New Cutting-Edge Combination Immunotherapy Clinical Trial Available

Collaborative-therapy: White American pelicans wintering in Florida Everglades; photo: BJ Gabrielsen;

Having advanced prostate cancer albeit at an early stage, I, in discussions with my Florida oncologist, had decided to pursue a course of immunotherapy first before using drugs that kill the cancer cells directly. I remembered writing previous website blogs in which several prominent oncologists and urologists recommended treating the cancer with immunotherapies first. I recently completed the three treatments comprising PROVENGE (sipuleucel-T) and recently posted a blog about the entire experience.

Meanwhile, I still keep in touch with former friends and colleagues at the National Cancer Institute (NCI) – National Institutes of Health (NIH) in Frederick and Bethesda, MD. Within a day or two of completing PROVENGE®, I received an email from an NCI friend describing a new NCI clinical trial in Bethesda, MD to determine the safety and efficacy of PROSTVAC (an NCI-discovered vaccine), coupled with two antibody therapies, nivolumab (OPDIVO®) and ipilimumab (Yervoy®), already approved for treating other cancers. The trial is recruiting two kinds of patients; men with localized prostate cancer who have elected radical prostatectomy and men like myself with advanced disease progressing on hormonal therapy. PROSTVAC is a cancer vaccine in that helps the immune system recognize and attack cancer cells, while ipilimumab (Yervoy) and nivolumab (OPDIVO) block certain mechanisms and signals within the body that prevent the immune system from attacking cancer cells. For specific trial information, see this link.

PROSTVAC is in late stage Phase III development (Prospect trial) for metastatic, hormone-resistant prostate cancer patients who are either asymptomatic or minimally symptomatic. It is a therapeutic pox virus cancer vaccine directed at PSA-producing cells. It is administered with or without GM-CSF (granulocyte macrophage colony-stimulating factor, a protein secreted by immune system cells that functions as a white blood cell growth factor. PROSTVAC immunotherapy (administered by s.c. injections) is intended to trigger a specific and targeted immune response against prostate cancer cells and tissue by using virus-based immunotherapies that carry the tumor-associated antigen PSA (prostate-specific antigen) along with 3 natural human immune-enhancing costimulatory molecules collectively designated as TRICOM (LFA-3, ICAM-1, and B7.1 When PSA-TRICOM is presented to the immune system in PROSTVAC, cytotoxic T lymphocytes (CTLs) are generated that may recognize and kill PSA-expressing cancer cells.

Nivolumab (OPDIVO®), is used as a first line treatment for inoperable or metastatic melanoma in combination with ipilumumab and as a second-line treatment for squamous non-small cell lung tumors and as a second-line treatment for renal cell carcinoma. It is a human IgG4 anti-PD-1 monoclonal antibody. Nivolumab works as a checkpoint inhibitor, blocking a signal that would have prevented activated T-cells from attacking the cancer, thus allowing the immune system to clear the cancer. PD-1 is a protein on the surface of activated T cells. If another molecule, called programmed cell death 1 ligand 1  or programmed cell death 1 ligand 2 (PD-L1 or PD-L2), binds to PD-1, the T cell becomes inactive. This is one way that the body regulates the immune system, to avoid an overreaction. Many cancer cells make PD-L1, which inhibits T cells from attacking the tumor. Thus, nivolumab blocks PD-L1 from binding to PD-1, allowing the T cell to work.

Ipilimumab (also known as MDX-101 and MDX-010 and marketed as Yervoy) is a human monoclonal antibody developed by Bristol-Myers-Squibb and approved for the treatment of melanoma. As a single agent, it failed in clinical trials in metastatic, hormone-refractory prostate cancer. However it may work better in combination therapy. It works by activating a patient’s own immune system by causing cytotoxic T-lymphocytes to potentially combat tumor cells. Specifically, it targets cytotoxic T-lymphocyte antigen-4 (CTLA-4), preventing the antigen from interacting with its ligands and thereby activating the patient’s own immune system by causing these T-cells to potentially combat tumor cells. More simply, Yervoy blocks a switch that turns off an anti-tumor cellular response. Therefore, Yervoy is an agent that “blocks a blocker” thereby aiding the immune system to fight the tumor. The bad news however is that prostate cancer responds to Yervoy by increasing the expression of two other immune checkpoint molecules, PD-L1 and VISTA. And both send a “don’t-eat-me signal” to immune cells. That reaction is why Yervoy, by itself, offers little patient benefit.

 

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