Immunotherapy is finally getting the cancer clinical and research community excited: A large portion of the presentation and discussion at the Melanoma International Congress, held in Tampa, Florida last week focused on immunotherapy approaches for the treatment of the disease.
With the approval of the anti-CTLA4 antibody, ipilimumab, for metastatic melanoma, which has shown an overall survival of 10.1 months in a second-line trial and is now approved as both a first-line and second-line treatment for the advanced disease, the immunology field is seeing a lot more of the limelight. Academic researchers working on novel immune-harnessing treatments and vaccines are garnering more interest from the pharmaceutical industry for commercialization.
While the enthusiasm for ipilimumab from both patients and clinicians continues, there is a already anticipated excitement about a novel immunotherapy currently in early development, an antibody called anti-PD1. Both CTLA4 and PD-1 are critical immunologic checkpoints that normally function to restrain the immune system. While multiple anti-PD1 agents are in development, the one with the most patient data is BMS-96558 (MDX-1106), a potent, fully human antibody against PD-1. Phase I trials in melanoma patients as well as other cancer patients have shown promising, durable responses.
Dr. Mario Sznol, professor of medicine and co-director of the Melanoma Program at the Yale Medical School, in his presentation said anti-PD1 “is one of the most promising approaches in melanoma.” Part of that reason is that, based on the less than 50 patients for whom there is longer-term data; the immunological adverse event rates appear more muted compared to those seen with ipilimumab.
The question of whether ipilimumab, in addition to anti-PD1 treatment is more efficacious than a single agent-treatment is being addressed in a small phase I trial that's carefully looking at the best tolerated dosage in order to minimize adverse events while increasing the response rate and durability of ipililumab monotherapy.
The congress presentations also highlighted both immunology agents and targeted treatments for melanoma. Importantly, the meeting emphasized a multi-disciplinary approach of combining these two treatments. Jedd Wolchok, MD, PhD from the Memorial Sloan Kettering Cancer Center, who was an integral part in the clinical trials that led to the approval of ipilimumab, described the rationale for combination therapy. Specifically, he discussed the combination of ipilimumab with vemurafenib, the targeted, oral BRAF inhibitor, as having the potential to achieve the balance of the high response rate of vemurafenib with the durable disease control seen with ipilimumab.
Dr. Antoni Ribas of the UCLA Jonsson Comprehensive Cancer Center presented preclinical data on the evidence that the combination may be effective. Using cell lines derived from a mouse model with a V600E mutation in BRAF, the mutation in BRAF that is targeted by vemurafenib, Dr. Ribas and his laboratory have shown that cells treated with both agents respond with apoptosis, as well as prevention of activation of the pathway components downstream of BRAF, namely the effector proteins, ERK and MEK. Importantly, the preclinical data shows that there is no effect of vemurafenib on lymphocyte viability, which is crucial for ipilimumab to achieve its effectiveness. A first in-human trial combining vemurafenib and ipillimumab in metastatic melanoma patients is scheduled to begin by 2012. The hope, according to the researchers, is that vemurafenib will increase the effectiveness of immunotherapy in part by facilitating tumor antigen presentation. The trial will also address whether the timing and rate of resistance to vemurafenib will be affected by concurrent ipilimumab therapy.
“In two years we will have our tenth anniversary. Before the IMC meetings began, there was no real galvanizing meeting that focused on melanoma research and the [Society for Melanoma Research] meeting has since evolved into the premier meeting, with the strong emphasis on research while also reaching out to our clinical colleagues. The research results from the laboratory translate very quickly into the clinics with ever increasing frequency and is a very broad effort,” said Meenhard Herlyn, Professor of Dermatology at the Wistar Institute and part of the University of Pennsylvania School of Medicine, commenting on the evolution of the annual melanoma meeting.
Looking to the future, researchers are coming together as part of the Breakthrough Consortium to begin important clinical trials, including promising combination therapies. Professor Herlyn advocates for better and more rigorous pre-clinical testing of these combinations before the start of patient trials.
“There is now a consortium established by the Melanoma Research Foundation, called the Breakthrough Consortium and this consortium has integrated 12 different institutions conducting clinical trials, with the specific goal of developing combination therapies. Both clinical trials are starting. Instead of going blindly into those clinical trials, we need more preclinical studies to carefully plan for them and so each clinical trial should have a solid rationale from pre-clinical studies. This will also be established through this consortium, which has five different sub-committees. We hope that in this way, the melanoma disease model will become the core of an adaptive, rapid learning community that provides each patient with the best possible outcome while aggregating results over all patients to advance the standard of care."
Melanoma has become a model example of a cancer for which clinical outcomes are refined based on molecular subtypes and for which there is a tremendous interaction of the melanoma clinical and research community. With many industry and academic-funded combination trials in the near future, there outcomes in the next few years should prove to be very interesting.