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CICON16: Beyond PD-1 and CTLA-4: The New Checkpoints

September 26, 2016

Checkpoint inhibitors have produced amazing responses against several types of cancer; however, many cancers are resistant to current checkpoint inhibitors and a significant percentage of patients do not respond. The second session here at the Second International Cancer Immunotherapy Conference, taking place in New York City this week, addressed this challenge, and discussed how current checkpoints fail, and explored the potential of other checkpoints that are being targeted to improve patient responses.

Three of the four currently approved checkpoint drugs--nivolumab (Opdivo®), pembrolizumab (Keytruda®), and atezolizumab (Tecentriq™)--act by blocking the activity of the PD-1 pathway in T cells, which can exhaust them and render them dysfunctional. Sometimes, anti-PD-1/PD-L1 therapy can rescue these exhausted T cells, but once the treatment is stopped, these cells typically revert back to their exhausted state.”

John WherryTo learn what governs this exhaustion, E. John Wherry, Ph.D., has characterized these exhausted T cells along with other T cell subtypes. Wherry—the director of the Institute for Immunology at the University of Pennsylvania Perelman School of Medicine, a former CRI-funded postdoctoral fellow, and the recipient of the 2016 Alt Award from CRI for his pioneering work in this area—revealed his latest findings.

He and Kristen Pauken, Ph.D., who is a CRI postdoctoral fellow in his lab, showed that the reason anti-PD-1 treatment can reinvigorate exhausted T cells only temporarily is that epigenetic enhancers in exhausted T cells promoted PD-1 expression much more than in other T cell subsets. They also showed that the epigenetic differences between exhausted T cells and their presumably-related functional counterparts were so extensive that they could be considered distinct lineages.

Dario Vignali, Ph.D., vice chair of immunology at the University of Pittsburgh School of Medicine, showed how anti-PD-1 checkpoint inhibition could be enhanced further when it was given in combination with a checkpoint inhibitor that targeted the immunosuppressive LAG-3 pathway. The combination was more effective than either treatment alone. Vignali is also targeting two other potential checkpoints: the Nrp1 receptor and the IL-35 receptor. Both are expressed by regulatory T cells (Tregs) and enable their immunosuppressive functions. When the Nrp1 gene was deleted in mice, it protected them from cancer, and crucially, didn’t disrupt Treg’s ability to maintain tissue homeostasis. Likewise, when the IL-35 receptor was blocked on Tregs, anti-tumor T cells were no longer suppressed and could exert their anti-tumor activity.

Susan KaechFinally, Susan Kaech, Ph.D., who is a professor at Yale University and a CRI-funded CLIP investigator, and Greg Delgoffe, Ph.D., an assistant professor at the University of Pittsburgh School of Medicine and a former CRI predoctoral fellow, highlighted the efforts involved in targeting new metabolic checkpoints. Kaech’s work was conducted with Guolang Cui, Ph.D., a CRI-funded postdoctoral fellow in her lab, and focused on the fact that activated T cells, which usually metabolize a lot of glucose, instead consumed high amounts of fatty acids in tumors, which promoted expression of the immunosuppressive PD-1 receptor. They identified the fatty acid transporter CD36 as a potential checkpoint inhibitor that supports tumor growth by contributing to suppression of T cells. When they blocked CD36, T cells were resistant to fatty acid-induced immunosuppression as determined by PD-1 expression.

Delgoffe focused on the competition between cancer cells and immune cells over the scarce resources in the tumor environment. Under these conditions, low oxygen levels are associated with dysfunctional T cells with diminished energy-supplying mitochondria. Interestingly, he found that metformin—a drug approved for diabetic patients to lower blood sugar—was able to slow down cancer’s mitochondrial oxygen consumption. This in turn provided more oxygen for the anti-tumor T cells, which enabled them to proliferate more effectively and restored their anti-tumor activity. Furthermore, metformin synergized with anti-PD-1 treatment, and the combination inhibited tumor growth more than either treatment alone.

Next up, we’ll be covering CICON16's session on the tumor microenvironment.

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*Immunotherapy results may vary from patient to patient.

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