Biomarkers may predict response to immunotherapy in prostate cancer
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Despite the success of immunotherapy in the treatment of patients with advanced malignancies, responses in metastatic castration-resistant prostate cancer have been limited.
Cancers such as melanoma and lung cancer that respond well to immune checkpoint inhibitors have high levels of underlying genetic mutations. Neoantigens produced as a result of these mutations may lead to an immune response.
Prostate cancer has relatively few underlying mutations and produces fewer neoantigens.
However, in a phase 2 trial published in Science Translational Medicine, researchers identified common biomarkers among men with metastatic castration-resistant prostate cancer who responded favorably to the CTLA-4 inhibitor ipilimumab (Yervoy, Bristol-Myers Squibb).
“Previous studies have put that number [of responders] at between 5% and 15% with immune checkpoint therapy,” Sumit K. Subudhi, MD, PhD, assistant professor of genitourinary medical oncology at The University of Texas MD Anderson Cancer Center and lead author of the study, said in an interview with Healio. “Among that 5% to 15%, these responses tend to be quite durable — they’re not just responding for a few months. They’re getting quite a benefit.”
Subudhi spoke with Healio about the study findings and their implications for future treatment of metastatic castration-resistant prostate cancer.
Question: Can you describe the design of your study?
Answer: We were looking at a simple question of whether we could detect T-cell responses to cancer neoantigens. Neoantigens are mutated proteins expressed on the cancer cell that can be recognized by the immune system. So, we wondered if a drug like ipilimumab would induce a T-cell response against these neoantigens. We were able to detect that.
We assessed 30 men who agreed to have either their primary prostate site or one of their metastatic sites biopsied or resected surgically, so we would have sufficient tissue to acquire enough DNA and RNA for our subsequent analysis. If they agreed to that, within 3 months they started treatment with ipilimumab at 3 mg/kg for a total of four doses.
Q: You stratified the men into cohorts that included a “favorable group” who did well on ipilimumab and an “unfavorable group” who did not respond as well. What did you learn about these groups?
A: We found three markers. One was a high density of CD8 T cells within the cancer cells themselves. CD8 cells are thought to be very important in promoting antitumor responses. It’s believed that most immunotherapy, especially checkpoint therapy, acts through the CD8 cells to mediate or kill the cancer. Another marker was a high-interferon gamma response gene signature. Interferon gamma is a cytokine used by immune cells, including CD8 T cells, to help fight the cancer. The third marker was antigen-specific T-cell responses. These are T-cell responses to neoantigens or to tumor-associated antigens, such as prostatic acid phosphatase or prostate-specific membrane antigen.
Not everyone had these markers. Men in the favorable group had either one or a combination of these markers.
This is a limited-size study. I wouldn’t use this in practice. However, these markers are simple enough that they can be examined in larger trials. If validated, we can improve patient selection. So, instead of just knowing that 5% to 15% respond, we might be able to know who responds. We might be able to select for a group that is closer to a 100% response.
We will look at these markers in future studies. If we see the same pattern in a larger group of patients, the final step is to do a prospective trial.
Q. What surprised you about your findings?
A. Cancers like melanoma and NSCLC, which are thought to be highly responsive to immunotherapy, have a high number of these mutations. In fact, the median is greater than 200 nonsynonymous somatic mutations in these conditions. In our cohort of 27 patients, the median was 76 nonsynonymous somatic mutations. What surprised us was that we were able to detect neoantigen responses or T-cell responses to neoantigen in patients with relatively low tumor mutational burden — less than the median 76.
Q. What is the core take-home message of this study?
A. Previous studies have shown that immune checkpoint therapy is most efficacious in tumors with high tumor mutational burden. These tumors also have a high frequency of neoantigens that can be recognized by the immune system. We were able to demonstrate that prostate cancers with low tumor mutational burden express neoantigens that elicit T-cell responses associated with favorable clinical outcomes to ipilimumab. We believe that ipilimumab-based treatment strategies are an additional area to study. Maybe ipilimumab on its own is good only for the subset of men we can identify; maybe it could be more impactful if we can combine it. – by Jennifer Byrne
Reference:
Subudhi SK, et al. Sci Transl Med. 2020;doi:10.1126/scitranslmed.aaz3577.
For more information:
Sumit K. Subudhi, MD, PhD, can be reached at 1515 Holcombe Blvd., Houston, TX 77030.
Disclosure: Subudhi reports an advisory role with Bristol-Myers Squibb.
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