Introduction by the Guest Editors: The PD-1 Axis in Cancer Therapy

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We are delighted to serve as guest editors for this important volume focused on the emerging role of the PD-1 axis in cancer therapy. Occasionally, our patients query us about the many acronyms used in the oncology lexicon. When the topic of PD-1 comes up, one can imagine a bit of an awkward and somewhat ironic discussion. As many are aware, PD-1 (CD279) is an abbreviation for “programmed death 1,” named for the identification of a molecule induced in T cells undergoing apoptosis. Given the potentially fatal diagnoses for which agents that block this pathway are being explored, the mention of “death” in the conversation would understandably raise some proverbial eyebrows. Thankfully, medicines that target PD-1 or one of its ligands, PD-L1, have proved (along with CTLA-4 blockade) to be foundational agents in the field of immunotherapy and have been shown to extend survival, perhaps “reprogramming death” in an even widening subset of cancer patients. At the time of this writing, PD-1 pathway–blocking antibodies have received regulatory approval in the United States based on significant antitumor activity, in the treatment of melanoma, non–small cell lung cancer, renal cell carcinoma, urothelial bladder cancer, Hodgkin lymphoma, Merkel cell carcinoma, head and neck squamous cell carcinoma, gastric cancer, and hepatocellular cancer. Intense study of biomarkers to explain the disease in which tumor regression occurred led to the hypothesis that those tumors rich in neoantigens, either by virtue of a high mutational burden or through viral etiology, were more likely to respond to checkpoint blockade through disinhibition of a preexisting immune response to these favorable antigens. Quickly following was a landmark event in oncology drug development when the first histology-agnostic approval was made for a PD-1–blocking antibody (pembrolizumab) for treatment of tumors arising as a result of inherited DNA mismatch repair deficiency.
Along with observations of clinical activity leading to cancer regression and lengthened survival, PD-1 pathway blockade also was observed to induce mechanism-based immune adverse events. This requires new skills to be acquired by clinicians to manage these symptoms in a different manner from those occurring with standard cytotoxic drugs. A deeper understanding of the molecular and cellular events following blockade of the PD-1 axis is needed to know how best to intervene to dampen toxicity, as well as for the identification of predictive and pharmacodynamics biomarkers. These are all concepts that are expertly addressed in the included manuscripts.
An additional topic of great importance is the observation of resistance to PD-1 pathway blockade. Understanding the biology underlying both initial refractoriness and acquired resistance to current agents will undoubtedly result in more effective treatment strategies, including combinations in the future. We trust that you will find the articles presented here to be informative and inspirational, as well as work to reprogram death from cancer in more effective ways.

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