PCa Immunotherapy (for people in a hurry)

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I just finished reading Niel deGrasse Tyson’s book on astrophysics that was pretty understandable. Although I am no immunology expert, and certainly not at the academic achievement level of Dr. Tyson, I have made monoclonal antibodies in my lab and participated in several prostate cancer immunotherapy trials, so I’ll give this a try. My inspiration comes from a truly excellent and comprehensive review on the topic by Laccetti and Subudhi that appeared in Current Opinion in Urology. I will follow their outline with my own “layman’s view” and comments.

Provenge (Sipuleucel-T) was the first immunotherapy ever approved for treating Pca, and has been available since 2010. To be eligible, you have to have failed standard androgen deprivation therapy (though not necessarily the newer agents) and have metastases that can be detected on bone or CT scans. While the treatment works, has been shown to slow the rate of PSA increase and prolong survival, it is complex to administer. You need to donate your own immune cells for “activation” in a treatment facility, following which you receive them back as a transfusion. The process is repeated 3 times and costs in the range of $100K. Many of us wish it was even more effective given the costs and inconvenience, and of course all patients want to see their PSA go down with ANY treatment, which doesn’t happen often with this treatment. Efforts to improve the efficacy have included earlier use when patients are still hormone sensitive and combining SipT with ipilimumab, an antibody that enhances immune responses.

A number of [somewhat] more traditional vaccines are in trials. In a phase II trial, Prostvac, utilized a pox virus approach to deliver PSA (as the antigen) along with co-stimulatory molecules to help the immune system recognize and kill PSA producing cells. Although the phase II data looked very promising, the phase III trial was closed in September when the data did not support continuing to treat patients. Given this disappointment, it is not surprising that the immunologists/clinicians pursuing the goal of a successful prostate cancer vaccine would turn to the “checkpoint therapies” as a possible way to induce the body to fight prostate cancer.

Perhaps the best known of these approaches (due in part to intense advertising on the evening news channels) are nivolumab (Opdivo™) and pembrolizumab (Keytruda). The general idea here is that the immune system would potentially constantly be fighting our own body parts if there wasn’t a way to turn it off. Examples include diabetes (immune system attacks the insulin secreting cells of the pancreas) or rheumatoid arthritis (immune system attacks your joints). The checkpoint system, known as PD-1 (programmed cell death protein 1) is a shutdown system whereby the attacking T-cells are turned off by the PD-l1 ligand, a protein that can also be secreted (unfortunately) by the cancer cells. Thus the cancer cells can turn off our own immune system which is trying to attack and kill the cancer. The checkpoint antibodies effectively throw a monkey wrench into this system, allowing the immune cells to do their thing (and of course, as you would predict, the side effects can include attack of other “self” organs like the lung or colon or pituitary gland). This approach has shown real promise in melanoma, lung cancer, head and neck cancer, bladder cancer, and in some patients with colorectal cancer. Another checkpoint player is ipilimumab, which was first approved for melanoma and also releases “blunted” T-cells to go on the attack. Unfortunately, none of these checkpoint inhibitors have been promising by themselves in early tests in advanced prostate cancer, but there is optimism that by combining them with some of the vaccines in trial, or, perhaps by timing their use with androgen deprivation or radiation therapy when lots of pca cells are dying we will see improved responses. There are 19 actively recruiting studies at clinicaltrials.gov with the terms “vaccine, prostate cancer, recruiting”.  As with many of the challenges in prostate cancer, the best time to use an immune approach is likely early on, when the disease burden is low (for example, a Gleason 9 patient with NO evident metastases). These trials are challenging because such patients are fortunately uncommon, and because these men also can live for many years with current treatments, making the evaluation of a new treatment modality difficult.

2017 was a year when we lost one of the most inspiring teacher/researchers in prostate cancer, Dr. Donald Coffey. The good news is that his legacy lives on in the large number of researchers who continue to push the frontiers of prostate cancer diagnosis and treatment. We owe him a great debt of gratitude for his tireless efforts to advance this field of medicine. I predict it won’t be long until we have the kinds of exciting pca immunotherapies that have made such a remarkable difference in melanoma and other cancers.