If cancer immunotherapy may be likened to a game of chess, then scientists at the Ludwig Institute for Cancer Research count as grandmaster players, especially now that they have introduced a new counter-counter strategy. They have shown that it is possible overcome a counterattack cancer uses to resist checkpoint blockade, a kind of cancer immunotherapy meant to unleash the full attack strength of T cells. The counterattack, which relies on the immune-suppression capabilities of tumor-associated myeloid cells (TAMCs), may be countered, the Ludwig scientists have demonstrated, by administering a targeted drug.

The Ludwig scientists, led by Taha Merghoub and Jedd Wolchok, presented their findings November 9 in the journal Nature, in an article entitled, “Overcoming Resistance to Checkpoint Blockade Therapy by Targeting PI3Kγ in Myeloid Cells.” The article describes how the scientists used a mouse model to demonstrate that a drug called IPI-549 selectively blocks a molecule in TAMCs called PI3Kγ, a phosphoinositide 3-kinase. IPI-549 effectively reprograms the TAMCs, switching them from immune suppression to immune activation.

“Though checkpoint inhibitors have durable effects when they work, not all patients respond to the treatment,” said Dr. Merghoub, an investigator at the Ludwig Memorial Sloan Kettering Collaborative Laboratory. “Part of the reason for this is that some tumors harbor TAMCs that prevent T cells from attacking tumor cells.”

To show that TAMCs were indeed involved in resistance to checkpoint blockade, the researchers used a specific growth stimulant to increase their number in melanoma tumors to create a suitable model for their studies. They found that this made the tumors less susceptible to checkpoint blockade. Then, having established a link between TAMCs and checkpoint inhibitor resistance, the researchers set out to test the hypothesis that blocking immune suppressor cell activity would improve immunotherapy response.

“Here we employ a pre-clinical mouse model system and show that resistance to ICB [immune checkpoint blocking] is directly mediated by the suppressive activity of infiltrating myeloid cells in various tumors,” wrote the authors of the Nature study. “Furthermore, selective pharmacologic targeting of the gamma isoform of PI3Kγ, highly expressed in myeloid cells, restores sensitivity to ICB.”

“We effectively reprogrammed the TAMCs, turning them from bad guys into good guys,” Merghoub asserted.

IPI-549 dramatically improved responses to ICB therapy for tumors with high concentrations of TAMCs. When checkpoint inhibitors were administered to mice with suppressed tumors, only 20% of the animals underwent complete remission. When the same drugs were administered with IPI-549, that number jumped to 80%. IPI-549 provided no benefit to tumors lacking the suppressor cells.

The Ludwig team also showed that tumors that were initially sensitive to checkpoint inhibitors were rendered unresponsive when their TAMC concentrations were boosted with growth stimulants.

“We demonstrate that targeting PI3Kγ with a selective inhibitor, currently being evaluated in a phase 1 clinical trial (NCT02637531), can reshape the tumor immune microenvironment and promote cytotoxic-T-cell-mediated tumour regression without targeting cancer cells directly,” the authors of the Nature article concluded. “Our results introduce opportunities for new combination strategies using a selective small molecule PI3Kγ inhibitor, such as IPI-549, to overcome resistance to ICB in patients with high levels of suppressive myeloid cell infiltration in tumours.”

Merghoub added that the findings could pave the way for a precision medicine approach to immunotherapy that will allow cancer treatments to be tailored to a patient's particular tumor profile: “We can now potentially identify patients whose tumors possess immune suppressor cells and add a drug to their treatment regimen to specifically disarm them.”

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