Moving Toward a Cure With Immunotherapy

Howard Kaufman, MD

A number of approaches have been explored over the past 20 years in the search for a potential cure for cancer. There have been times when this cure seemed attainable, as was proclaimed across the covers of magazines likeTimeandNewsweek. In many instances, those hopes did not pan out; however, this time, it is different. With the advent of immunotherapy, the possibility of curing some patients is becoming reality. It has been a roller coaster, but the latest advances are truly exemplified in melanoma, where there have been numerous FDA approvals.

One of the newly approved therapies, talimogene laherparepvec (T-VEC), represents the first in a class of therapies known as oncolytic viruses. Traditionally, viruses have been thought of as our enemies. Now, however, we are discovering they are powerful allies. This connection makes sense, since viruses are associated with the most powerful immune responses.

The FDA approved T-VEC in October 2015, based on findings from the phase III OPTiM study. The pivotal phase III trial with T-VEC randomized 436 patients with advanced melanoma. Two-thirds of the patients received T-VEC and one-third received a control, which, in this case, was recombinant GM-CSF. This was selected as the control, because GM-CSF is actually part of T-VEC and, at the time that this trial was initiated in 2008, there was some evidence that GM-CSF might have some activity in both stage III and stage IV melanoma. The study was designed to look at durable response rate (DRR), which meant that patients needed to achieve an objective response and then that response had to be maintained for 6 months or longer. In a final readout of the study, the DRR was 16.3% with T-VEC compared with 2.1% with GM-CSF. The objective response rate was 26.4% with T-VEC and 5.7% with GM-CSF.

The approval of T-VEC opens up the field to other virus-based therapies, and it allows for combination studies. In phase II studies, biopsy from some of the T-VEC injected lesions showed evidence of melanoma-specific CD8 T cells along with a decrease in regulatory T cells and myeloid-derived suppressor cells. This suggests a local immune response. Studies are now looking at T-VEC with immune checkpoint inhibitors, such as pembrolizumab and ipilimumab. In general, the field of immunotherapy has progressively moved toward combination strategies, such as these.

With the quest for precision immunology, biomarker discovery is of the utmost importance. Once implemented, biomarkers may help patients and physicians select the most promising therapeutic option while avoiding treatment strategies that are unlikely to work. For T-VEC specifically, there are a number of studies ongoing looking at viral shedding and the induction of the immune response. For the PD-1 inhibitors, several clinical trials have reported an association between clinical benefit and tumor cell expression of PD-L1, the ligand for PD-1. Additionally, mutation load has shown great promise at predicting responses.