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Why has checkpoint immunotherapy been ineffective in treating prostate cancer?
A PCF-funded study by Dr. Padmanee Sharma unlocks the mystery and opens the door for new treatments and a new clinical trial.

Checkpoint immunotherapy, the relatively new type of cancer treatment making headlines for being able to seemingly cure some patients with melanoma and other cancers, has been notoriously ineffective in prostate cancer.  At the 2017 American Association for Cancer Research (AACR) Annual Meeting, Dr. Padmanee Sharma presented the discovery of at least one reason why — several resistance molecules get turned on by prostate tumors during treatment with checkpoint immunotherapy and block the efficacy of the therapy.   Targeting these resistance molecules may be the key to getting checkpoint immunotherapy to work in prostate cancer.

T cells are a major part of our bodies’ natural pathogen-defense force and patrol the body constantly, looking for any signs of danger, including invading pathogens and cancer.  Each T cell born is genetically unique, having a different “sworn enemy”– a never-before-seen protein fragment (“antigen”) that if encountered, could only be the product of a foreign invader like a pathogen, or a really messed-up cell, like cancer.  A T cell that meets up with a cell displaying its “sworn enemy” antigen becomes activated, and transforms from a passive surveillance cell to a fully-loaded executioner, killing the offending cell and multiplying many times over, to unleash an army of T cells targeting the enemy.

However, what happens when the battle is over and the invading enemy is defeated?  If not deactivated, these trigger-happy killer T cells could accidentally start taking out innocent targets in the body, causing autoimmunity.  Enter immune “checkpoint” molecules, which are like tuning devices on T cells, dialing down their activity from red alert, to yellow, blue, or green, or even putting them into a state of hibernation, so that a coalition of sleeper T cells can be retained and reactivated, should that particular enemy ever try to invade again.  Unfortunately, tumors may have become too large to be eliminated completely by the T cells and the T cells control systems kick in and send the anti-tumor killer T cells into hibernation far before their battle is over.

Padmanee Sharma, MD, PhD

Dr. Sharma, a PCF-funded physician-scientist and Professor at The University of Texas MD Anderson Cancer Center, is one of the first scientists to study the idea that targeting these immune checkpoints could reawaken hibernating tumor-targeting T cells and send them back into battle.  Thus far, therapies that target the T cell checkpoint molecules CTLA-4 (ipilimumab) and PD1 (nivolumab, pembrolizumab), as well as the PD1-partner PD-L1 (atezolizumab, avelumab), have demonstrated remarkable, cure-like activity in some patients with melanoma, bladder cancer, lung cancer, and several other cancer types – but not prostate cancer.  In these lucky patients, checkpoint immunotherapy reawakens the T cells who have declared the tumor cells as their sworn enemy, and the T cells kill off tumor cells, sending patients into tumor-free states that have lasted from months to decades.

Dr. Sharma wanted to figure out why checkpoint immunotherapy hasn’t worked in prostate cancer.  Specifically, she questioned whether additional checkpoint pathways were being turned on in prostate tumors that were preventing the effects of ipilimumab, which blocks a key checkpoint pathway, CTLA-4.   To study what goes on in prostate tumors after treatment with ipilimumab, Sharma and team examined untreated and ipilimumab-treated tumor samples from patients on clinical trials.

“We were able to actually convert this “cold” prostate tumor microenvironment to a “hot” tumor microenvironment, meaning that you can see in the pre-treatment samples very little, in terms of immune infiltration, but [in ipilimumab-treated samples], you can see lots more immune infiltration in terms of macrophages and T cells into the tumor tissue,” said Sharma.

Dr. Sharma found that ipilimumab treatment increased the numbers of T cells in prostate tumors, but none of the patients had complete tumor regressions.  This suggested that despite being able to enter tumors, these T cells were still underperforming.  When Sharma investigated whether this was because prostate tumors had manipulated T cells to express other immune checkpoint pathways so that they couldn’t be fully reactivated by ipilimumab, she found that her hunch was correct – two resistance pathways were highly amped up: PD-L1 and VISTA.  Both of these checkpoint pathways are known to shut-down T cells, whether they are expressed by the T cells themselves, or by other cells that interact with T cells.

Macrophages are an immune cell type that act as a surveillance partner to T cells, gobbling up dying cells and debris and showing the digested pieces to T cells, so that they may more easily find their “sworn enemy,” and become activated killers.  However, if macrophages are covered in checkpoint molecules such as PD-L1 (which triggers PD1 expressed by T cells), they will instead shut T cells down. In Sharma’s study, PD-L1 and VISTA were also highly turned up in macrophages in prostate tumors following treatment with ipilimumab.  When Sharma compared prostate tumors to melanoma, which tend to be more responsive to ipilimumab, she found that T cells and macrophages in melanomas had upregulated PD-L1 and VISTA after treatment with ipilimumab, but not to the same degree as the prostate tumors – and likely not to the degree that it takes to render ipilimumab inactive.

Sharma also looked at gene expression patterns and found that macrophages from prostate tumors had a more T cell-hostile personality compared with those from melanoma.  This is because macrophages can have a bi-polar personality – one type activates T cells, while another type plays a role in wound-healing and shut T cells down.  Apparently, macrophages are more able to see melanoma as an enemy, while they view prostate tumors as wounds that need to be healed (and not attacked by T cells).

Together, Sharma’s findings suggest that even if one checkpoint pathway such as CTLA-4 is therapeutically targeted, prostate tumors are able to manipulate immune cells to turn on other checkpoint pathways, keeping tumor-killing T cells turned off.  This also suggests that co-treatment with therapies targeting these resistance pathways may be a strategy for getting checkpoint immunotherapy to work in prostate cancer.

Based on these findings, Sharma is conducting new checkpoint immunotherapy clinical trials at MD Anderson Cancer Center.  An ongoing phase II trial is testing the combination of ipilimumab plus nivolumab (anti-PD1) in metastatic castration-resistant prostate cancer patients.  A VISTA-targeting therapy is currently in phase I clinical trials, and if shown to be safe, will likely be tested in combination with other checkpoint immunotherapies in prostate cancer.

At MD Anderson Cancer Center, Sharma leads a massive program evaluating patient samples from over 100 immunotherapy clinical trials, and has identified several other immunotherapy resistance mechanisms in various tumors types, including upregulation of other checkpoint pathways, as well as tumor cell loss of immune-recognition genes, which enable them to hide-in-plain-sight from T cells.  Some of these resistance mechanisms may also be active in prostate cancer.

“These data indicate that CTLA-4 and PD-1/PD-L1 are just the tip of the iceberg and many other immune modulating pathways play a role in regulating anti-tumor immune responses, which require that we conduct in-depth studies, both from a basic science perspective and translational perspective with human clinical trials, in order to define effective rational combination strategies to successfully treat patients,” said Sharma.  “Our work is far from over but we’re heading in the right direction and some patients are reaping the rewards. We need a team effort, as presented in this study, with academic organizations, pharmaceutical companies, government agencies and philanthropic partners so as to make greater strides and provide benefit for even more patients. ”

The 2017 AACR Annual Meeting was held from April 1-5, 2017, in Washington, D.C.  This PCF-funded study by Sharma and team has also recently been published in the highly regarded scientific journal, Nature Medicine.

Andrea Miyahira
Dr. Andrea Miyahira has a PhD in cancer immunology, and is Director of Research at the Prostate Cancer Foundation.