Building upon the initial successes of anti–PD-1 and anti–CTLA-4 therapies has been a major focus of drug development over the past several years—basically, in search of other agents that could generate “immune-synergy.” What the term means and implies is critically important: It refers to drugs that work better together than alone (or in sequence) through their individual mechanisms of action to enhance the host immune-response to cancer.
Arjun V. Balar, MD
Building upon the initial successes of antiPD-1 and anti–CTLA-4 therapies has been a major focus of drug development over the past several yearsbasically, in search of other agents that could generate “immune-synergy.” What the term means and implies is critically important: It refers to drugs that work better together than alone (or in sequence) through their individual mechanisms of action to enhance the host immune-response to cancer.
Ever since the first studies of checkpoint inhibitors were reported, we’ve been on an exhaustive search to find the best partners for PD-1 and CTLA-4 antibodies to get more tumors to respond to the immune system. One of the most intriguing approaches involves the notion of generating an “in vivo vaccine.” Initial approaches included focused high-dose and hypofractionated radiation therapy at 1 or a few sites of metastatic disease given concurrently with systemic immunotherapy. In this scenario, the radiation induces “immunogenic” cell death, which is a unique dying process of the cancer cell in which the tumor releases otherwise hidden mutated proteins into the microenvironment. These proteins are then recognized and taken up by antigen-presenting cells, which subsequently instruct T cells to attack the cancer. This critical step of antigen recognition is requisite for the activation of the host immune system against cancer. Anecdotal observations showed that radiation could improve responses to checkpoint inhibitor therapy, and they have served as the basis for subsequent larger studies testing the addition of radiation to systemic immunotherapy.1,2
Of particular interest at this year’s European Society for Medical Oncology 2019 Congress were data from EV-103, a phase I trial of the checkpoint inhibitor pembrolizumab (Keytruda) combined with the novel antibody-drug conjugate (ADC) enfortumab vedotin (EV) in advanced bladder cancer (see pages 37-38).3We’ve speculated that chemotherapy could similarly induce immunogenic cell death but the data were not compelling, probably because chemotherapy regimens are highly varied with the type and delivery of the agent. EV targets nectin-4, which is a cell-surface protein highly overexpressed in virtually 100% of urothelial cancers, and the attached payload is a highly potent microtubule disrupting agent called monomethyl aurostatin-E (MMAE).
In EV-103, the objective response rate for the combination in 45 patients was an eye-popping 71%, and 93% of patients had at least some decrease in tumor size.
I have personal experience in treating patients with EV early on, and along with others, I have speculated that EV had immunologic properties that made it an attractive partner to pair with antiPD-1 therapies. I think these data are compelling, to say the least, and have broad implications beyond just urothelial cancer if proven to be valid. For instance, one could envision developing similar ADCs with MMAE as a payload but targeting a variety of different cell-surface proteins unique for different cancer types, if in fact it is MMAE that induces the immunogenic cell death that we’ve been coveting so much. The technology of ADC development has made significant strides in the last few years and I’m excited to see what the future holds.