Although surgery, radiation therapy and chemotherapy dominated cancer medicine during the 20th century, one of the first systematically applied systemic therapies for cancer was a crude immunotherapeutic, developed in the 1880’s by New York surgeon William Coley. Many years later his observations led to the identification of key cytokine mediators of inflammation including TNFa. Subsequently interferons and interleukins were identified and tested as anti-cancer agents with modest success for a limited range of cancer types. Although the fashion for immune-directed approaches ebbed and flowed, the science underpinning immuno-oncology evolved and the cellular and humoral mediators of immune rejection were identified and an understanding of their functions grew. Australia’s Nobel laureate Macfarlane Burnet described immunosurveillance in the 1960’s and although popular culture embraced the importance of immunity in cancer control, this was equally questioned by the clinical establishment as a broadly relevant mechanism. Organ transplant registries and the HIV epidemic nonetheless pointed to a clear association; at least in cases of virus-associated cancers.
Key laboratory observations included Doherty and Zinkernagel’s description of MHC and T cell recognition and the identification of dendritic cells by Steinman in the 1970’s. In the early 1990’s the first human cancer antigens were characterized by scientists at the Ludwig Institute and NCI.
From the late 1950’s, Donnell Thomas pioneered allogeneic marrow transplantation, arguably the first widely applied immunotherapy in the modern era. Later, BCG administered intralesionally in melanoma and intravesically in bladder cancer re-established a role for bacterial products as anti-cancer agents via immune stimulation. During the 1980’s the roll-out of global vaccination programmes for Hepatitis B has impacted on liver cancer, and the principle of vaccination to prevent virus-associated cancers was further extended more recently with vaccination against human papilloma virus.
Contemporary excitement exploded with the demonstration that immune regulation often plays a critical role constraining anti-cancer immunity and that the simple intervention of blocking molecular immune checkpoints can unleash potent anti-cancer effects. Jim Allison’s demonstration by blocking CTLA4 and the subsequent observation that blocking PD1 can have even greater impact heralded a decade of extraordinary progress. The recognition of an expanding range of mechanisms, the identification of numerous additional molecular immune targets and the extraordinary investment by industry in the field, all point to an even more exciting decade of discovery as biomarkers are identified, combinations are developed and approaches are optimized. We will see more effectively targeted immunotherapy, greater personalization and substantial societal challenges as we grapple with the costs of highly effective and increasingly costly anti-cancer immunotherapies.