ASCO 2013: Humanity Meets Immunity

Andrew L. Pecora, MD

Editor-in-Chief

Oncology & Biotech News

Chief Innovations Officer, Professor, and Vice President of Cancer Services President, Regional Cancer Care Associates, LLC John Theurer Cancer Center at Hackensack University Medical Center

Long before people were able to conceive that elements within them were capable of defending their lives from foreign and internal invaders, the human immune system had developed to such capacity. Darwinian evolution has taught us that life will find a way to thrive, even in hostile environments adapting to survive. We have come to believe that evading natural human immune surveillance is at the core of cancer’s ability to grow and spread, causing death of the host.

The mechanism by which cancer evades immune surveillance is complex and multifaceted, but we have now learned that a key component involves cancer turning off T-cell responses that otherwise would limit progression. T-cell checkpoints have been known about for some time. By modulating T-cell checkpoints through ligands, our immune system is able to limit responses enough to kill invaders but not cause autoimmunity. Unfortunately, cancer has evolved to hijack immune modulatory mechanisms and until recently, there was little we could do to turn T cells back on.

Consequently, Jedd D. Wolchok, MD, PhD, Memorial Sloan-Kettering Cancer Center, and colleagues got everyone’s attention at the 2013 ASCO Annual Meeting by presenting their data on the effect of administering a combination of so-called anti-T-cell checkpoint inhibitors in patients with advanced malignant melanoma (abstract 9012). The two checkpoint targets in Wolchok et al’s study included programmed death-1 protein (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4). Specifically, the research involved the anti—PD-1 agent nivolumab and the anti CTLA-4 drug ipilimumab. Both drugs are monoclonal antibodies, and each alone has activity in melanoma but is somewhat delayed in time to effect and effect duration. Wolchok et al demonstrated, however, that concurrent treatment of previously treated advanced melanoma patients (stage III and IV) with nivolumab and ipilimumab resulted in a striking objective response rate of 40%.

Wolchock noted that time to response was unusually rapid (a few months) and the degree of response was also unusually significant. Tumor regressions ≥80% were observed in 31% of patients. Of importance was the observation that concurrent therapy was more active when compared with the agents given sequentially.

Experience with other inhibitors of checkpoints of T-cell responses also presented at ASCO 2013 included an antibody directed to the ligand of PD-1 (anti-PD-L1). The antibody MPDL3280A, an anti-PD-L1, demonstrated single-agent activity in a number of solid tumors (Herbst RS, abstract 3000), particularly non—small cell lung cancer, renal cancer, and melanoma. Of the 171 patients reported on in this trial, a median of three prior therapies were given before MPDL3280A. The response rate was 21% among these diverse disease types and some were durable.

The idea that unleashing our own immune systems to do what nature intended is beyond exciting. Millions of years of evolution has provided each of us a system so finely tuned to react but not overreact to almost any challenge when given enough time. The same attributes of our immune system that keep it from overreacting have been taken advantage of by malignant cells. While the anti-T-cell-checkpoint approach is far from perfect with significant immune-mediated toxicities reported, including deaths, the demonstrated ability for humanity to overcome evolutionary design and break tumor cell tolerance to turn the tide against cancer is nothing less than inspiring.