Georgetown Lombardi-Led Study Reveals Why Checkpoint Inhibitors May Fail in 85% of Situations

Aug 6, 2019 | Cancer, Checkpoint Inhibitors, Immuno-oncology, Immunotherapy, Oncology, PD-1, PD-L1

Georgetown Lombardi-Led Study Reveals Why Checkpoint Inhibitors May Fail in 85% of Situations

Powerful immunotherapy treatments have been developed over the past decade that have truly helped make miracles for some cancer patients and their loved ones. These drugs help use the body’s own immune system to turn on the cancer and fight it from within. But it may work only 15% of the time. Now Georgetown University-led research has uncovered a mechanism thought to explain why some cancers don’t respond to a common form of immunotherapy called “checkpoint inhibitors” or anti-PD-1. Moreover, the researchers believe they may have a solution to helping more cancer patients benefit from immunotherapy.

Study Title

Titled PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1 +CD38hi and anti-PD-1 resistance, the study was published in Nature Immunology.

Who Led the Study

Samir N. Khleif, MD director of The Tony and Jeannie Loop Immuno-Oncology Laboratory at Georgetown Lombardi Comprehensive Cancer Center 

What is the Problem

Up to 85% of cancer patients whose cancer is treated with checkpoint inhibitors don’t benefit from these powerful new drugs.

What are checkpoint inhibitors?

A form of cancer immunotherapy currently under research. The therapy targets immune checkpoints, key regulators of the immune system that stimulate or inhibit its actions, which tumors can use to protect themselves from one’s immune system attacks. Checkpoint therapy can block inhibitors checkpoints, restoring the immune system to function. The first anti-cancer drug targeting an immune checkpoint was ipilimumab, a CTLA4 blocker approved in the United States in 2011.

Current checkpoint inhibitors target the molecules CTLA4, PD-1 and PD-L1.

PD-1 is the transmembrane programmed cell death 1 protein, which interacts with PD-L1. The latter on the cell surface binds to PD1 on an immune cell surface, which inhibits immune cell activity. PD-L1 acts as a key regulatory role on T cell activities. It appears that (cancer-mediated) upregulation of PD-L1 on the cell surface may inhibit T cells that might otherwise attack. Antibodies that bind to either PD-1 or PD-L1 and therefore block the interaction may allow the T-cells to attack the tumor.

What is the Mechanism that might explain why cancers don’t respond to checkpoint inhibitors?

Dr. Khleif and team have uncovered a mechanism thought to explain why some cancers don’t respond to checkpoint inhibitors (or anti-PD-1). As it turns out, the condition of immune cells (T cells) prior to anti-PD-1 therapy is a crucial determinant for the ability of cancer to respond. Dr. Khlief notes “if the immune cells are not in the appropriately activated state, treatment with anti-PD-1 drives these T cells into a dysfunctional, non-reprogrammable state, including resistance to further immune therapy.”

Evidently, the body has incredible ways of protecting itself. The body actually protects normal cells from being attacked by the immune system. Cancer cells have evolved to exploit this system of checkpoints in order to put the brakes on immune surveillance to protect themselves and grow. Checkpoint inhibitors release those brakes, reported Georgetown Lombardi in its press release on this breakthrough.

These inhibitors target molecules, such as PD-1, that sit on the surface of a T cell and the molecule PDL-1 that is present on tumor cells and bind PD-1. This pairing inhibits the normal functioning of T cells, known as killer CD8+, which would otherwise attack the cancer cell. Drugs (in form of antibodies that bind to either PD-1 or PDL-1) work to remove that protection—enabling the T cells to identify and attack the tumor.

Scientists are aware that checkpoint inhibitors are more effective with those tumors that have already engaged the immune system, such as melanoma and cancers that express lots of mutations. Khlief and team sought to answer the question why the checkpoint inhibitors don’t work on immunologically “quiet” tumors.

How do they propose to fix the problem?

Thanks to this Georgetown Lombardi-led research team and a series of experiments using animal models and patient tumor samples, we learn that for checkpoint inhibitors in patients to work better, they must first be active by using a simple vaccine or a removal of dysfunctional T cells. In fact, Georgetown is now conducting clinical trials to substantiate these findings.

Moving forward, investigators are pursuing the “priming” of tumors with the the development of patient tumor-specific cancer vaccines to ultimately invigorate T-cell activity and enhance PD-1 inhibitors.

Conclusion

The study is helping to progress the body of knowledge as to how checkpoint inhibitors can help more cancer patients—only 15% benefit now. The findings point to a combined effort to use cancer vaccines with anti-PD-1 therapy. Moreover, the research team identified a biomarker identifies resistant patients that may turn out to be a cost-effective drug response prediction mechanism.

Lead Research/Investigator

Samir N. Khleif, MD director of The Tony and Jeannie Loop Immuno-Oncology Laboratory at Georgetown Lombardi Comprehensive Cancer Center

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