Efforts are underway to identify the molecular reasons why some patients exhibit an enduring response to immune checkpoint inhibitor therapy. These patients have been called “exceptional” responders or “super” responders. Some patients that have cancers with a lot of DNA mutations (high mutational burden) are better responders to immune checkpoint therapy compared with patients that have cancers with low mutational burden. The molecular basis is thought to be the production of many neoantigens (newly formed antigens) by the tumor because of the many DNA mutations.
However, McGranahan and colleagues found that in some patients the best response was associated with less neoantigen heterogeneity in the tumor and with neoantigens that were present on all the tumor cells (clonal tumor neoantigens). In this case, a higher rate of mutations could result in many different neoantigens, with the result that many different populations of T cells would be needed to recognize all the variant tumor cells. These neoantigens could function as subdominant antigens that do not trigger an effective immune response. Alternatively, the high rate of mutation could remove neoantigens that had been targeted by the T cells, thereby enabling immune evasion.
If the T cells from the few patients that show a durable response could be isolated, then the antigens that they recognize could be identified. If these T cells recognized antigens common to cancers in other patients, these could serve as potential vaccine targets (Figure 1). If they recognize antigens unique to that patient’s cancer, they could be expanded and used as a cell-based personalized therapy or the antigens could be used like a vaccine to enhance the patient’s own immune response. Recent results from clinical trials provide tantalizing evidence, albeit with very small numbers of patients, that personal neoantigen-based vaccines and immune checkpoint inhibitor treatment may be effective.
Related Reading
Immunotherapy for kidney cancer: Who are the “exceptional responders?” Discovery 13 (2017). http://www.hopkinsmedicine.org/brady-urology-institute/patient-information/books-publications/discovery/_docs/Discovery_News_2017.pdf
J. Kaiser, Personalized tumor vaccines keep cancer in check. Science (12 April 2017) DOI: 10.1126/science.aal1044 http://www.sciencemag.org/news/2017/04/personalized-tumor-vaccines-keep-cancer-check
N. McGranahan, A. J. Furness, R. Rosenthal, S. Ramskov, R. Lyngaa, S. K. Saini, M. Jamal-Hanjani, G. A. Wilson, N. J. Birkbak, C. T. Hiley, T. B. Watkins, S. Shafi, N. Murugaesu, R. Mitter, A. U. Akarca, J. Linares, T. Marafioti, J. Y. Henry, E. M. Van Allen, D. Miao, B. Schilling, D. Schadendorf, L. A. Garraway, V. Makarov, N. A. Rizvi, A. Snyder, M. D. Hellmann, T. Merghoub, J. D. Wolchok, S. A. Shukla, C. J. Wu, K. S. Peggs, T. A. Chan, S. R. Hadrup, S. A. Quezada, C. Swanton. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463-1469 (2016). PubMed
Cite as: N. R. Gough, Immune checkpoint inhibitor super responders. BioSerendipity (1 June 2017) https://www.bioserendipity.com/2017/05/31/immune-checkpoint-inhibitor-super-responders/.