Development of immuno-oncology drugs — from CTLA4 to PD1 to the next generations

| Since the regulatory approval of ipilimumab in 2011, the field of cancer immunotherapy has been experiencing a renaissance. This success is based on progress in both preclinical and clinical science, including the development of new methods of investigation. Immuno-oncology has become a sub-specialty within oncology owing to its unique science and its potential for substantial and long-term clinical benefit. Immunotherapy agents do not directly attack the tumour but instead mobilize the immune system — this can be achieved through various approaches that utilize adaptive or innate immunity. Therefore, immunooncology drug development encompasses a broad range of agents, including antibodies, peptides, proteins, small molecules, adjuvants, cytokines, oncolytic viruses, bi-specific molecules and cellular therapies. This Perspective summarizes the recent history of cancer immunotherapy, including the factors that led to its success, provides an overview of novel drug-development considerations, summarizes three generations of immunotherapies that have been developed since 2011 and, thus, illustrates the breadth of opportunities these new generations of immunotherapies represent. NATURE REVIEWS | DRUG DISCOVERY ADVANCE ONLINE PUBLICATION | 1 PERSPECTIVES © 2016 Macmillan Publishers Limited. All rights reserved. Nature Reviews | Drug Discovery Cloning of CTLA4 gene First patient treated Phase II: • Novel responses • Delayed separation of KM curves for OS • Primary endpoints of two Phase III trials changed to OS • No OS interim analyses Phase III positive on OS Regulatory approval in the USA Treatment of mouse tumours with CTLA4 Immune-regulatory role of CTLA4 in mice B7-1 and B7-2 are CTLA4 ligands CIC founded to solve methodological problems of the immunotherapy field CIC workshop showing delayed separation of curves for Phase III immunotherapy trials CVCTWG workshop suggesting new response kinetics and criteria CIC and BMS: immune-related response critria Preclinical science Clinical science Pre-clinical science milestones Conventional clinical milestones Novel clinical science milestones CIC workshops driving changes in clinical science 1985 199