Results from an early-stage clinical trial, and data from a mouse tumor model suggests that adding a second immune checkpoint inhibitor antibody to a combination therapy of irradiation plus anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) antibody immunotherapy could result in more tumor shrinkage.
Results from an early-stage clinical trial, and data from a mouse tumor model suggests that adding a second immune checkpoint inhibitor antibody to a combination therapy of irradiation plus anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) antibody immunotherapy could result in more tumor shrinkage and higher response rates compared to treatment with the CTLA-4 antibody plus radiotherapy.
The results were published online March 2015 in Nature.
In a phase I clinical study of escalating fractions of stereotactic body radiotherapy combined with the immune checkpoint inhibitor ipilimumab in metastatic melanoma, 18% of 22 patients had a partial response, 18% had stable disease, but the majority of patients (64%) had progressive disease and did not respond to treatment. The radiotherapy was administered to a single metastatic lesion. Of the patients who did not respond--but were evaluated by positron emission tomography (PET)--none had progressive disease in the irradiated lesion. After a median follow up of 21.3 months, the median overall survival was 10.7 months. The median progression-free survival was 3.8 months after a median follow up of 18.4 months.
Both treatment-naive and previously treated metastatic patients were enrolled on the study.
Andy J. Minn, MD, PhD, assistant professor of radiation oncology at the University of Pennsylvania in Philadelphia, and colleagues then examined responses of the combination treatment in a mouse melanoma model. Concurrent radiotherapy plus anti-CTLA-4 therapy and radiotherapy followed by the immunotherapy yielded similar results. More mice receiving the combination responded to treatment compared to those who only received anti-CTLA-4 therapy, but overall, only 17% of mice responded to the combination, similar to the rate observed in the human clinical trial.
Analysis of the unirradiated mouse tumors treated with the combination therapy showed those tumors unresponsive to the combined treatment regimen. They were not intrinsically resistant to radiotherapy, but had high levels of PD-L1, the ligand for anti-programmed cell death 1 (PD-1) receptor. The PD-L1 gene was among the most highly upregulated genes in these resistant tumors.
The results, according to the authors, suggest that targeting both the CTLA-4 and PD-1 pathways along with radiation therapy may result in the best tumor response in patients with melanoma.
Irradiated tumor cells are believed to release antigens from the killed tumor cells, and in turn, the immune system launches a more robust attack on the remaining tumors in the body.
The combination of anti-CTLA-4 and PD-1 antibodies has already been tested in metastatic melanoma patients in an early-phase clinical trial, and a phase III clinical trial NCT01844505 is currently testing the efficacy of this dual immunotherapy combination in metastatic melanoma patients.
"These new immunotherapies are potent treatment options that have generated a lot of excitement in the past few years, but we know that many patients fail to respond, underscoring the need to further improve the drugs' abilities," said Minn in a statement. "Anecdotally, we know that combining radiation with immunotherapy can be powerful, so we were very motivated to move forward with both a clinical trial to demonstrate that this combination is a promising route to pursue and with laboratory studies to understand why response happens and why it does not."
The CTLA-4 antibody, ipilimumab (Yervoy, BMS), and two anti-PD-1 antibodies, pembrolizumab (Keytruda, Merck) and nivolumab (Opdivo, BMS), are currently approved by the US Food and Drug Administration (FDA) for treatment of advanced melanoma.
Adding an anti-PD-1 antibody therapy on top of an anti-CTLA antibody and radiation therapy resulted in an 80% complete response rate. This and analyses of T-cell responses in treated and untreated mice suggest that the PD-1 pathway is the dominant resistance mechanism in these tumors.