Cancer therapy may work in unexpected way | News Center … – Stanford Medical Center Report

Using antibodies to PD-1 or PD-L1 is one of the major advances in cancer immunotherapy, said Weissman, who is also the Virginia and D.K. Ludwig Professor for Clinical Investigation in Cancer Research, director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine and director of the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford. While most investigators accept the idea that anti-PD-1 and PD-L1 antibodies work by taking the brakes off of the T-cell attack on cancer cells, we have shown that there is a second mechanism that is also involved.

What Weissman and his colleagues discovered is that PD-1 activation also inhibits the anti-cancer activity of other immune cells called macrophages. Macrophages that infiltrate tumors are induced to create the PD-1 receptor on their surface, and when PD-1 or PD-L1 is blocked with antibodies, it prompts those macrophage cells to attack the cancer, Gordon said.

This mechanism is similar to that of another antibody studied in the Weissman lab: the antibody that blocks the protein CD47. Weissman and his colleagues showed that using anti-CD47 antibodies prompted macrophages to destroy cancer cells. The approach is now the subject of a small clinical trial in human patients.

As it stands, its unclear to what degree macrophages are responsible for the therapeutic success of the anti-PD-1 and anti-PD-L1 antibodies.

The practical implications of the discovery could be important, the researchers said. This could lead to novel therapies that are aimed at promoting either the T-cell component of the attack on cancer or promoting the macrophage component, Gordon said.

Another implication is that antibodies to PD-1 or PD-L1 may be more potent and broadly effective than previously thought. In order for T cells to attack cancer when you take the brakes off with antibodies, you need to start with a population of T cells that have learned to recognize specific cancer cells in the first place, Weissman said. Macrophage cells are part of the innate immune system, which means they should be able to recognize every kind of cancer in every patient.

Other Stanford co-authors of the study are associate professor of pathology Andrew Connolly, MD, PhD; visiting scholar Gregor Hutter, MD, PhD;instructor Rahul Sinha, PhD; postdoctoral scholars Roy Maute, PhD, Daniel Corey, MD, and Melissa McCracken, PhD; graduate students Benjamin Dulken, Benson George and Jonathan Tsai; and former graduate student Aaron Ring, MD, PhD.

The research was supported by the D.K. Ludwig Fund for Cancer Research, the A.P. Giannini Foundation, the Stanford Deans Fellowship, the National Institutes of Health (grant GM07365), the Swiss National Science Foundation and the National Center for Research Resources.

Weissman is a founder of the company Forty Seven Inc., which is sponsoring the clinical trial of the anti-CD47 antibody.

Stanfords departments of Pathology and of Developmental Biology also supported the work.

More:
Cancer therapy may work in unexpected way | News Center ... - Stanford Medical Center Report