Stories of immunotherapy’s success against metastatic melanoma in patients such as former President Jimmy Carter are well publicized, but the treatment doesn’t work for everyone.
In fact, checkpoint blockade drugs such as pembrolizumab and nivolumab, which inhibit protein molecules on T cells that keep the immune system from attacking tumors, only work for about one-third of patients.
Why do some tumors respond to immunotherapy and others don’t? That’s a question MD Anderson’s Weiyi Peng, M.D., Ph.D., and her team of investigators are getting closer to answering.
Peng, an assistant professor in Melanoma Medical Oncology, led a study that showed a link between the loss of a tumor-suppressor gene called PTEN and resistance to checkpoint inhibitor immunotherapy.
Patients with inactive PTEN had fewer T cells in their tumors, indicating that a lack of PTEN suppresses the immune response against melanoma. Patients with inactive PTEN also had worse outcomes when treated with checkpoint inhibitors compared to melanoma patients with intact PTEN.
These findings indicate PTEN loss may be an important biomarker to predict melanoma patients’ resistance to immunotherapy. The study also showed that treatment with an experimental drug that blocks a molecular pathway called PI3K improved the effectiveness of anti-PD-1 treatment in laboratory models of melanomas with loss of the PTEN gene.
“These results allowed us to devise a means of combating resistance to immunotherapy due to PTEN loss in melanoma patients,” Peng says.
Findings of the study, which was Cancer Discovery’s February 2016 cover story, have led to a Phase I and II clinical trial that will test a combination of immunotherapy and targeted therapy in patients with metastatic melanoma who lack the PTEN gene.
Hussein Tawbi, M.D., Ph.D., associate professor of Melanoma Medical Oncology, is leading the Phase I and II clinical trial of pembrolizumab, an FDA-approved anti-PD-1 antibody, and GSK2636771, a PI3K-beta inhibitor, in patients with metastatic melanoma who lack the PTEN gene.
The study represents the first clinical trial to test the effects of the PI3K-beta inhibitor in melanoma patients — and the first to test its effects in combination with immunotherapy in any cancer type.
“About one-third of melanoma patients respond to pembrolizumab, which means there are two-thirds of patients in whom we need to do better,” Tawbi says. “This trial is a very significant step in that direction.”
This research and trial capitalize on the skills of targeted therapy experts such as Michael Davies, M.D., Ph.D., deputy chair of Melanoma Medical Oncology and co-leader of the Melanoma Moon Shot™, and immune therapy experts like Peng and Patrick Hwu, M.D., chair of Melanoma Medical Oncology and head of Cancer Medicine. Davies and Hwu were co-senior authors on the article.
“This exciting clinical trial builds upon the collaborative research we have undertaken at MD Anderson to understand the interactions between oncogenic signaling pathways in cancer cells and the regulation of the anti-tumor immune response, based on our extensive expertise and resources in these two areas,” Davies says. “In addition to representing an important new clinical trial for patients with advanced melanoma, the results and translational research from this trial may have impact for the many other cancer types in which loss of PTEN occurs.”
How checkpoint blockade drugs work
PD-1 is a checkpoint protein on T cells — white blood cells that find and kill invaders — that acts as an “off switch” when it binds with the protein PD-L1 on healthy cells, protecting them from attack. However, PD-L1 can also be found on cancer cells, allowing them to prevent an immune response by joining with a T cell’s PD-1. Anti-PD-1 immunotherapies target the checkpoint and prevent it from binding with PD-L1 on a cancer cell, effectively turning “on” an immune attack against cancer.