Combination of Immunotoxic Factors and Checkpoint Blocker Clears Mesothelioma in Mice, Study Reports

Combination of Immunotoxic Factors and Checkpoint Blocker Clears Mesothelioma in Mice, Study Reports

Combining mesothelioma-targeted therapies with one that prevents tumors from evading the immune system led to the eradication of mesothelioma in most mice involved in a study, researchers said.

The mesothelioma-specific therapies, known as immunotoxic factors, target the mesothelin protein that the cancer produces. The other therapy is known as a CTLA-4 checkpoint inhibitor because its purpose is to block the CTLA-4 protein that helps tumors evade the immune system.

Basically, the immunotoxic factors make the checkpoint inhibitor more effective in treating mesothelioma, researchers at the National Cancer Institute and Roche reported.

Injecting mice with a combination of an immunotoxic molecule and a checkpoint blocker cleared mesothelioma tumors in most of the mice in the study, the researchers said. In addition, when they injected the mice with another type of tumor cell, the combo prevented the animals from developing tumors.

The results, published in the journal Cancer Immunology Research, indicated that the combination triggered what scientists call anti-tumor immunity. The findings also prompted the researchers to suggest that the approach be tried in humans.

The report was titled “Combining Local Immunotoxins Targeting Mesothelin with CTLA-4 Blockade Synergistically Eradicates Murine Cancer by Promoting Anti-Cancer Immunity.”

Immunotoxins are man-made molecules that link an antibody targeting a tumor component with a toxic factor. The immunotoxins used in the study, SS1P and LMB-100, target the mesothelin protein. Researchers are evaluating the two, in combination with other therapies, as treatments for various cancers.

Earlier studies showed that targeting CTLA4, the molecule that helps tumors evade the immune system, benefitted just a few mesothelioma patients.

But certain features of the two kinds of therapies prompted the researchers to suspect that combining immunotoxins with an immune checkpoint blocker could provide results that the checkpoint drug alone couldn’t.

The researchers first injected mesothelioma tumors into mice. Then they treated the tumors in various ways: using the compounds by themselves or combining SS1P or LMB-100 with anti-CTLA-4.

While the compounds had little impact on tumor regression when given independently, combining anti-CTLA4 with SS1P cleared tumors in eight out of 11 mice. And a combination of anti-CTLA4 and LMB-100 yielded similar results: Eight out of 13 tumors vanished.

When researchers injected mice with a type of tumor cell that did not produce mesothelin, the cells did not grow in mice treated with combo therapies. This suggested that the mice had developed an immune response to cancer cells in general.

Researchers also discovered that the treated tumors contained a lot of immune cells attracted by the treatment.

The team confirmed that immune processes were at work by blocking T-cells, which are known to be involved in immune processes against tumors. The blocking led to the combinations largely losing their ability to clear tumors.

Because the mice seemed to tolerate the treatment well, the team suggested that the combination be tried in human mesothelioma patients.

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Magdalena is a writer with a passion for bridging the gap between the people performing research, and those who want or need to understand it. She writes about medical science and drug discovery. She holds an MS in Pharmaceutical Bioscience and a PhD — spanning the fields of psychiatry, immunology, and neuropharmacology — from Karolinska Institutet in Sweden.

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