New targeted drug demonstrates potential to overcome suppressive immune cells in immunotherapy

Researchers at Ludwig Cancer Research (New York, NY, USA) may have identified a novel drug that could be utilized to overcome resistance to checkpoint blockade in immunotherapy.

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Nov 29, 2016
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Researchers at Ludwig Cancer Research (New York, NY, USA) have demonstrated in pre-clinical murine models that an experimental drug, currently undergoing Phase I clinical trials (NCT02637531), has the capacity to overcome resistance to immune checkpoint blocking in patients with high levels of suppressive myeloid cell infiltration in tumors by reshaping the tumor immune microenvironment and promote cytotoxic-T-cell-mediated tumor regression without targeting cancer cells directly.

The team established that resistance to immune checkpoint blocking is directly mediated by the suppressive activity of infiltrating myeloid cells in various tumors. Additionally, they displayed that selective pharmacologic targeting of the gamma isoform of phosphoinositide 3-kinase (PI3Kγ), which is highly expressed in myeloid cells, restores sensitivity to immune checkpoint blocking.

“Though checkpoint inhibitors have durable effects when they work, not all patients respond to the treatment,” commented study leader Taha Merghoub (Ludwig Memorial Sloan Kettering Collaborative Laboratory). “Part of the reason for this is that some tumors harbor tumor-associated myeloid cells (TAMCs), that prevent T cells from attacking tumor cells.”

To demonstrate that TAMCs are involved in the resistance to checkpoint blockade and could be reversed by an appropriately targeted therapy, the researchers utilized a specific growth stimulant to increase their number in melanoma tumors to create a suitable model. They distinguished that increased TAMCs made the tumors less susceptible to the checkpoint blockade.

Having established a link between TAMCs and immune checkpoint blocking, the team attempted to inhibit immune suppressor cell activity by utilizing an experimental drug manufactured by Infinity Pharmaceuticals, termed IPI-549, to block PI3Kγ. “We effectively reprogrammed the TAMCs, turning them from bad guys into good guys,” Merghoub elaborated.

The addition of IPI-549 dramatically improved responses to immune checkpoint blockade therapy for tumors with high concentrations of TAMCs. When checkpoint inhibitors were administered to murine models with suppressed tumors, only 20% of the animals underwent complete remission, but when combined with IPI-549, the number increased to 80%. However, no benefit was observed in tumors lacking the suppressor cells.

The results of the study indicate that TAMCs promote resistance to checkpoint inhibitors and utilizing IPI-549 can selectively block these cells, overcoming their resistance. These findings could have the potential to pave the way for a precision medicine approach to immunotherapy that could allow tailored cancer treatments 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,” Merghoub added.

Sources: De Henau O, Rausch M, Winkler D. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells. Nature 539, 443–447 (2016);

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Peter Brown

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