A small subset of patients with metastatic castration-resistant prostate cancer (mCRPC) has responded favorably to ipilimumab, an immune checkpoint inhibitor, suggesting a potential new approach to treat these advanced malignancies.
In a phase II study published in the April 1 issue of Science Translational Medicine, a team of researchers at the University of Texas MD Anderson Cancer Center also identified specific biomarkers that might allow physicians to predict which patients would benefit from this therapy (2020; doi: 10.1126/scitranslmed.aaz3577).
"Our study indicates that immune checkpoint therapies can be clinically effective in a subset of patients with metastatic prostate cancer," said Sumit Subudhi, MD, PhD, Assistant Professor of Genitourinary Medical Oncology at MD Anderson and the study's first author. "We have identified predictive immunologic biomarkers, which may improve patient selection, that need to be validated in a larger cohort of patients."
Added Russell Pachynski, MD, Assistant Professor of Oncology at the Washington University School of Medicine: "The potential for induction of potent anti-tumor immunity and long duration of clinical responses will hopefully augment the current FDA-approved treatment choices [for mCRPC], which are largely composed of hormone and chemotherapies." Pachynski did not participate in this study but is familiar with its results.
Unlike traditional treatments that target tumor cells, immune checkpoint inhibitors block certain proteins made by T cells and some cancer cells that prevent the immune system's T cells from killing cancer cells. Blocking these inhibitors unleashes T cells, freeing the body's immune system to attack and destroy cancer cells.
Also different from many early-stage prostate cancers that need normal levels of testosterone to grow, mCRPC continues to grow even when the amount of testosterone in the body is reduced to castration levels. While the 5-year survival rate for early stages of prostate cancer is almost 100 percent, the 5-year survival rate for prostate cancer spread to distant parts of the body is about 30 percent.
Thus far, best-case treatment scenarios with checkpoint inhibitors have been tied to malignancies with high tumor burden, such as melanoma and lung cancer. These cancers also have high levels of underlying gene mutations that lead to the production of mutant proteins, or neoantigens, that can be recognized by the immune system. Prostate cancers tend to have low mutation rates and fewer neoantigens present, thus generally resulting in poor responses to checkpoint inhibitors, as witnessed in two previous phase III trials.
That said, researchers in the previous immune checkpoint inhibitor trials observed that a small subset of patients with mCRPC experienced durable clinical benefit. These results, hinting of a possible positive response of checkpoint inhibitors for some late-stage prostate patients, spurred the launching of a phase II trial. It consisted of a collaboration with MD Anderson's immunotherapy platform, which analyzes tumor samples before, during, and after treatment, to understand how drugs work for some patients and not for others.
From January 2015 to May 2018, some 30 patients with mCRPC were enrolled in the trial, with 29 patients receiving at least a single dose of ipilimumab. Median follow-up from administration of the first dose was 45.5 months.
Across all patients, median progression-free survival (PFS), according to radiographic imaging, was 3 months; median overall survival stood at 24.3 months. Eight patients developed grade 3 toxicities attributed to treatment, the most common being dermatitis and diarrhea. No grade 4 or 5 toxicities were observed.
Two distinct groups of patients were identified, "favorable" and "unfavorable," based on radiographic and/or clinical PFS. Nine patients were listed as "favorable," with PFS greater than 6 months and overall survival greater than 1 year. The "unfavorable" cohort of 18 patients experienced PFS less than 6 months and overall survival less than a year.
What's more, six of the nine patients in the "favorable" cohort were still alive at the time of analysis, with survival ranging from 33 to 54 months following treatment. All 10 patients in the "unfavorable" group succumbed to their disease, with survival ranging from 0.6 to 10.3 months.
The research team also compared pretreatment tumor tissues and peripheral T cells from the two cohorts. Samples from the "favorable" group revealed a distinct biomarker signature that included a higher density of cytotoxic and memory T cells, as well as increased expression of interferon-gamma signaling. Further, the researchers showed that T cells isolated from patients in the "favorable" cohort were capable of recognizing and responding to neoantigens present in their tumor, whereas T cells from patients in the "unfavorable" group did not appear to have the same responses.
"To our surprise, we were able to detect peripheral T-cell responses to mutated cancer neoantigens in two patients with extremely low frequency of non-synonymous mutations (a measure of tumor mutational burden)," said Padmanee Sharma, MD, Professor of Genitourinary Medical Oncology and Immunology at MD Anderson, co-leader of the Immunology Platform, and corresponding author. "Both of these patients had 'favorable' outcomes, which suggest the immune checkpoint blockade strategies can be used to improve survival of patients with metastatic prostate cancer."
A larger, multi-institutional study to validate its results is planned for the future.
An international trial also is evaluating patients with mCRPC, testing the efficacy of ipilimumab alone against a drug combination of ipilimumab plus nivolumab. The two drugs target different proteins on T cells. Ipilimumab works by unlocking CTLA-4 (cytotoxic T-lymphocyte associated protein 4), a protein on T cells that shuts down the immune system, while nivolumab releases PD-1 (programmed cell death-1), a separate brake on T cells, or its main activating ligand, PD-L1, found on tumors and normal cells.
"We believe that combinatorial strategies with immune checkpoint therapies may provide a survival benefit to a similar cohort of patients with the possibility of offering curative responses in a subset," said Subudhi.
The researchers also are testing the value of an algorithm, NetMHCpan, that may offer an in silico approach to predict neoantigens in prostate patients for vaccine clinical trials. Similar vaccines already are being developed to combat melanoma and glioblastoma.
"We believe this can be used to develop personalized vaccines targeting prostate neoantigens," noted Sharma. "Our group is involved in designing trials that use this approach to combine neoantigen vaccines with immune checkpoint inhibitors."
Pachynski, along with and Robert Schreiber, PhD, the AM Bursky & JM Bursky Distinguished Professor, Pathology & Immunology at the Washington University School of Medicine, also have launched the first trial of neoantigen vaccines in combination with checkpoint inhibitors (ipilimumab and nivolumab) in metastatic prostate cancer patients and in metastatic hormone-sensitive patients.
Warren Froelich is a contributing writer.
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