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Oiseth et al. Cancer immunotherapy

Table 1: Timeline of selected key events in modern cancer immunology, 1868-2017
Year Event
1868 First report of an intentional infection of a cancer patient with erysipelas by Wilhelm Busch, with notable shrinkage of the tumor [11]
1883 Elie Metchnikoff publishes a key paper describing phagocytic cells (macrophages) in frogs [102] ; awarded Nobel Prize in 1908
1890 Discovery of antibodies (diphtheria and tetanus) by Emil von Behring and Kitasato Shibasaburō [103] ; Nobel Prize awarded to
von Behring in 1901
1891 William Coley injected his first of many cancer patients with bacteria, reporting tumor regressions in many of them [14]
1895 Discovery of complement, by Jules Bordet [104] ; awarded Nobel Prize 1919
1897-1901 Paul Ehrlich “Side-chain” theory of antibody specificity (adaptive immunity, autoimmunity) [105] ; awarded Nobel Prize in 1908
1901 Serological discovery of blood groups, by Karl Landsteiner [106] ; awarded Nobel Prize in 1930
1901-08 Rejection of transplanted tumors in mice, reported by Carl Jensen & Leo Loeb [107,108]
1914 Genetic basis for the rejection of transplantable tumors, reported by Clarence Little [109]
1909-20 Establishment of inbred strains of mice by Leonell Strong and Clarence Little [110]
1948 First report of histocompatibility antigens being the basis for transplant rejection, by P. Gorer, S. Lyman, & G. Snell [111] . 1908
Nobel Prize awarded jointly to G. Snell,B. Benacerraf, & J. Dausset in 1980
1955 Natural-Selection Theory of Antibody Formation, first formulated by N. Jerne [112] ; awarded Nobel Prize in 1984
1956 Discovery of acquired immunological tolerance by R. Billingham, L. Brent & P.Medawar. Nobel Prize awarded to Medawar & F.
Burnet in 1960 [113,114]
1957 Immune rejection of transplanted syngeneic tumors (i.e., each tumor is antigenically unique) [115] . Reported by Richmond Prehn &
Joan Main.
1957 Interferon discovered, described as a factor that conferred the property of viral interference [116] , reported by Alick Isaacs and
Jean Lindenmann. Its anti-leukemic effect is reported in 1984.
1959 Immune surveillance of cancer theory by Lewis Thomas & F. Macfarlane Burnet [30-32]
1959 Chemical structure of antibodies, by Gerald Edelmann & Rodney Porter [117-120] ; Nobel Prize awarded to both in 1972.
1959 BCG shown to have anti-tumor effects in a mouse model, reported by Lloyd Old, Donald Clark, & Baruj Benacerraf [18]
1973 First description of dendritic cells, by Ralph Steinman & Zanvil Cohn [121] ; Steinman awarded Nobel Prize in 2011 for discovery
of the dendritic cell and its role in adaptive immunity
1974 First reports of the specificity of cell-mediated immunity by Peter Doherty and Rolf Zinkernagel [122,123] ; Nobel Prize awarded to
both in 1996
1975 Monoclonal antibodies manufactured by George Koehler & Caesar Milstein [124,125] ; Nobel Prize awarded to Koehler, Milstein & N.
Jerne (for his theoretical contributions) in 1984
1975 Discovery of tumor necrosis factor, reported by Lloyd Old, with Elizabeth Carswell, Robert Kassel, S. Green, N. Fiore, & B.
Williamson [19]
1975 First description of NK cells on a functional basis according to their ability to lyse tumor cells in the absence of prior
stimulation [126] . Reported by Ronald Herberman, Myrthel Nunn, Howard Holden, & David H. Lavrin.
1976 Discovery of the genetic principle for generation of antibody diversity, by Susumu Tonegawa [127,128] ; awarded Nobel Prize in 1987.
1982 Discovery of the T-cell receptor in 1982, reported by James Allison, B. McIntyre, & D. Bloch [101]
1984 First report of interferon response in patients with hairy cell leukemia [129]
1991 First report of a human tumor antigen recognized by T-cells, reported by Pierre van der Bruggen, C. Traversari, P. Chomez, et al. [36]
1996 Discovery that CTLA-4 blocking antibodies could treat tumors in animal models, reported by Dana Leach, Matthew Krummel &
James Allison [72]
1998 Discoveries regarding the activation of innate immunity, by R. Medzhitov, P. Preston-Hurlburt, C. Janeway; & B. Beutler;
Beutler awarded Nobel Prize in 2011 [130,131]
2001 Rag2 -/- immunodeficient mice, with no B or T cells, show increased susceptibility to spontaneous and carcinogen-induced
tumors, reported by V. Shankaran, with L.J. Old, R. Schreiber, et al. [132]
2005 Memory T-cells in colorectal tumors shown to predict clinical outcome, reported by F. Pagès, A. Berger, M. Camus et al. [133]
2010 First autologous cell-based cancer vaccine (sipuleucel-T) is approved by the FDA for the treatment of metastatic, asymptomatic
stage IV prostate cancer [43,134]
2010 First successful use of gene-edited T-cells for the treatment of CD19+ hematologic malignancies in humans, reported by W.
Qasim, H. Zhan, S. Samarasinghe et al. [135]
2011 Anti-CTLA-4 (ipilimumab), is the first inhibitory checkpoint inhibitor (ICI) approved by the FDA for treatment of stage IV
melanoma [136]
2012 Discovery of the CRISPR/Cas9 system, a simpler and more efficient method of genome editing, reported byJ.A. Doudna & E.
Charpentier, with M. Jinek, K. Chylinski, I. Fonfara, & M. Hauer [49]
2013 First use of CRISPR/Cas9 technique in eukaryotic cells, reported by F. Zhang, with L. Cong, F. Ran, D. Cox, S. Lin, R.
Barretto, N. Habib, P. Hsu, X. Wu, W. Jiang, & L. Marraffini [50]
2016 A second class of ICIs, anti-PD-1 (pembrolizumab), is approved for the treatment of melanoma [137]
2016 First characterization of the role of dendritic cell CTLA-4 in Th-1 immunity, reported by M. Halpert, V.Konduri, D. Liang et al. [138]
2016 A third class of ICIs, PD-L1(atezolizumab), is approved for treatment of bladder cancer [139]
2016 First test in humans of CRISPR gene-editing technique for CAR T-cell therapy [51]
2017 Phase I/IIa study of an inhibitor of indoleamine 2,3-dioxygenase (IDO1), a non-membrane-attached enzyme with a checkpoint
inhibitor function, shows promise [95]
Not all of the events listed are discussed in the text, but all are referenced to the pertinent literature

252 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ October 31, 2017