Uterine Cancer: The Next Immunotherapy Frontier?


CancerConnect News: All gynecologic cancers are challenging to treat. They can be hard to find and are usually diagnosed when they are advanced. Although these cancers can be held at bay with surgery or chemotherapy, they often return and become difficult to control. Researchers at Memorial Sloan Kettering are exploring whether harnessing the power of the immune system could better combat these stubborn diseases.

There are logical reasons to think that gynecologic cancers may respond to immunotherapy. Some of these cancers carry genetic mutations that are known to respond to these drugs. Others bear clinical markers showing that the immune system is already primed to respond. Ovarian cancers, for example, are typically infiltrated by immune cells that were drawn to the tumor, even if they ultimately were not effective. This means the immune cells were drawn to these cancer cells, even if they ultimately were not effective. Most cases of cervical cancer are caused by the human papillomavirus (HPV), which the immune system normally fights off.

Endometrial Cancer: Boosting Checkpoint Inhibitors

One type of immunotherapy showing great promise is a class of drugs called immune checkpoint inhibitors.

Immune checkpoint inhibitor drugs are currently the most widely used and publicized precision immunotherapy treatment. A patient’s cancer cells can express molecules that activate PD-1 or CTLA-4 inhibitory “receptors” on their “T-cells” or other cells in the immune system.  When these receptors are activated on the T-cells, they are prevented from attacking the cancer cells and evade the immune response.  Checkpoint inhibitor drugs that block PD-1, PD-L1, or CTLA-4 work to “release the brakes” allowing the cancer cells to be detected and attacked by T-cells.

A major development in the last year was the FDA approval of Keytruda (pembrolizumab) – a checkpoint inhibitor for cancers that have a genetic abnormality called mismatch repair (MMR) deficiency. This genetic flaw prevents cells from fixing mistakes that occur when DNA copies itself. As a result, MMR-deficient cells can have hundreds or even thousands of mutations, compared with just a few dozen in a typical cancer cell. This pattern of widespread genetic change is called microsatellite instability.

The effectiveness of checkpoint blockade drugs against MMR-deficient tumors bodes especially well for the treatment of endometrial cancer, since about 30% of endometrial tumors are MMR-deficient.  The approval of Keyturda for the MMR subtype of endometrial cancer was the proof of principle that this type of immunotherapy can be successful in a gynecologic cancer. We know there’s some loss of immune control that allows gynecologic cancers to develop or recur. So it makes sense to take an immunotherapy approach for these diseases.

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