A multi-institutional\u00a0study\u00a0led by\u00a0Mayo Clinic\u00a0and published in Cell Reports Medicine reports that pairing a next-generation\u00a0immunotherapy with standard hormone therapy before surgery may help overcome a long-standing barrier in early-stage\u00a0prostate cancer\u00a0treatment.\u00a0<\/p>\n
Immunotherapy<\/a> has been\u00a0generally ineffective\u00a0for prostate cancer\u00a0because the tumors are considered immunologically\u00a0“cold,”\u00a0meaning they do not attract enough\u00a0immune cells to mount a strong\u00a0attack.\u00a0Hormone therapy\u00a0commonly used\u00a0for prostate cancer, called\u00a0androgen deprivation therapy\u00a0(ADT), can temporarily make tumors more responsive by drawing immune cells into\u00a0the cancer. But that benefit is short-lived: the treatment also increases levels of\u00a0regulatory T cells<\/a>\u00a0(Tregs),\u00a0which act as brakes on the immune system and blunt its anti-cancer effects.\u00a0<\/p>\n In\u00a0the first-in-human, early-phase randomized trial, researchers\u00a0tested whether adding a next-generation immunotherapy to hormone therapy before surgery could counteract\u00a0that\u00a0immune-suppression.\u00a0The combination reduced\u00a0Treg\u00a0levels inside prostate tumors. Patients whose tumors showed the greatest reductions were more likely to remain cancer-free during follow-up.\u00a0<\/p>\n
<\/p>\n This trial provided a unique opportunity to test a new immunotherapy drug in patients who have localized prostate cancer. They\u00a0don’t\u00a0have metastatic disease yet, but they are at\u00a0high risk\u00a0of reaching that stage. These are patients who\u00a0possibly can\u00a0be cured.”<\/p>\n
Casey Ager, Ph.D., cancer immunology researcher at Mayo Clinic and first author of the study<\/p>\n
<\/p>\n ADT\u00a0starves cancer cells of male hormones like testosterone, which they use as fuel.\u00a0Desirable immune effects of ADT are\u00a0cut short by\u00a0Tregs, which\u00a0normally\u00a0keep the immune system from overreacting to substances and attacking the body. In the case of prostate cancer, Dr. Ager says they limit immunotherapy effectiveness.\u00a0<\/p>\n “Hormonal therapy brings\u00a0many types of\u00a0immune cells in that can attack and kill the tumor.\u00a0But\u00a0this comes with\u00a0an equal and opposite reaction where\u00a0Tregs\u00a0also\u00a0come in and suppress the immune system, allowing the tumor to\u00a0ultimately progress,” says Dr. Ager. He and a team of Mayo Clinic researchers collaborated with colleagues at Columbia University Irving Medical Center,\u00a0Memorial Sloan Kettering Cancer\u00a0Center\u00a0and Bristol Myers Squibb\u00a0to 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.\u00a0<\/p>\n 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\u00a0Tregs\u00a0inside tumors compared with hormone therapy alone.\u00a0<\/p>\n “Selective\u00a0Treg\u00a0depletion in\u00a0tumors\u00a0has been a\u00a0long-sought\u00a0goal\u00a0of the\u00a0oncology\u00a0field for\u00a0some time.\u00a0We had the opportunity to test a drug\u00a0that’s\u00a0been engineered to better deplete\u00a0Tregs\u00a0than the drugs we previously had. It targets CTLA-4, which is highly expressed on\u00a0Tregs, particularly within tumors,” says Dr. Ager.\u00a0<\/p>\n The findings provide the first clinical evidence that an engineered anti-CTLA-4 therapy can deplete regulatory T cells within prostate tumors.\u00a0<\/p>\n Because the treatment was given before surgery, researchers\u00a0also\u00a0were\u00a0able to analyze\u00a0large\u00a0sections of the surgically removed\u00a0prostate tumors\u00a0following\u00a0treatment, rather than\u00a0being limited to minuscule tissue biopsies,\u00a0which harbor few immune cells to study. Dr. Ager says this rare opportunity allowed them to use\u00a0multiple\u00a0advanced technologies\u00a0in parallel\u00a0to\u00a0map at unprecedented depth\u00a0how\u00a0this novel immunotherapy treatment affected\u00a0the complex immune milieu of prostate cancer,\u00a0down to the level of individual immune cells. This comprehensive look inside the tumor provided new clues about\u00a0how the therapy affects immune cells,\u00a0which patients may benefit most,\u00a0and\u00a0identified\u00a0potential biomarkers to guide future trials.\u00a0<\/p>\n “These findings\u00a0establish the clinical feasibility of immunotherapy in\u00a0early-stage prostate cancer, and\u00a0they\u00a0provide an invaluable dataset from which to\u00a0develop\u00a0and deploy\u00a0new,\u00a0evidence-based immunotherapy\u00a0approaches\u00a0in these patients,”\u00a0says\u00a0Dr. Ager.\u00a0<\/p>\n
<\/p>\n 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\u00a0less effective,\u00a0more intensive\u00a0and can significantly affect quality of life.”<\/p>\n
Casey Ager, Ph.D.<\/p>\n
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