In Nature in September 2022 an article by Anthony King identified the difficulties associated with creating an immunotherapy for prostate tumours. The 2010 FDA-approved vaccine, sipuleucel-T, “raised hopes for a surge of cancer treatments”, which the article suggests have not been delivered for the prostate.
The vaccine originally targeted prostate tumours. The process involves extracting antigen-present cells from the patient’s blood and inserting a marker found on prostate tumours, before returning them to the patient. The idea, the article explains, is to direct “other immune cells” to “attack the cancer”.
Dr Lawrence Fong of the University of California is quoted emphasising the “big challenge” of prostate cancer. Although sipuleucel-T “delivered a slight survival benefit”, the American Cancer Society suggests that it “hasn’t been shown to stop prostate cancer from growing”.
Since 2010 there have been several “disappointing” immunotherapy attempts for prostate cancer. There are still gaps in our knowledge, which present a “key obstacle to getting immunotherapy to work”. However, momentum will not be stopped. Researchers are beginning to better understand this cancer, and promising approaches are progressing through trials.
So, what do we know about prostate cancer? Dr Charles Drake of Janssen Pharmaceutical suggests that because prostate cancers mutate less than other cancers, they offer fewer targets: “there’s just not as much fodder for T cells to recognise”. Another issue is that the prostate “has an unusually dialled-down immune environment”.
“Researchers using genetic sequencing to look for immune cells in the prostate will often come away empty-handed.”
The low T cell count means that checkpoint inhibitors encounter problems. When combined with the cancer, which “secretes a chemical messenger that further dampens immunity”, a “tricky environment” is created.
So far, therapeutic candidates have been “a bit of a let-down”. However, some scientists believe that a combination approach could be effective. This would involve a vaccine and a checkpoint inhibitor, working together. This could work based on a study of sipuleucel-T; it revealed that “people who received the treatment contained three times as many activated T cells”.
Trialling this is Dr James Gulley and his group in the US. Using a vaccine called Prostvac (PSA-TRICOM), which “disappointed in a phase III trial”, he hopes to “break the blockade”. Although Prostvac was insufficient alone, Dr Gulley’s group is trialling it alongside a checkpoint inhibitor targeting PD1, which tumours use to dodge detection by the immune system. Early signs a promising; “not a home run, but an interesting early signal”, for Dr Gulley. His “next step”, the article reports, is adding a third element. Interleukin-15 is a cytokine molecule that is involved in immune signalling. Despite positive early responses, this project must “clear tough regulatory hurdles”.
Targeting treatment and looking ahead
In order to achieve the most successful outcome, immunotherapies must be “targeted to the right people”. The article suggests that personalisation is common in other cancers but is “lagging” for prostate cancer. Furthermore, there is a “consensus” that the timing of immunological intervention “could be crucial”. We often see immunotherapy in patients with advanced disease, but the longer the battle with cancer, the “more entrenched it can become”. Considering immunotherapy “immediately after surgery or radiation therapy” is an avenue to explore.
In the face of numerous challenges, there is optimism. Dr Gulley identifies “little signals” that we can achieve “long-term durable responses”. Although “we haven’t quite cracked it” he believes there could be a “path forward”.