An unexpected success for cancer immunotherapy treating prostate cancer

In 2009, at the age of 75, Ralph Stuart was diagnosed with prostate cancer, the second leading cause of cancer death in American men. Because of his age, and a previous diagnosis of Alzheimer’s disease, his doctors “just kind of left it alone,” according to Stuart’s wife, Austine.

That could be a reasonable approach for an older man with a slow-growing disease. Mr. Stuart’s cancer didn’t immediately progress. It was there, but did not seem to be growing much, if at all. By the time he reached his early 80s, however, it gradually became clear the cancer was progressing.

“To make a long story short,” Mrs. Stuart said, “we went looking for a new physician.” The Stuarts interviewed several prostate cancer experts. They chose Akash Patnaik, MD, PhD, a national authority on prostate cancer and a faculty member at the University of Chicago Medicine.

By the time they found Patnaik the cancer had become difficult to deal with. It had spread to additional sites and was now stage 4.

A revolutionary approach

Standard therapies were no longer an option. So Patnaik spoke with the family about enrolling Stuart in a clinical trial based on a new and promising — some would say revolutionary — approach to treating cancer.

Unlike many forms of cancer chemotherapy, which are toxic to cancer cells and can be harmful to healthy cells, immunotherapy helps the patient’s own immune system get rid of tumors.

“Instead of attacking a tumor directly, these drugs turn on patients’ T cells, one of the immune system’s most formidable anti-cancer weapons, to unleash an attack against the cancer,” Patnaik said. The drugs, known as checkpoint inhibitors, help T cells invade the tumor environment, find cancer cells and kill them.

For Stuart, Patnaik suggested treatment built around immunotherapy. He had recently launched a phase 2 clinical trial, known as CheckMate 650, for men with metastatic prostate cancer that is resistant to hormonal therapy. The study combined two immune system-boosting drugs: ipilimumab (marketed as Yervoy ®) and nivolumab (Opdivo ®). The trial is currently open at five institutions in the United States and four in France.

These drugs, both monoclonal antibodies, work in slightly different ways. Ipilimumab blocks a protein called cytotoxic T-lymphocyte antigen 4 (CTLA-4) that sits on the surface of T cells and prevents them from doing their job, attacking cancerous cells. When ipilimumab, the first known immune checkpoint inhibitor, attaches itself to CTLA-4 on T cells, it can help those cells get back in action, destroying cancer cells. It also inhibits activity of other cells, such as regulatory T cells, that further hinder an immune response.

With ongoing research efforts linking an individual cancer’s genetic make-up with responsiveness to immunotherapy, we are at the cusp of this revolution.

Nivolumab blocks a different pathway, known as PD-1. Tumors exploit the pathway to protect themselves from T cells. PD-1 is an immune checkpoint that shuts down T cell-mediated attack on tumors. PD-1 inhibitors, such as nivolumab, can restore the ability of T cells to penetrate and attack tumors.

“In the last five years or so, this checkpoint inhibitor approach has led to a long series of conquests,” Patnaik said. Ipilimumab was first tested in melanoma, a skin cancer, where it worked well for a small but significant group of patients, quickly becoming a standard of care. The combination of ipilimumab with nivolumab produced higher response rates than either agent alone, but with greater toxicity.

These drugs have since gained approval for use in advanced kidney cancer, metastatic lung cancer and many others. However, these medicines still do not work in large subsets of patients with different types of cancer. “In particular, the responses to checkpoint inhibitors in advanced prostate cancer have been few and far between,” Patnaik said.

The main problem facing the Stuarts was that immunotherapy had not, at this point, demonstrated much success in the treatment of end-stage prostate cancer. Results from previous trials suggested that standard immunotherapy may not work for this disease. When tested separately as prostate cancer treatments, both nivolumab and ipilimumab fell short.

But when combined, ipilimumab and nivolumab have certain advantages. Ipilimumab helps active T cells infiltrate tumors, but it can trigger increased PD-1 activity, which prevents T cells from mounting the desired anti-tumor response. Nivolumab, however, targets the PD-1 pathway and can potentially enhance the T cell attack on the tumor.

“Multiple local factors, such as the tumor micro-environment, play a central role in this,” explained Patnaik. This is a complex problem, with a tangle of pathways that are unique to each patient, but “we are investigating several targeted, personalized medicine approaches based on the genetic signature of an individual patient’s cancer,” he said. “With ongoing research efforts linking an individual cancer’s genetic make-up with responsiveness to immunotherapy, we are at the cusp of this revolution.”

Reason for optimism

“Using this convergent approach of integrating precision medicine with immunotherapy, we have good reason to be optimistic about future treatment options for end-stage prostate cancer patients,” said Patnaik.

The approach worked for Stuart. “It took more than eight months to get him into the study,” said his wife. “There weren’t any openings, at first, but once he was accepted and started getting the infusions, his cancer began to go down.”

There were four infusions of both drugs, once every few weeks, with a few additional infusions of nivolumab. At one point, the tumors briefly “sized back up again,” she recalled, “but then they started going back down and they kept going that way.”

Stuart’s only treatment-related side effect was a persistent itch. “That bothered him quite a bit,” his wife said. “But they gave him an ointment that seemed to help.”

Once he started responding, his prostate specific antigen (PSA) level — a measure of disease severity — started to plummet. It was high when he first started, “significantly high,” said Mrs. Stuart. But by the time of the last infusion, “it had gone way down,” she said. “Now it’s about 0.04, and it’s staying down.”

Levels less than 0.05 are considered “disease that is below the level of detection,” Patnaik said, suggesting a potential cure for Stuart.

“That’s pretty much the whole story,” Mrs. Stuart said. Then she remembered one more crucial element of their success. “Dr. Patnaik,” she said, “was pleased.”