New approach to immunotherapy provokes a robust anti-tumor immune response in preclinical models

New approach to immunotherapy provokes a robust anti-tumor immune response in preclinical models

A new approach to cancer immunotherapy that uses one type of immune cell to kill another rather than attacking the cancer directly. provokes a robust anti-tumor immune response that shrinks ovarian, lung and pancreatic tumors in preclinical disease models, according to researchers at the Icahn School of Medicine at Mount Sinai in New York. The results were published October 11, 2022 in the journal Cancer Immunology Research [ https://doi.org/10.1158/2326-6066.CIR-21-1075 ].

The study involved a twist on a form of therapy that uses immune cells known as CAR-T cells. CAR-T cells currently in clinical use are engineered to directly recognize cancer cells and have successfully treated several blood cancers. However, there have been challenges that prevent their effective use in many solid tumors.

Most solid tumors are heavily infiltrated by another type of immune cell called macrophages. Macrophages help tumors grow by blocking entry of T cells into tumor tissue, which prevents CAR T cells and the patient's own T cells from destroying the cancer cells.

To address this immunosuppression at the source, researchers engineered T cells to produce a “chimeric antigen receptor” (CAR) that recognizes a molecule on the surface of macrophages. When these CAR T cells encountered a tumor macrophage, the CAR T cell was activated and killed the tumor macrophage.

Treating mice with ovarian, lung and pancreatic tumors with these macrophage-targeting CAR-T cells reduced the number of tumor macrophages, shrank the tumors and prolonged their survival.

Killing tumor macrophages allowed the mouse's own T cells to access the cancer cells and kill them. The researchers further showed that this anti-tumor immunity is driven by the release of the cytokine interferon-gamma - a molecule involved in regulating inflammatory responses - from the CAR-T cells.

Our original goal was just to use the CAR T cells to kill the immunosuppressive macrophages, but we discovered that they also boost tumor immunity by releasing this powerful immune-boosting molecule. It was a double whammy from that single treatment.”

Brian Brown, PhD, senior author, director of the Icahn Genomics Institute and deputy director of the Marc and Jennifer Lipschultz Precision Immunology Institute (PrIISM) at Icahn Mount Sinai

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Shifting the focus of CARs from cancer cells to tumor macrophages potentially addresses another important obstacle to the successful elimination of solid tumors with CAR T cells. There are very few proteins that are found exclusively on cancer cells and not on healthy tissue and can be used to directly attack cancer cells in solid tumors without damaging healthy tissue.

The immunity-suppressing macrophages found in tumors are very similar across different cancers and are very different from macrophages in healthy tissue. This has led to interest in macrophage-depleting agents for cancer therapy, but approaches developed to date have had limited success in clinical trials.

"Our molecular studies in human tumors have shown that macrophage subsets are present in human tumors rather than normal tissues and are similar between tumors and patients. So macrophage-targeted CAR-T cells could be a broad way to target different types of solid tumors and improve immunotherapy," said Miriam Merad, MD, PhD, co-author of the study and director of PrIISM.

Next, the researchers are working on tumor macrophage-specific CAR, generating humanized versions of the genetic instructions so they can be introduced into cancer patients' own T cells.

Source:

Mount Sinai Health System

Reference:

Sánchez-Paulete, AR, et al. (2022) Targeting macrophages with CAR-T cells delays solid tumor progression and improves anti-tumor immunity. Cancer immunology research. doi.org/10.1158/2326-6066.CIR-21-1075.

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