4:27 PM
Mar 07, 2019
 |  BC Innovations  |  Targets & Mechanisms

Flipping the switch in immuno-oncology

Turning suppressive myeloid cells in tumors into immune-activating ones

Tumor myeloid cells are emerging as prime candidates for filling a hole in the immuno-oncology tool box, offering targets that can simultaneously release the brakes and rev up the gas in the immune system.

As immuno-oncology companies look to extend the efficacy of marketed checkpoint inhibitors by pairing them with other immunotherapies, they generally pick a combination partner that either removes a second brake from the immune system, for example by blocking another checkpoint protein, or that directly activates immune cells, by amplifying proinflammatory signaling.

A single compound that simultaneously does both could increase efficacy without layering on toxicities.

Because myeloid-derived immune cells represent a major source of immunosuppression in tumors, they are a growing focus among the new strategies in cancer immunotherapy.

In the majority of tumor types, the most abundant myeloid-derived cells are tumor-associated macrophages (TAMs) and monocyte-derived suppressive cells (MDSCs); myeloid dendritic cells (mDCs) can also contribute to the immunosuppressive environment.

The cells use several mechanisms to dampen antitumor T cell responses, including reducing antigen presentation and increasing expression of inhibitory cytokines.

The first wave of myeloid-targeted approaches, the most advanced of which are in Phase III testing, have focused on inhibiting these cells, preventing their infiltration into tumors or depleting them from tumors. In addition, by analogy to the use of PD-1 inhibitors to unleash T cells, at least 17 companies are harnessing macrophages by blocking their checkpoint proteins -- such as CD47, SIRPA, VISTA and SIGLEC15 -- according to BioCentury’s BCIQ database.

The next-wave strategies aim to take advantage of the large presence of myeloid cells in tumors by converting the cells into tumor-suppressing agents, rather than inhibiting or depleting them. The idea is that because it involves wholesale reprogramming of cell identity, this approach could prove more effective than blocking individual checkpoints.

Flipping the behavior of myeloid cells would go beyond relief of immunosuppression, enabling the cells to actively coordinate a T cell attack.

The next-wave strategies aim to take advantage of the large presence of myeloid cells in tumors by converting the...

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