Sperling Prostate Center

Combination Immunotherapy Offers New Possibilities in Metastatic Prostate Cancer

You may never know how many times a microscopic system in your body saved your life. You can’t see or feel this built-in mechanism, but it tackles start-up cancers and other diseases before they can take over. This is the work of your immune system, made up of various components that work together to keep you safe. In this respect, your immune system is like a diverse detective and law enforcement team whose member protect and defend you from internal criminals and external invaders.

T cells are one immune system component. There are two types, helper T cells and cytotoxic (killer) T cells. With respect to cancer, the killer T cells’ job is to act like a SWAT team against tumors.

A 911 call to the immune system

We all know that cancer is dangerous because it is made up of mutated cells that have no self-control and clone themselves like crazy. If they take root and multiply, the body’s alarm system sends out a 911 call to the immune system. The tumor quickly finds itself under attack, especially from killer T cells that can infiltrate the tumor and kill cancer cells. Now it’s cancer’s turn to mobilize defenses.

Cancer sabotages T cells

Cancer cells have biochemical strategies to prevent the immune system’s antitumor activity. One of these ploys takes advantage of checkpoint proteins on the surface of killer T cells. These checkpoints help T cells recognize and keep from attacking normal cells. How does this work? Normal cells have molecular “signals” that manage the checkpoints, switching them off in order to put the brakes on a T cell’s killer function. On the other hand, if a killer T cell meets a cancer cell that lacks these signals, its killer function switches on and it destroys the foreigner. It doesn’t always work, however, since cancer cells come from normal cells; thus, some still bear normal cells’ checkpoints, making them “invisible” to T cells. This is one way cancer protects itself from killer T cells. The American Cancer Society points out two other ways cancer cells can prevent a sustained barrage from the immune system:

  • Sometimes the immune system recognizes the cancer cells, but the response might not be strong enough to destroy the cancer (weakened immune system).
  • Some cancer cells can actually generate their own molecular signals to switch off T cell checkpoints—in other words, they sabotage the T cells by biochemically applying the brakes.

A special type of immunotherapy called Immune checkpoint inhibitors (ICI) has been developed to counteract this type of sabotage. Here’s the principle: if cancer has switched off a T cell’s checkpoints, then inhibiting (blocking) the checkpoint altogether makes it useless, and automatically switches the T cell’s killer function on again.

Combination immunotherapy for metastatic prostate cancer

Scientists have determined that there are two distinct tumor types, depending on the kind of cancer: “hot” tumors and “cold” tumors. Hot tumors have a lot of T cell infiltration activity because the T cells and other immune system components bypassed cancer’s defenses and are at work trying to defeat it from within. Hot tumors like lung cancer and melanoma often respond well to ICI immunotherapies.

Cold tumors, on the other hand, have very little infiltration because they’re “invisible” to T cells. Prostate cancer is such a cold tumor and so far, the results of administering a single ICI drug targeted to a single type of checkpoint protein (monotherapy) have been disappointing when used to treat metastatic castration-resistant prostate cancer (mCRPC). Sharma, et al. (2020) write, “The lack of benefit in unselected mCRPC is likely due to the immunologically ‘cold’ nature of the tumor, with relatively few tumor-infiltrating T cells in most men.”[i]

However, 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. This immunotherapy combination has already been shown to improve overall survival in cases of metastasized melanoma, certain lung cancers and kidney cancer.

The mCRPC study included 90 patients divided into 2 cohorts: 1) those with no prior chemotherapy, and 2) those who had chemotherapy. All patients were on androgen deprivation and continued it during the study. The authors reported an “objective response rate of 25% in cohort 1 and 10% in cohort 2. A total of 2 complete responses were observed in each cohort, and partial responses were seen in 6 patients in cohort 1 and 1 patient in cohort 2. … Additionally, 13 patients achieved stable disease in cohort 1 and 11 patients in cohort 2.”[ii] However, there were adverse side effects experienced by 42-53% of study patients, so not all patients completed all doses. Modifications in dose will be needed for future studies.

The Sharma team’s study added to the growing body of data on combination immunotherapy drugs for metastatic prostate cancer. Another benefit of their work is the identification of biomarkers that may indicate which patients are most likely to benefit from the nivolumab/ipilimumab combination. As research goes forward, immunotherapy remains an exciting and promising direction for treating metastatic cancer.

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] 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.
[ii] Goodman, Alice. “Nivolumab Combined With Ipilimumab Shows Activity in Prostate Cancer Subsets.” The ASCO Post, Apr. 10, 2019.

About Dr. Dan Sperling

Dan Sperling, MD, DABR, is a board certified radiologist who is globally recognized as a leader in multiparametric MRI for the detection and diagnosis of a range of disease conditions. As Medical Director of the Sperling Prostate Center, Sperling Medical Group and Sperling Neurosurgery Associates, he and his team are on the leading edge of significant change in medical practice. He is the co-author of the new patient book Redefining Prostate Cancer, and is a contributing author on over 25 published studies. For more information, contact the Sperling Prostate Center.

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