The American Association for Cancer Research Annual Meeting was held in New Orleans in April. Dr. Andrea Miyahira, PCF’s Director of Global Research and Scientific Communications, has identified key updates that were presented at the meeting. This week, we highlight two presentations on potential ways to optimize the use of immunotherapy.
Making Immunotherapy More Effective in Prostate Cancer
The immunotherapy drug pembrolizumab is FDA-approved for advanced solid tumors, including prostate cancer, with high levels of certain mutations (such as microsatellite instability or MSI). These mutations help the body’s immune system recognize the tumor as “foreign,” and when immune cells engage the cancer, immunotherapy can be effective.
However, one challenge is that prostate cancer is relatively “cold” to the immune system compared to other cancers, and immunotherapy is not effective in many patients. Luis Diaz, MD, of Memorial Sloan Kettering Cancer Center and colleagues aimed to induce more mutations in cancer cells by exposing them to existing chemotherapy drugs.
The team found that the combination of two drugs, temozolomide + cisplatin, resulted in a high number of these “immunogenic” mutations. Tumors in mice treated with temozolomide + cisplatin were infiltrated by immune system cells and were completely eradicated by treatment with immunotherapy.
These results suggest that treatment with agents such as temozolomide + cisplatin, which promote certain mutations, can turn immunologically “cold” tumors “hot,” and sensitize them to immunotherapy. A proof-of-concept clinical trial testing a combination of three drugs (temozolomide + cisplatin + the immunotherapy agent nivolumab) is underway.
Take-home point: Treatment with existing drugs may turn “cold” prostate tumors “hot,” and be a strategy to improve the effectiveness of immunotherapy.
Factors Affecting the Immune System and Response to Immunotherapy
Immune system cells called T cells recognize “foreign” proteins (for example, on cancer cells or infectious bacteria) and prompt the immune system to attack the invader. However, cancer cells often develop ways to evade detection, allowing them to grow and spread. Thomas Gajewski, MD, PhD of the University of Chicago, and team, found that there are two distinct types of melanoma. One type expresses genes that activate the patient’s immune cells, recruiting T cells to the tumor—and the cancer cell survives by ramping up immune-suppressing genes. The other type of melanoma is able to “exclude” T cells and avoid detection. Understanding these factors may help optimize the “precision” use of immunotherapy in different patients. Dr. Gajewski presented on several factors that affect interactions between tumor cells and the immune system.
1) The tumor itself. Some tumors have mutations which impact the immune system. For instance, mutations in genes in the WNT pathway were found to suppress anti-tumor immune functions.
2) Gut microbiome. Bacteria and other “bugs” naturally occurring in the gut may affect response to immunotherapy. In melanoma, experiments with fecal microbe transplants have shown that when the microbes from feces of patients who responded to immunotherapy are transplanted into mice, the mice also respond to immunotherapy. On the other hand, fecal microbe transplants from human non-responders caused mice to be non-responders as well. The offspring of the mice even retained the same microbiome profile and response characteristics as their parents. Specific factors in the gut microbiome that boost or dampen the immune response to cancer are under study.
3) Inherited gene variations. We know that the genes that come from our parents are important in prostate cancer; for example, certain different forms (variants) of genes such as BRCA1 and BRCA2 are linked to increased risk of the disease. Another approach is to study gene variants associated with autoimmune diseases. For instance, variants in the autoimmune-related gene PKCδ on T cells may affect how our immune cells recognize and attack tumors. These genes may be possible targets for improving anti-tumor immune responses.
Take-home Point: The interaction between tumors and the immune system is complex and dynamic. These many factors offer several potential pathways for new and more precise treatments.
Read Part 2 of the AACR Highlights here.