinical-stage small molecule FAS signaling modulators with T cell therapies should be a focus of future research,” the researchers wrote in the study. “These approaches may prevent—rather than treat—cancer relapse due to antigen escape by targeting both tumor cell antigens as well as tumor cell geography.”

Story Source: https://www.fiercebiotech.com/research/boosting-cancer-immunotherapy-by-improving-protein-signaling

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