Protein biomarker may predict immunotherapy response in metastatic melanoma

Issue: October 25, 2015

Patients with metastatic melanoma appeared more likely to respond to the anti–PD-1 therapy pembrolizumab when they had a higher frequency of T cells positive for proteins CD8, PD-1 and BIM, according to study results presented at the American Association for Cancer Research International Cancer Immunotherapy Conference.

Thus, measuring BIM protein levels in tumor-reactive PD-1– and CD8-positive T cells may select patients likely to benefit from the therapy and provide a new and noninvasive way to monitor response to anti–PD-1 blockade in this patient population, the researchers reported.

Roxana Dronca

“The discovery of biomarkers of sensitivity are vital not only for informing clinical decisions, but also to help identify which patients with melanoma, and possibly other malignancies, who are most likely to benefit from PD-1 blockade,” Roxana Dronca, MD, a hematologist at Mayo Clinic in Rochester, Minnesota, said in a press release. “This will allow us to expose fewer patients to inadequate treatments and their associated toxicities and costs.”

Dronca and colleagues found that the pro-apoptosis molecule BIM up-regulates at protein levels following PD-1 engagement with B7-H1 (PD-L1) and that higher BIM expression leads to more T cell apoptosis following PD-1/PD-L1 engagement.

Further, the establishment of soluble B7-H1 (sB7H1) in the sera of patients with cancer showed that the protein is biologically active and capable of triggering signals in targeted T cells due to the retention of PD-1 binding domains.

The researchers, thus, hypothesized that the upregulation of BIM in tumor-reactive CD8 T cells reflected the degree of PD-1 engagement with PD-L1 and may predict the level of reversibility of PD-1–positive, CD8-positive tumor-reactive T cells to PD-1 blockade. Further, they believed that consistently elevated BIM levels in serially measured peripheral blood samples of patients with metastatic melanoma undergoing treatment with anti–PD-1 blockade are associated with treatment resistance, whereas decreasing BIM levels may identify patients sensitive to therapy.

The researchers collected peripheral blood samples from patients with metastatic melanoma receiving treatment with pembrolizumab (Keytruda, Merck) at baseline and at radiographic tumor evaluation. The patients received 2 mg/kg of pembrolizumab every 3 weeks.

The researchers had access to baseline samples from 38 patients, of whom 18 had serial samples available. They observed that patients who achieved objective responses following four treatment cycles of anti–PD-1 therapy had a higher frequency of BIM-positive and PD-1–positive CD8 T cells at baseline than patients with radiographic progression (51.5% vs. 36.5%; P = .0068).

Further, BIM-positive and PD-1–positive CD8 T cells decreased significantly after the first 3 months of treatment among patients responding to treatment (P = .0098).

Patients who experienced clinical benefit after four treatment cycles had higher soluble PD-L1 levels at baseline (2.1 vs. 1.1 ng/mL).

Study limitations include the small number of patients and that only one anti–PD-1 therapy was evaluated.

Researchers are currently validating these results in a larger, prospective cohort of patients with metastatic melanoma and lung cancer.

“If I know that a patient has a very high likelihood of responding to anti–PD-1 therapy, I am going to be more inclined to recommend that treatment and feel better about the choice,” Dronca said. – by Cameron Kelsall

Reference:

Dronca R, et al. Abstract A007. Presented at: AACR International Cancer Immunotherapy Conference; September 16-19, 2015; New York.

Disclosure: The study was funded by the NIH and the Cancer Research Institute. Most patients were treated on the pembrolizumab Expanded Access Program, of which Merck is the sponsor. One other study researcher is the inventor of technology related to this research.