Ipilimumab Plus Local Treatment Improves Malignant Melanoma Survival

Ipilimumab, a monoclonal antibody, works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.

Marketed under the name name Yervoy, the immunotherapy has revolutionized the treatment of malignant melanoma, a very aggressive type of skin cancer, according to Sebastian Theurich, MD, lecturer and physician-scientist in the Center of Integrated Oncology (CIO) at the University Hospital of Cologne.

About 20 percent of patients who receive ipilimumab achieve durable responses, which is a major advance compared with historic outcomes, but physician-scientists are looking for ways to increase the percentage of patients who gain long-term benefit from this immunotherapy, he added.

Currently, local peripheral treatments are not used to try and cure patients with malignant melanoma; rather, they are used to provide relief from symptoms caused by the melanoma tumors, explained Theurich.

Theurich and his colleagues analyzed data from 127 patients with malignant melanoma who were treated consecutively at four cancer centers in Germany and Switzerland. Eighty-two patients received ipilimumab only and 45 received ipilimumab and local peripheral treatment to relieve tumor-related symptoms.

Median overall survival for patients receiving ipilimumab and local peripheral treatment was 93 weeks, compared with 42 weeks for those receiving only ipilimumab.

Ipilimumab Plus Local Treatments Doubled Survival Chances

After excluding patients with brain metastases from the analysis, because these patients were not distributed equally among the two treatment groups, the median overall survival benefit for those receiving ipilimumab and local peripheral treatment remained, 117 weeks compared with 46 weeks for those receiving only ipilimumab.

“We found that adding local peripheral treatments, including external radiotherapy, electrochemotherapy, or internal radiotherapy, to systemic ipilimumab treatment doubled survival chances in our patient cohort and did not increase immune-related side effects,” said Theurich. “Importantly, this survival advantage seemed to overcome even traditional risk factors of poor outcomes. This suggests that this combination could be an option for all patients with malignant melanoma, and this is being tested in ongoing prospective clinical trials.

Our results are concordant with those previously reported for 29 patients treated in the United States with ipilimumab and local radiotherapy,” continued Theurich. “Having data from different parts of the world improves the validity of the results, especially if you deal with retrospective analyses. Moreover, all our patients were treated with the same dose of ipilimumab, whereas those in the previous study received varying doses because they were being treated in a dose- escalation clinical trial.”

Cytotoxic T lymphocytes (CTLs) can recognize and destroy cancer cells. However, an inhibitory mechanism interrupts this destruction. Ipilimumab turns off this inhibitory mechanism and allows CTLs to function.

Cancer cells produce antigens, which the immune system can use to identify them. These antigens are recognized by dendritic cells that present the antigens to cytotoxic T lymphocytes (CTLs) in the lymph nodes.

The CTLs recognize the cancer cells by those antigens and destroy them. However, along with the antigens, the dendritic cells present an inhibitory signal. That signal binds to a receptor, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), on the CTL and turns off the cytotoxic reaction. This allows the cancer cells to survive.

Ipilimumab binds to CTLA-4, blocking the inhibitory signal, which allows the CTLs to destroy the cancer cells.

“We were also able to begin to investigate the potential immunologic mechanism underlying the benefit of adding local peripheral treatment to ipilimumab,” added Theurich. “It seems that local peripheral treatments activate immune cells, which are then able to attack tumors at sites away from the local treatment site. However, we are investigating this further in prospective studies.”

According to Theurich, the main limitations of the study are that the data were not collected prospectively and in a randomized fashion, but the validity of the results is now being tested in prospective clinical trials.

Sebastian Theurich, et al
Local Tumor Treatment in Combination with Systemic Ipilimumab Immunotherapy Prolongs Overall Survival in Patients with Advanced Malignant Melanoma
Cancer Immunology Research, July 2016 DOI: 10.1158/2326-6066.CIR-15-0156

Image: Normal spleen showing B cells and T cells. Peter Lane and Fiona McConnell, Wellcome Images