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Kathleen N. Moore, MD
The success of immunotherapy in endometrial cancer involves identifying patients with inflamed tumors who will respond to treatment and those who will not, and finding ways to treat non-inflamed tumors with endometrial cancer. Immunotherapy, said Kathleen Moore, MD, at the SGO 2019 Annual Winter Meeting.1
The inflamed tumors, she says, are those such as high tumors with polε mutations or microsatellite instability (MSI) that the immune system can recognize and kill. However, the process is more complicated than that.
"If it worked, we would not have cancer at all. Our innate surveillance systems have always taken care of this, "said Moore, deputy director of cancer research, director of the Stephenson Cancer Center, Oklahoma's TSET Phase I program, and holder of the Jim and Christy Everest Chair of Cancer Research at the University of Oklahoma and Director of the Gynecologic Oncology Research Fellowship at the University of Oklahoma Health Sciences Center.
"There are so many different things that contribute to what we call the cancer immune set point," she added. "This is where the personalization of medicine comes into play and why some people respond to or do not respond to immunotherapy."
Moore said that there is preclinical data suggesting that these "hot" tumors are sensitive to immunotherapy. These tumors express increased infiltration of CD8 T cells into the surrounding tumor and stroma. In addition, these tumors exhibit a high preponderance of genes involved in expressed and transcribed T cell mediated toxicity such as TIM3, PD-L1 and LAG3. Moore added that these patients support a high tumor burden and express a large number of neo-antigens, which should mean that they are ready to respond to immunotherapy.
"In addition, tumors with POLε and MSI are also called tertiary lymphoid structures," said Moore, "they are so inflamed and there are so many tumor-infiltrating immune cells that they are actually trying to create new lymph nodes." in the tumor. "
The FDA's approval in 2017 of pembrolizumab (Keytruda) as an agnostic tumor treatment for tumors at high MSI or deficient mismatch repair repair (dMMR) further suggests that these tumors might respond to immunotherapy, was -she adds.
Some receptors, such as TIM3 and LAG3, inhibit T cells and others, such as CD28 and OX40, enhance T cell activation. Researchers are investigating the possibility of targeting 1 such receptor in the part of a Phase I study (NCT03538028) of INCAGN02385, a LAG3-targeting antagonist antibody, intended for the treatment of several advanced advanced malignant tumors following treatment, including endometrial cancer.
"The LAG3 alone may not be the right thing. We may need to use it in combination or use it from the beginning. We do not know yet, "Moore said. "We are in our infancy with regard to the use of these drugs, but they are already undergoing clinical trials in endometrial cancer."
For immune-excluded or so-called "cold" tumors, those in which the immune system is activated but can not enter the tumor, he said that it would be possible to treat those with VEGF inhibitors and by stimulating the Priming of T lymphocytes with chemotherapy. "VEGF is a highly immunosuppressive molecule. It's not just an angiogenic molecule, "she said. "It directly inhibits T cell function and T cell trafficking to the tumor, which explains its interest in these immuno-excluded tumors.
"There is a lot of data in other tumors, kidney cell being the key to treatment, indicating that if you badociate immune therapy with antiangiogenic agents such as bevacizumab [Avastin]you improve infiltration of previously excluded T cells into the tumor. "
Vikky Makker, MD, and colleagues evaluated the combination of lenvatinib (Lenvima), a VEGF multikinase inhibitor, and pembrolizumab for the treatment of patients with advanced endometrial cancer (NCT02501096). Patients with histologically confirmed disease, regardless of MSI status or ORR status, were badigned 20 mg lenvatinib daily plus 200 mg pembrolizumab every 3 weeks.
In the results presented at the ASCO 2018 annual meeting, Maaker et al. Found that the combination induced an overall objective response rate (ORR) of 39.6% (95% CI, 26.5-54.0) by an independent investigator with unresolved response time (range, 7.4 month-NR). The TRG was 50.0% (95% CI, 6.8 to 93.2) in the subset of MSI-high (n = 4). Median progression-free survival was 7.4 months (95% CI, 5.0-NR).2
Moore said that the ORR for patients with recurrent disease is typically about 15% with a progression-free survival of 3 months. "It's really a special case when we think about the data that has been presented on endometrial cancer," she added.
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