A multi-institutional study led by Mayo Clinic and published in Cell Reports Medicine reports that pairing a next-generation immunotherapy with standard hormone therapy before surgery may help overcome a long-standing barrier in early-stage prostate cancer treatment.
Immunotherapy has been generally ineffective for prostate cancer because the tumors are considered immunologically "cold," meaning they do not attract enough immune cells to mount a strong attack. Hormone therapy commonly used for prostate cancer, called androgen deprivation therapy (ADT), can temporarily make tumors more responsive by drawing immune cells into the cancer. But that benefit is short-lived: the treatment also increases levels of regulatory T cells (Tregs), which act as brakes on the immune system and blunt its anti-cancer effects.
In the first-in-human, early-phase randomized trial, researchers tested whether adding a next-generation immunotherapy to hormone therapy before surgery could counteract that immune-suppression. The combination reduced Treg levels inside prostate tumors. Patients whose tumors showed the greatest reductions were more likely to remain cancer-free during follow-up.
"This trial provided a unique opportunity to test a new immunotherapy drug in patients who have localized prostate cancer. They don't have metastatic disease yet, but they are at high risk of reaching that stage. These are patients who possibly can be cured," says Casey Ager, Ph.D., a cancer immunology researcher at Mayo Clinic and first author of the study.
ADT starves cancer cells of male hormones like testosterone, which they use as fuel. Desirable immune effects of ADT are cut short by Tregs, which normally keep the immune system from overreacting to substances and attacking the body. In the case of prostate cancer, Dr. Ager says they limit immunotherapy effectiveness.
"Hormonal therapy brings many types of immune cells in that can attack and kill the tumor. But this comes with an equal and opposite reaction where Tregs also come in and suppress the immune system, allowing the tumor to ultimately progress," says Dr. Ager. He and a team of Mayo Clinic researchers collaborated with colleagues at Columbia University Irving Medical Center, Memorial Sloan Kettering Cancer Center and Bristol Myers Squibb to investigate whether suppressing Tregs could overcome this hurdle by safely releasing the immune system's "brakes" to help it mount a better response against prostate cancer.
The study, which was designed to evaluate safety and biological effects, enrolled 24 men with high-risk, localized prostate cancer and found that adding the investigational Fc-enhanced anti-CTLA-4 antibody BMS-986218 to hormone therapy significantly reduced Tregs inside tumors compared with hormone therapy alone.
"Selective Treg depletion in tumors has been a long-sought goal of the oncology field for some time. We had the opportunity to test a drug that's been engineered to better deplete Tregs than the drugs we previously had. It targets CTLA-4, which is highly expressed on Tregs, particularly within tumors," says Dr. Ager.
The findings provide the first clinical evidence that an engineered anti-CTLA-4 therapy can deplete regulatory T cells within prostate tumors.
Because the treatment was given before surgery, researchers also were able to analyze large sections of the surgically removed prostate tumors following treatment, rather than being limited to minuscule tissue biopsies, which harbor few immune cells to study. Dr. Ager says this rare opportunity allowed them to use multiple advanced technologies in parallel to map at unprecedented depth how this novel immunotherapy treatment affected the complex immune milieu of prostate cancer, down to the level of individual immune cells. This comprehensive look inside the tumor provided new clues about how the therapy affects immune cells, which patients may benefit most, and identified potential biomarkers to guide future trials.
"These findings establish the clinical feasibility of immunotherapy in early-stage prostate cancer, and they provide an invaluable dataset from which to develop and deploy new, evidence-based immunotherapy approaches in these patients," says Dr. Ager.
"If we can make a difference in this early setting, we may be able to prevent patients from progressing to metastatic disease, where treatment becomes less effective, more intensive and can significantly affect quality of life."
Casey ager, Ph.D.
For a complete list of authors, disclosures and funding, review the study.
