Novel immunotherapy eradicates solid tumors in mice without adverse side effects

Scientists have developed a new immunotherapy that eradicates solid tumors in mice without adverse side effects, according to a new study published today in eLife.

The newly developed chimeric antigen receptor-T cell (CAR-T cell therapy) could soon be tested in clinical trials. In addition, the researchers used a new mouse model that could be used to test the safety, efficacy and mechanisms of CAR-T cell treatments for patients with solid cancers in future.

In CAR-T cell therapy, immune cells called T cells are collected from a blood sample of patients and reprogrammed with CAR molecules that recognize cancer-specific antigens expressed on cancer cells. When the CAR-T cells are given back to patients, they not only kill the antigen-expressing cancer cells directly but also switch on the immune system to fight the tumor.

One of the challenges with developing CAR-T cells is that, sometimes, the CAR-T cells work against tumor antigens that are also present in lower amounts on normal cells, causing serious side effects which we only find out about in clinical trials. We proposed that if human CAR-T cells can cross-react with the mouse antigens and detect antigens found on normal mouse cells, we could test human CAR-T cells in mouse tumor models. This would allow more robust tests of both safety and effectiveness before the treatments reach clinical testing."

Tomonori Yaguchi, co-corresponding author, Visiting Assistant Professor in the Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Japan

The team developed a CAR-T cell treatment targeting an antigen called glycipan-1 (GPC1). This antigen is found in large amounts on several types of human tumor cells, and also exists in low amounts on normal human and mouse cells. When the scientists tested CAR-T cells on mice bearing mouse tumors they found that the CAR-T cells effectively inhibited tumor growth without causing adverse side effects. In fact, for one of the mouse tumors, four out of five of the mice receiving CAR-T cell treatment remained completely tumor-free for at least 100 days. The team also found that the CAR-T cells enhanced immune responses against other tumor antigens than GPC1.

One of the most important new immunotherapy treatments for cancer are drugs called immune checkpoint inhibitors. These work by taking the brake off immune cells so that they can destroy cancer cells. When the team combined the CAR-T cells with a checkpoint inhibitory drug that blocks the activity of the PD1-protein found on T cells, this further enhanced the anti-tumor effects of CAR-T cell treatment, even though the checkpoint inhibitor alone had no effect on its own. This suggests that using CAR-T cells targeting GPC1 alongside a checkpoint inhibitor could be an effective combination treatment for cancer.

"We have generated CAR-T cells targeting GPC1 in both humans and mice and shown their effectiveness in mouse solid tumor models," concludes senior author Yutaka Kawakami, Professor in the Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine. "By establishing a new type of model, we were able to test both the effectiveness, safety and anti-tumor mechanisms of CAR-T cells, showing the importance of choosing the most appropriate models for evaluating these novel types of cancer treatment."

Source:
Journal reference:

Kato, D., et al. (2020) GPC1 specific CAR-T cells eradicate established solid tumor without adverse effects and synergize with anti-PD-1 Ab. eLife. doi.org/10.7554/eLife.49392.

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