Cancer Immunosurveillance Comes of Age

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As oncologists learn to target the immune response to “self and non-self,” a delicate therapy balance will eventually be achieved with predictable outcomes, benefits, and toxicity in the fight against
As oncologists learn to target the immune response to “self and non-self,” a delicate therapy balance will eventually be achieved with predictable outcomes, benefits, and toxicity in the fight against

The study of how the immune system recognizes friend and foe, or as the immunologist Sir Macfarlane Burnet phrased it, “distinguishes between self and non-self,” has driven important discoveries that are transforming our ability to treat cancer.

Over the last century, scientists and clinicians have unraveled the complex interactions (both in innate and adaptive immunity) that lead to the eradication of viruses, bacteria, parasites, and now, cancer. Notable cellular players include T cells, B cells, natural killer (NK) cells, neutrophils, eosinophils, basophils, dendritic cells, and macrophages, along with a host of secreted mediators —antibodies, complement, cytokines, and chemokines — each of which fulfills particular immunologic functions.

When the immune system fails to regulate these processes, autoimmune disease can be a consequence. These diseases also occur if shared antigens are recognized by the immune system in normal and in cancer cells; one example is Lambert-Eaton syndrome. Monoclonal antibodies that target tumor reactive T cells (eg, nivolumab and pembrolizumab) can also cause autoimmune disease; other examples include graft-vs-host disease (GVHD) in allogeneic bone marrow transplant recipients and cytokine release syndrome (CRS), which is associated with adoptive T cell therapy.

Through the efforts of thousands of investigators, starting with Dr William Coley over a century ago and more recently including researchers such as Drs Macfarlane Burnet, Lewis Thomas, Steven Rosenberg, Carl June, James Allison, and Lloyd Old,1-7 oncologists can now offer patients effective US Food and Drug Administration (FDA)-approved immunotherapy treatments designed to directly or indirectly attack cancer.

Historical timeline for FDA approval of representative immunotherapy and related drugs and selected indications:8,9

1983: Recombivax: To prevent hepatitis B infection and hepatocellular cancer caused by viral infection
1986: Interferon alfa 2b: Hairy cell leukemia; subsequent approval for renal cell cancer, melanoma and Kaposi sarcoma
1990: BCG: Superficial bladder cancer
1991: Filgrastim: Neutropenia from chemotherapy
1992: Interleukin 2: Renal cell cancer; subsequent approval for melanoma
1993: Epoetin alfa: Anemia from chemotherapy
1997: Rituximab: Non-Hodgkin Lymphoma; subsequently approved in other cancer types and for other indications
1998: Trastuzumab: Breast cancer; subsequent approval for gastric cancer, esophageal cancer
2001: Alemtuzumab: Chronic lymphocytic leukemia
2004: Bevacizumab: Colorectal cancer; subsequent approval in many other cancers — breast, lung, glioblastoma multiforme, uterine, cervical
2004: Cetuximab: Colorectal cancer; subsequent approval in head and neck cancers
2010: Sipuleucel: Prostate cancer
2011: Ipilimumab: Melanoma
2014: Nivolumab: Melanoma; subsequent approval for many cancer types including non–small cell lung cancer, hepatocellular cancer, Hodgkin lymphoma, bladder cancer, renal cancer, colorectal cancer
2014: Pembrolizumab: Melanoma; subsequent approval for non–small cell lung cancer, gastric cancer and many other cancers that are microsatellite high expression or deficient in mismatch repair functions
2014: Gardasil: To prevent human papilloma virus (HPV) infection and cervical cancer and other cancers caused by viral infection
2015: Talimogene laherparepvec: Melanoma
2017: Durvalumab: Non–small cell lung cancer and bladder cancer
2017: Tisagenlecleucel: Acute lymphoblastic leukemia
2017: Axicabtagene ciloleucel: Lymphoma

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