Highlighted Studies

Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic

Timothy A. Chan. Mark Yarchoan, Elizabeth Jaffee, Charles Swanton, Sergio A. Quezada, Albrecht Stenzinger, Solange Peters Annals of Oncology. 2019 Jan; 30(1): 44-56.

The Chan lab discovered that mutation and neoantigen burden and MSI are primary drivers of immune checkpoint blockade therapy efficacy. The timeline of discoveries are summarized in this review. These findings sparked the FDA approval of the first tumor-agnostic approvals for cancer therapy.

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ICB, immune checkpoint blockade; 1L, first line; 2L, second line; +, and others; IPI, ipilimumab; NIVO, nivolumab; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer; TMB, tumor mutational burden. 1. Snyder A, et al. N Engl J Med. 2014;371(23):2189-2199. 2. Rooney MS, et al. Cell. 2015;160(1-2):48-61. 3. Rizvi NA, et al. Science. 2015;348(6230):124-128. 4. Rosenberg JE, et al. Lancet. 2016;387(10031):1909-1920. 5. Kowanetz M, et al. Poster presentation at ESMO 2016. Abstract 77P. 6. Kowanetz M, et al. Oral presentation at WCLC 2016. Abstract 6149. 7. Balar AV, et al. Lancet. 2017;389(10064):67-76. 8. Seiwert TW, et al. J Clin Oncol. 2018;36(suppl 5S; abstract 25). 9. Chalmers ZR, et al. Genome Med. 2017;9(1):34. 10. Zehir A et al. Nat Med. 2017;23(6):703-713. 11. Carbone DP, et al. N Engl J Med. 2017;376(25):2415-2426. 12. Galsky MD, et al. Poster presentation at ESMO 2017. Abstract 848PD.13. Gandara DR, et al. Oral presentation at ESMO 2017. Abstract 1295O. 14. Fabrizio DA, et al. Poster presentation at ESMO 2017. Abstract 102P. 15. Mok T, et al. Poster presentation at ESMO 2017. Abstract 1383TiP. 16. Antonia SJ, et al. Oral presentation at WCLC 2017. Abstract 11063. 17. Riaz N, et al. Cell. 2017;171(4):934-949. 18. Foundation Medicine. http://investors.foundationmedicine.com/releasedetail.cfm?ReleaseID=1050380. Accessed Dec 11, 2017. 19. US Food and Drug Administration. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm585347.htm. Accessed Dec 1, 2017. 20. Hellmann MD, et al. N Engl J Med. 2018, DOI:10.1056/NEJMoa1801946. 21. Forde PM, et al. N Engl J Med. 2018, DOI:10.1056/NEJMoa1716078.

Recurrent SERPINB3 and SERPINB4 mutations in patients who respond to anti-CTLA4 immunotherapy

Nadeem Riaz, Jonathan J. Havel, Sviatoslav M. Kendall, Vladimir Makarov, Logan A. Walsh, Alexis Desrichard, Nils Weinhold, and Timothy A. Chan

Nat Genet. 2016 Nov;48(11):1327-1329.

Immune checkpoint blockade has shown significant promise as an anticancer treatment, yet the determinants of response are not completely understood. Here we show that somatic mutations in SERPINB3 and SERPINB4 are associated with survival after anti-CTLA4 immunotherapy in two independent cohorts of patients with melanoma (n = 174). Interestingly, serpins are homologs of the well-known ovalbumin antigen and are associated with autoimmunity. Our findings have implications for the personalization of immunotherapy.

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Oncoprints of SERPINB3 and SERPINB4 mutations in cohort 2 (top). Location of variants on the 3D protein structures of SERPINB3 (c) and SERPINB4 (d). Red, mutated amino acid; blue, putative RCL domain.

Diversity and divergence of the glioma-infiltrating T cell receptor repertoire

Jennifer S. Sims, Boris Grinshpun, Yaping Feng, Timothy H. Ung, Justin A. Neira, Jorge L. Samanamud, Peter Canoll, Yufeng Shen, Peter A. Sims, and Jeffrey N. Bruce

Proc Natl Acad Sci. 2016 Jun 21;113(25):E3529-37.

High-throughput sequencing of T cell receptor (TCR) repertoires provides a high-dimensional biomarker for monitoring the immune system. We applied this approach, measuring the extent to which the TCR repertoires of T cell populations infiltrating malignant brain tumors diverge from their peripheral blood counterparts. Our analytical strategy separates the statistical properties of the repertoire derived from VJ cassette combination usage from the VJ-independent contribution that reflects the antigen-binding component of the receptor. We discovered a TCR signature strongly inversely correlated with the VJ-independent divergence between the peripheral and tissue-infiltrating repertoires of these patients. Importantly, this signature is detectable in peripheral blood and could serve as a means of noninvasively monitoring immune response in patients.

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VJ-independent divergence between blood (PBMC) and tissue-infiltrating lymphocytes (TIL) distinguishes glioma from nonneoplastic tissue. The average sample-size corrected Jensen-Shannon Divergence Metric (JSMD,corr) of the TCRα and TCRβ chains is plotted for each patient with colored bars indicating clinical status (Glioblastoma, red; Low-grade glioma, green; and nonneoplastic, black).

TCR contact residue hydrophobicity is a hallmark of immunogenic CD8+ T cell epitopes

Diego Chowell, Sri Krishna, Pablo D. Becker, Clément Cocita, Jack Shu, Xuefang Tan, Philip D. Greenberg, Linda S. Klavinskis, Joseph N. Blattman, and Karen S. Anderson

Proc Natl Acad Sci. 2015 Apr 7;112(14):E1754-62.

The design of effective T cell vaccines against pathogens and tumor antigens is challenged by the highly inefficient identification of the subset of peptides from a given antigen that effectively stimulate an immune response. Here we report that the relative hydrophobicity of T cell receptor contact residues is markedly enriched in immunogenic major histocompatibility complex class I epitopes in both human and murine MHCs, and in both self and pathogen-derived immunogenic epitopes. Incorporating hydrophobicity into T cell epitope prediction models increases the efficiency of epitope identification, which will reduce the time and cost of T cell vaccine development. Amino acid hydrophobicity may represent a biochemical basis by which T cells discriminate immunogenic epitopes within the background of self peptides.

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Efficiency of predicting experimentally defined HLA-A0201–restricted immunogenic epitopes using mean hydrophobicity of TCR contact residues (straight lines) compared with IEDB consensus binding tool (IEDB-Bind; dashed lines). Tegument protein pp65 from cytomegalovirus (CMV) and polyprotein from dengue virus type 1 were used for predictions. Predicted peptides from the IEDB-Bind were reranked using the mean hydrophobicity of TCR contact residues.

Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer

Naiyer A. Rizvi, Matthew D. Hellmann, Alexandra Snyder, Pia Kvistborg, Vladimir Makarov, Jonathan J. Havel, William Lee, Jianda Yuan, Phillip Wong, Teresa S. Ho, Martin L. Miller, Natasha Rekhtman, Andre L. Moreira, Fawzia Ibrahim, Cameron Bruggeman, Billel Gasmi, Roberta Zappasodi, Yuka Maeda, Chris Sander, Edward B. Garon, Taha Merghoub, Jedd D. Wolchok, Ton N. Schumacher, and Timothy A. Chan

Science. 2015 Apr 3;348(6230):124-8

Checkpoint blockade immunotherapy provides stronger benefits in some patients than in others. This study of using pembrolizumab, an antibody which blocks the programmed cell death-1 (PD-1) “exhaustion” receptor on T cells, to treat non-small cell lung cancer (NSCLC) shows that the number of protein-altering mutations (and higher predicted neo-antigen load) in the tumor correlates with objective response, durable clinical benefit, and progression-free survival. Signature types of nucleotide mutations and mutations in DNA repair pathways were also enriched among anti-PD-1 responders. We also study the neo-antigen-specific CD8+ T cell responses in one patient, which coincided with tumor regression, providing a circumstantial mechanistic link between the anti–PD-1 therapy and the antitumor effects of neo-antigen-specific T cells.

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Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade

Nicholas McGranahan, Andrew J. S. Furness, Rachel Rosenthal, Sofie Ramskov, Rikke Lyngaa, Sunil Kumar Saini, Mariam Jamal-Hanjani, Gareth A. Wilson, Nicolai J. Birkbak, Crispin T. Hiley, Thomas B. K. Watkins, Seema Shafi, Nirupa Murugaesu, Richard Mitter, Ayse U. Akarca, Joseph Linares, Teresa Marafioti, Jake Y. Henry, Eliezer M. Van Allen, Diana Miao, Bastian Schilling, Dirk Schadendorf, Levi A. Garraway, Vladimir Makarov, Naiyer A. Rizvi, Alexandra Snyder, Matthew D. Hellmann, Taha Merghoub, Jedd D. Wolchok, Sachet A. Shukla, Catherine J. Wu, Karl S. Peggs, Timothy A. Chan, Sine R. Hadrup, Sergio A. Quezada, and Charles Swanton

Science. 2016 Mar 25;351(6280):1463-9

Antitumor immunity is influenced by the repertoire of neo-antigens created by somatic mutations within a tumor. These mutations occur heterogeneously, in some tumor cells and not others, within the same tumor, which leads to heterogeneity between tumor cells in the corresponding neo-antigens by which the immune system can recognize them. Some neo-antigens are present in virtually all tumor cells (clonal), while others are present only in a fraction of cells (subclonal). This study demonstrates that enrichment for clonal neo-antigens is associated with an improved clinical outcome with checkpoint blockade immunotherapy, and increased tumor infiltrating lymphocytes.

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Genetic basis for clinical response to CTLA-4 blockade in melanoma

Alexandra Snyder, Vladimir Makarov, Taha Merghoub, Jianda Yuan, Jesse M. Zaretsky, Alexis Desrichard, Logan A. Walsh, Michael A. Postow, Phillip Wong, Teresa S. Ho, Travis J. Hollmann, Cameron Bruggeman, Kasthuri Kannan, Yanyun Li, Ceyhan Elipenahli, Cailian Liu, Christopher T. Harbison, Lisu Wang, Antoni Ribas, Jedd D. Wolchok, and Timothy A. Chan

N Engl J Med. 2014 Dec 4;371(23):2189-99

Higher numbers of mutations, leading to increased numbers of neo-antigens, may be recognized by the immune system as foreign. This study was the first to demonstrate in human patients that tumors with increased mutational loads are indeed associated with improved outcomes after immunotherapy. Furthermore, T cells were identified in several patients that responded to the neo-peptides predicted by our computational pipeline — but not to their respective wild-type peptides. Although many different types of antigens — such as cancer-testis antigens, viral antigens, and neo-antigens — could lead to immune recognition of a tumor as foreign, this study provided the first evidence from patients that neo-antigens in particular play a critical role in this process, while the clinical evidence for other classes of antigens remains poor, to date. Relatedly, the commonality of certain features of the tumor-associated neo-peptides (e.g. homology to known antigens or particular amino acid motifs) suggested that these features may be helpful in identifying patients who would respond strongly to therapy.

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