1. Gallagher, Amy

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In recent years, cancer immunotherapy has been effective in treating patients with immunogenic tumors, known as "hot" tumors, which show increased presence of immune cells in and around the tumors. Prostate cancer, however, is considered a "cold" tumor, with fewer immune cells recognizing and infiltrating prostate malignancies. Accordingly, prostate cancer has been found to respond poorly to the class of immunotherapies known as immune checkpoint inhibitors (ICI).

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The need for improved therapies for treating prostate cancer and the positive results of ICI in advanced cancers, such as lung cancer and melanoma, created the rationale for researching the effectiveness of ICI as a potential therapy to treat a subset of prostate cancer, which resulted in a surprising outcome.


In recently published work, Beth Israel Deaconess Medical Center (BIDMC) medical oncologists identified a subset of prostate cancers looking at samples from 115 cases that exhibited characteristics more typical of hot cancers, with 29 meeting the criteria consistent with immune response.


"About one-quarter of patients with localized prostate cancer have high-risk disease, which is prone to relapse despite surgery and/or radiation," said co-corresponding author David J. Einstein, MD, medical oncologist at BIDMC and Assistant Professor of Medicine at Harvard Medical School (HMS). "In about one-quarter of the high-risk localized prostate cancers that we examined, we were surprised to find features of more traditionally immunogenic cancers."


These high-risk patients are those who may unfortunately go on to develop biochemical or metastatic recurrence, so may need new options to increase their likelihood of cure, he noted.


PD-L1 Expression & T-Cell Infiltration

Einstein and colleagues, including co-corresponding author Steven Balk, MD, PhD, a physician-scientist at BIDMC and Professor of Medicine at HMS, focused on two characteristics that make traditionally immunogenic cancers susceptible to immunotherapy.


PD-L1 is a protein involved in tumor evasion of the immune system; T cells are the sentinels of the immune system, patrolling the body for potential pathogens or disease. The researchers identified prostate cancers that had been removed from patients, looking for those that had areas of high PD-L1 expression, and then looked for the presence of infiltrating T cells.


Next, the team compared the T-cell landscape in the more immunogenic prostate cancers to that of more typical prostate cancers, as well as to kidney cancer, one of the most immunogenic tumor types. Finally, the team used DNA sequencing to compare the genetic profiles from these immunologically hot areas to that of the so-called cold areas in the same tumors, as well as to the genomic landscape of immunogenic cancers in general.


The scientists were surprised to learn how many more T cells infiltrated the immunogenic prostate cancers compared with more typical prostate cancers, and to observe T-cell subsets previously seen in traditionally immunogenic cancers like kidney cancer in these immunogenic prostate cancers.


"We examined genomic changes in these tumors using a customized array of about 800 genes involved in cancers in general and prostate cancer specifically, as well as immune targets of interest," said Einstein.


They noted significantly more loss of some key tumor suppressor genes in these immunogenic prostate cancers compared with typical prostate cancer, a difference that could help provide a mechanistic link and might also potentially serve as markers to find cancers more treatable with immunotherapies.


"We're interested in this subset of patients with localized prostate cancer whose cancers might be more recognized by the immune system, and whether these cancers might therefore be more treatable with immunotherapies," Einstein stated. These would also be some of the patients at greatest risk for relapse and metastatic spread.


Personalized Clinical Trials

The team is currently conducting a clinical trial to test the effect of a PD-1 inhibitor in prostate cancer patients that will allow them to gather evidence as to whether any of these findings in previous surgical specimens translate into clinical responses in response to PD-1 inhibition.


"We're hoping to be able to identify patients with immunogenic tumors in advance of treatment, so that we can develop clinical trials for this subset of patients and offer a more personalized strategy than treating all-comers the same way," noted Balk.


The current related clinical trial involves patients who have experienced a relapse, with an increasing/rising PSA after a previous surgery and/or radiation, according to Einstein.


"They do not have visible metastases on scans, but are at high risk for developing metastases in the coming months to years," he said. "There aren't curative options in this situation. While hormone therapies can be used, the optimal timing is unclear, there are clear side effects, and their effect is time-limited, meaning that patients will eventually develop resistance."


The researchers are looking at patients with biochemically recurrent, "micrometastatic" disease that is at high risk of progressing to overt metastatic disease, with the hope of offering better therapies with long-lasting effects in this situation, Einstein noted.


"More specifically, we're looking at patients who experience a rapid rise in PSA after primary therapy. We're treating the PD-1 inhibitor nivolumab and then looking at the PSA over several months," he said.


While Einstein stated their research is promising in some patients, he knows it is not the full answer. "We will study those patients who have a response then progress again. We will also study patients who have never responded to begin with. This will set the stage for the next generation of clinical trials."


Fundamentally, the researchers are looking at identifying a unique subset of prostate cancer that may be more likely to allow the use immune therapies successfully.


"All of us in oncology are excited about harnessing the immune response to direct one's immune system to fight cancer," said Einstein. "The dogma is prostate cancer that is not recognized by the immune system, but that doesn't seem to be universally true.


"While we're surprised by the finding, we know this demands further pre-clinical and clinical research, together with our patients who are critical to everything we do," he noted. "If we can find tumors that are already recognized by the immune system, there is a greater chance of immunotherapy success."


Amy Gallagher is a contributing writer.