Immuno-oncology therapies like checkpoint-inhibiting drugs have been largely ineffective in prostate cancer. Researchers at the University of Texas MD Anderson Cancer Center want to change that—and they believe they’ve found a drug combination strategy that could work.
The challenge in treating prostate cancer is that when the tumors spread to bone, they destroy tissue, and in so doing they block the development of immune-boosting T cells that are critical to the success of checkpoint inhibitors. The MD Anderson team scrutinized that process in the hopes of finding a therapy that would prevent it.
They discovered that when tumors destroy bone, massive amounts of a protein called transformational growth factor-beta (TFG-beta) are produced. That prevents helper T cells from transforming into the Th1 CD4 effector cells that would normally prompt the immune system to recognize and attack cancer in response to treatment with checkpoint inhibitors. Combining an anti-TGF-beta drug with a checkpoint inhibitor could be the answer, they suggested in a study published in the journal Cell.
The project was helmed by Padmanee Sharma, M.D., Ph.D., professor of genitourinary medical oncology and immunology at MD Anderson. Sharma had previously led research combining two checkpoint inhibitors—the anti-CTLA-4 drug Yervoy and the anti-PD-1 Opdivo, both from Bristol-Myers Squibb—in men with prostate cancer. The team discovered that the combo was ineffective against prostate tumors that had spread to bone.
To try to understand the problem, the researchers studied tissue samples from prostate cancer patients. They found that men who had been treated with Yervoy had ample Th1 CD4 effector cells in their soft tissues, but virtually none in their bones.
Then they developed mouse models of prostate cancer that had spread, either to the bone or to soft tissues. When they tested the Yervoy-Opdivo combo in those animals, the results mirrored those in people: Mice with soft-tissue metastases did well, while those with bone tumors did not. And again, the researchers found no Th1 effector cells in the bones.
But they did find high levels of TGF-beta in prostate bone metastases. The researchers confirmed that the same phenomenon happens in human prostate cancer by comparing TGF-beta levels in healthy people to those in prostate cancer patients with or without bone metastases. Those with prostate cancer that spread to the bone had higher levels of TGF-beta than the other two groups did.
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The MD Anderson researchers went on to test a combination of an anti-TGF-beta drug with Yervoy and Opdivo in mouse models of prostate cancer that had spread to the bone. That combo halted tumor growth, they reported. Combining Yervoy just with the anti-TGF-beta drug was also effective.
Nearly 80% of men with stage 4 prostate cancer will develop bone metastases, and most men with the disease are at risk of becoming resistant to hormone therapy, developing what’s known as metastatic castration-resistant prostate cancer (mCRPC).
Several immuno-oncology combinations are being tried in prostate cancer. Merck, for example, said earlier this year it would test its blockbuster checkpoint inhibitor Keytruda in three separate combination studies.
Tmunity Therapeutics is taking a different approach to applying immunotherapy to prostate tumors. It is currently running a phase 1 trial of a CAR-T engineered cell therapy to treat mCRPC. The company raised $100 million in a series A funding in 2018 to advance that and other research projects.
The MD Anderson research was partly supported by the Parker Institute for Cancer Immunotherapy, funded by Facebook and Napster billionaire entrepreneur Sean Parker. MD Anderson was one of six cancer centers to receive funding in 2016 to set up Parker Institute outposts, and Sharma was appointed to direct the effort there.
The next step for the MD Anderson team is to design a clinical trial of a CTLA-4 inhibitor combined with an anti-TGF-beta drug in metastatic prostate cancer, Sharma said in a statement.