UCSF physician-scientists and PCF-funded investigators David Oh, M.D., Ph.D., and Larry Fong, M.D., are doing something that would have been unthinkable even a couple years ago: they are aggressively going after hormone-sensitive cancer that has escaped the prostate, as soon as it is diagnosed. Not waiting for it to get worse, but going after it hard and hoping for a cure. Using the best ammunition they’ve got – our smartest, most promising therapies – against cancer while it is more vulnerable, before it can evolve and become even harder to treat. Their strategy: a multi-sided approach aimed at unleashing the body’s most powerful weapon of all: its immune system.
Oh, a PCF Young Investigator, and his mentor, cancer biologist Fong, are at the frontier of a sea change in how we attack advanced prostate cancer. Gone are the bad old days, when treatment for metastatic cancer was more reactive than proactive, and cancer wrote the rules of engagement: when men started androgen deprivation therapy (ADT – usually the drug, Lupron) and with their doctors, anxiously checked the PSA, MRI and bone scans, hoping nothing would change. Then, if cancer progressed, starting chemo (docetaxel) and/or second-line hormonal therapy (androgen receptor blockers such as abiraterone; note: some of these drugs are now given at the same time as ADT, with excellent results). And only then, trying an experimental agent – checkpoint immunotherapy, perhaps.
Checkpoint immunotherapy – so successful in some cancers, such as melanoma and lung cancer – has, so far, only been effective in a minority of men with metastatic prostate cancer.
And yet: in a few men, checkpoint immunotherapy has worked spectacularly well. Oh wants to know why, and with a PCF Challenge Award funded by the Barry Family, he is hoping to find some answers that will help many more men with metastatic prostate cancer. “What are the immune responses that these few men are generating,” says Oh, “and how does this compare to what’s happening with most of the men, who don’t respond?”
Specifically, what mechanisms of the very complex immune system have kicked in? Is it the killer T-cells – immune system warriors, whose job is to kill cancer cells, viruses, and other hostile invaders? One of prostate cancer’s most evil tricks is to cast a sleeping spell on these T-cells – to immobilize them with molecular “checkpoints” – minuscule cups of relaxing chamomile tea, in effect – that cause these T-cells to snooze on the job. There’s nothing wrong with these zoned-out T-cells: they could function perfectly well, if only they could wake up! Checkpoint-inhibiting drugs (when they work) sound the alarm. They play a rousing chorus of “Reveille,” the military bugle wake-up call, and roll those sleepy soldiers out of bed. The alerted T-cells spring into action: they recognize the enemy cells in their midst and attack them – achieving, in some cancers, what seems to be a cure.
Can the immune systems of the men who don’t respond somehow be tweaked? That’s the big hope, if the mystery of the exceptional responders can be cracked; Oh and Fong are studying these patients in an ongoing immunotherapy clinical trial led by Fong, funded by a PCF Challenge Award.
With his Barry-funded PCF award, Oh is studying the T-cell responses in men with newly diagnosed, hormone-sensitive cancer that has escaped the prostate. These men are being treated with a combination of hormonal therapy, external-beam radiation, and checkpoint immunotherapy. Here are some of the things Oh is hoping to find out: Is what’s happening in the prostate tumor environment also happening to T-cells in the blood? Does checkpoint immunotherapy simply activate the T-cells that are already there, or does it also bring new platoons of soldiers to the battlefield?
Oh believes treatment timing may play a critical role in this trial: The earlier the cancer, the lower the burden of disease on the body; also, cancer is more vulnerable sooner rather than later. As cancer grows and evolves, it develops molecular and genetic armor that helps it withstand attack. Oh hopes to get a better window on what’s happening as cancer progresses, as well: he hopes to find out, “were these immune responses there to begin with? Or were they newly generated by these therapies we are trying?”
Does Radiation Help Jump-Start the Immune System?
If the cancer has already left the prostate, what use is radiation? It’s all about jump-starting the immune system: The radiation being administered in this study isn’t the same as the multi-day course of treatment commonly used to kill a tumor that’s localized to the prostate area. Instead, this is a “priming dose,” as Oh puts it, and the purpose is “to see whether we are able to generate a heightened immune response. The backbone of the trial is hormonal therapy (Lupron and abiraterone plus prednisone), and then we’re layering the radiotherapy and multiple modalities of immunotherapy to activate the anti-tumor immune response.”
The immunotherapy strategy here is twofold: Participants will receive checkpoint immunotherapy – pembrolizumab (Keytruda), a PD-1 inhibitor that has been FDA-approved to treat other cancers. But just in case the pembrolizumab doesn’t pack a powerful-enough punch on its own, Oh is adding an immunotherapy version of brass knuckles: a second line of attack, a compound called SD-101. It’s an innovative approach, one that has shown success in other cancers. Promising results using both SD-101 and pembrolizumab were recently reported in a clinical trial of patients with advanced head and neck cancer: a third of patients developed tumor-fighting immune responses. Pembrolizumab goes into the bloodstream, but SD-101 is injected directly into the tumor; it is designed to stimulate the immune system by “turning on antigen-presenting cells,” Oh explains. Antigens are foreign or abnormal proteins that cause an immune reaction in the body – the production of antibodies, for instance. Antigen-presenting cells basically shine a spotlight on these antigens for the immune system to see – think of soldiers pointing lasers at the missile target. So the idea here is to tell the immune system two things: “Hey, wake up!” And, “Get these bad guys!”
Interestingly, after nine months in the study, the men will go off their hormonal therapy, says Oh, “to see if the immunotherapy made a difference in terms of PSA and progression.” Treating advanced prostate cancer earlier and more aggressively is already paying off. For example, giving ADT together with abiraterone or docetaxel has been shown to “dramatically improve how long patients survive. What we’re really trying to do here is see whether giving immunotherapy intensively with radiation early on can bend that curve even further, eventually moving towards potentially even cure. We would really like to just knock back advanced cancer as early as we can.”
Oh credits his Young Investigator Award from the Prostate Cancer Foundation, funded by the generosity of the Barry Family, for helping to make this out-of-the-box research possible. “I can wholeheartedly say that this award from the PCF is not only a vote of confidence, it’s critical support that came at exactly the right time for me to get this novel research program off the ground.”
Oh and Fong are actively recruiting patients for this first-in-field trial: they’re looking for men who are newly diagnosed with metastatic hormone-sensitive prostate cancer, who have just started Lupron, and who want to go after their cancer as aggressively as science warrants. “We have to start these immunotherapies within three months of initiating Lupron” (for this study). This study is being run by the UCSF Cancer Immunotherapy Clinic: Click here or call: (415) 353-2051. “We would love to hear from interested patients,” says Oh.
