Bone Tumors Stop Immunotherapy Working For Prostate Cancer

News

Immunotherapy drugs called immune checkpoint inhibitors have revolutionized therapy for several types of cancer. However, so far these drugs have been mostly ineffective for one of the most common types, prostate cancer.

New work from researchers at MD Anderson Cancer Center in Texas has revealed a major new clue as to why immunotherapy has been largely unsuccessful o far in these patients.

The research published this week in the journal Cell, describes how the metastatic prostate tumors destroy bone, unleashing a protein called TGF-Beta (β), which disrupts tumor-busting immune cells. They show that T-cells which would normally be stimulated to attack the tumor after treatment with immune checkpoint inhibitors are blocked by TGF-β.

Prostate cancer is a common cancer in men and often becomes significantly more serious for the patient after spreading to other sites in the body such as the bones. In 60-70% of men, the cancer spreads to the bones and is then even more difficult to effectively treat.

Previous work by the researchers treated men with prostate cancer with a combination of checkpoint inhibitor therapies targeting PD-1 and CTLA-4, finding that individuals with metastatic bone tumors were resistant to the therapies. The researchers theorized that perhaps, these bone metastases were directly producing something to disrupt this immune response.

“Our studies indicated high Th17 cells, as opposed to high Th1 cells, in bone marrow of patients with metastatic castration-resistant prostate cancer involving the bone,” said Padmanee Sharma, M.D., PhD, professor of genitourinary medical oncology and immunology at MD Anderson and senior author on the paper. “Additional studies demonstrated that these patients also had high TGF-β levels in the bone marrow,” she added.

These Th17 and Th1 cells, types of T-cells, are part of an orchestra of multiple, complex parts which if perfectly conducted can mount an immune response against tumors. TGF-β in this case is a protein called a growth factor, which causes an overproduction of Th17 cells rather than Th1, meaning that the correct cells to trigger an immune response after immune checkpoint therapies are simply not present in the bone tumors.

The researchers next used a mouse model of prostate cancer, giving them a drug to inhibit TGF-β alongside immune checkpoint therapy, finding that this combination stifled growth of bone metastases in the mice.

“We need to be more thoughtful about the immune microenvironment in different areas of metastasis to take into account different immune responses in those microenvironments when we develop treatments,” said Sharma.

To test the hypothesis in humans, the researchers compared TGF-β levels in the bone marrow of healthy donors and prostate cancer patients with and without bone metastases. There was no difference in TGF-β levels between healthy controls and patients without bone metastases, while patients with bone tumors had very high levels of TGF-β in their bones.

The researchers next hope to see whether the approach of inhibiting TGF-β alongside immune checkpoint inhibitors will work in people with prostate cancer with bone metastases and believe that the work may also be applicable to other types of tumor that have spread to the bones.

“We’re working to develop a combination clinical trial of anti-CTLA-4 and anti- TGF-β for metastatic prostate cancer. This mechanism may be at play in other tumor microenvironments and needs to be studied further,” said Sharma.

Products You May Like

Articles You May Like

Bristol-Myers reports positive data on cancer treatment acquired in Celgene deal
Luxembourg expands its space resources vision
Inmarsat delists from stock exchange after buyout 
In New York lab, centuries-old corals hold clues to climate shifts
Where Extreme Weather Caused The Most Fatalities Over The Past Two Decades [Infographic]

Leave a Reply

Your email address will not be published. Required fields are marked *