Originally published 1/5/2015
When we posted our first blog on immunotherapy at the start of the 2015 New Year, hopes were rosy that immunotherapies were bringing treatment for metastatic prostate cancer to the brink of a new treatment threshold. Since then, it was found that immunotherapy drugs that worked quite well for other metastatic cancers such as melanoma and certain lung cancers had little to no impact on metastatic castration-resistant prostate cancer (mCRPC).
Clinical research determined that prostate cancer has “complex immune evasion mechanisms”.[i] This means it escapes detection and recognition of the body’s immune defenses. Whereas melanoma or lung cancer cells could be infiltrated by killer T cells when their defensive powers were boosted by immunotherapy, this was not happening with mCRPC. As stated by Rathi, et al. (2021), “This immune evasion in the case of prostate cancer has been attributed to tumor-intrinsic factors, an immunosuppressive tumor microenvironment, and host factors, which ultimately make it an inert ‘cold’ tumor.”[ii] Thus, mCRPC is labeled a cold tumor, as opposed to hot tumors that trigger immune alarms.
Therefore, scientists began asking how to convert prostate cancer into a hot tumor, raising its visibility for the immune system’s detection abilities. Whereas administering a single immunotherapy (mono immunotherapy) has repeatedly failed to control mCRPC, a more feasible approach is to combine two immunotherapies in a class of drugs called immune checkpoint inhibitors (ICI).
As we recently posted in a blog on combined immunotherapy, “…a recent study by the Sharma team found that combining two ICI drugs, nivolumab and ipilimumab, increased the antitumor ability of killer T cells to infiltrate mCRPC tumors. Each drug targets a different checkpoint protein, so using the two drugs together blocks two separate molecular signals that prevent T cells from attacking cancer.”[iii] This combined approach is proving more effective in managing mCRPC, once again raising expectations.
Another approach has been to use tumor cells from the patient’s own body to develop a personalized biological vaccine. As just one example, a company called Perseus has developed a 4-stage injection therapy over four months, based on the patient’s cancer cells. (Note: as of this writing, it is not yet approved in the U.S. so patients must travel to the Cayman Islands for the treatment.)
A cautionary word: many more clinical trials will be needed to determine correct dosage levels. In the Sharma study, side effects were so adverse that roughly half of the participants discontinued participation in the study. Nonetheless, immunotherapy continues to hold promise against mCRPC.
One of the most exciting new directions for dealing with cancer is the field of immunotherapy. The word itself suggests using the body’s own defenses against disease as a way of healing illness. The idea is certainly not new, but I want to offer some general information and then a couple of specific adaptations of immunotherapy for use against prostate cancer.
According to the American Cancer Society, there are 3 types of immunotherapy[iv]:
- Monoclonal antibodies are manmade versions of immune system proteins that can go after certain parts of cancer cells.
- Cancer vaccines can be used to stimulate an immune system response to certain diseases.
- Non-specific immunotherapies are not directed at a particular disease or condition, but generally boost the immune system to work more effectively.
The immune system itself is complex. It has several components, each of which has a part to play:
- Antibodies, white blood cells, and other proteins and chemicals that can recognize, attack and destroy foreign bodies such as bacteria, viruses, and cancer cells.
- The thymus gland, which makes T cells.
- The lymph system, which circulates lymphatic fluid throughout the body, sweeping up foreign particles. In turn, the fluid is filtered by the lymph nodes, where the particles are destroyed by special white blood cells called lymphocytes.
- Bone marrow, which produces red and white blood cells.
- Dendritic cells, which capture antigens (proteins on the surface of cells) to identify threats, and relay that information to T cells which can then destroy it upon encounter.
Recent discoveries about T cells helped uncover the ways in which the body normally puts the “brakes” on these cells, with their power to attack and destroy. Scientists reasoned that when a patient has a particularly aggressive cancer, such as melanoma—the most dangerous skin cancer—taking the brakes off of T cells would liberate them to wage war against the disease in a more concerted fashion. Researchers began work on drugs that would turn off the braking mechanism. One drug, ipilumilab, proved so successful at extending life for melanoma patients in clinical trials that in 2011 it was approved for treating metastatic melanoma.
According to the Cancer Research Institute, “In immunotherapy, prostate cancer has been at the vanguard.”[v] You may already know about Provenge®(developed by Dendreon), the first therapeutic vaccine approved for any type of cancer. It harnesses the power of dendritic cells to trigger an immune response against a specific antigen produced by most prostate cancer cells. Ways to improve its effectiveness are being tested. Other prostate cancer vaccines are also in development.
Another immunotherapy area of research against prostate cancer is called checkpoint inhibitors/immune modulators. An example is clinical studies that combine ipilumilab with another drug in an effort to free up immune system components to target prostate cancer cells that may be circulating in the body, or have begun to form solid tumors outside of the prostate.
Finally, a technique called adoptive cell therapy involves removing a prostate cancer patient’s T cells, treating them with chemicals or modifying them genetically to invigorate them, and returning them to the patient’s body. Clinical trials are underway.
My particular interest in immunotherapy has to do with its potential use in conjunction with focal therapy. No one knows all the reasons why an otherwise healthy person develops prostate cancer, though factors like heredity or exposure to environmental toxins might be factors. When we treat a prostate tumor with focal laser ablation (FLA) we want to provide that patient with resources so he can fortify his immune system—a modified form of non-specific immunotherapy. Much research points to the power of correct nutrition, exercise, stress management, supplements, etc. to create positive genetic change, minimizing a person’s risk of recurrence. I look forward to the day when, in addition to these lifestyle changes, a simple prostate cancer vaccine will be available to reinforce the effectiveness of FLA. These three things—focal treatment, personal immune empowerment, and a vaccine—may prove to be the crucial ingredients in a long and cancer-free life following treatment.
NOTE: This content is solely for purposes of information and does not substitute for diagnostic or medical advice. Talk to your doctor if you are experiencing pelvic pain, or have any other health concerns or questions of a personal medical nature.
[i] Bou-Dargham, M.J., Sha, L., Sang, QX.A. et al. Immune landscape of human prostate cancer: immune evasion mechanisms and biomarkers for personalized immunotherapy. BMC Cancer 20, 572 (2020).
[ii] Rathi, N., McFarland, T.R., Nussenzveig, R. et al. Evolving Role of Immunotherapy in Metastatic Castration Refractory Prostate Cancer. Drugs 81, 191–206 (2021).
[iii] Sharma P, Pachynski RK, Narayan V, Flechon A et al. Nivolumab Plus Ipilimumab for Metastatic Castration-Resistant Prostate Cancer: Preliminary Analysis of Patients in the CheckMate 650 Trial. Cancer Cell 38, 1-11, October 12, 2020.
[v] See more at: http://www.cancerresearch.org/prostate-cancer#sthash.oE11uxoG.dpuf