Dr. Greenbaum’s main research interests have long centered around the fundamental question of self vs non-self discrimination: How does the immune system recognize and target particular molecular patterns and sequences as ‘foreign’, and how does this affect the evolution of tumors and viruses? As the director of Computational Immuno-Oncology within the Computational Oncology Service, Dr. Greenbaum combines statistical physics and information theory with evolutionary biology. After a PhD in theoretical physics from Columbia University he focused on the effect of the innate immune system on viral evolution: his models predicted how the 1918 influenza virus evolved after the pandemic and continued to be cited during Covid-19. His next step took him from virally transcribed RNA to viral mimics: RNA produced from genomic repeat elements in cancer cells. He applied methods from statistical physics to quantify how the immune system recognizes these aberrantly transcribed self-RNAs. Dr. Greenbaum developed the first models to quantify this ‘viral mimicry’, molecular patterns reminiscent of pathogens that can activate the innate immune system. Within the last few years Dr. Greenbaum’s group and his collaborators also created models to predict the role of neoantigens in tumor evolution, and they established the concept of ‘neoantigen quality’ to assess the likelihood that a neoantigen will induce an immune response. His team discovered an immune tradeoff in cancer evolution: oncogenic mutations with lower fitness present poorly to the immune system, while mutations with high fitness generate potent neoantigens. Dr. Greenbaum’s work is supported by various federal and philanthropic grants and awards and has contributed to several clinical trials, including a phase II trial to test an inhibitor of repeat elements in colorectal cancer and a phase I trial for an mRNA vaccine against neoantigens in pancreatic cancer.
Rojas LA, Sethna Z, Soares KC, Olcese C, Pang N, Patterson E, Lihm J, Ceglia N, Guasp P, Chu A, Yu R, Chandra AK, Waters T, Ruan J, Amisaki M, Zebboudj A, Odgerel Z, Payne G, Derhovanessian E, Müller F, Rhee I, Yadav M, Dobrin A, Sadelain M, Łuksza M, Cohen N, Tang L, Basturk O, Gönen M, Katz S, Do RK, Epstein AS, Momtaz P, Park W, Sugarman R, Varghese AM, Won E, Desai A, Wei AC, D’Angelica MI, Kingham TP, Mellman I, Merghoub T, Wolchok JD, Sahin U, Türeci Ö, Greenbaum BD*, Jarnagin WR, Drebin J, O’Reilly EM, Balachandran VP*. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature. 2023 Jun;618(7963):144-150. PMCID: PMC10171177.
Hoyos D, Zappasodi R, Schulze I, Sethna Z, de Andrade KC, Bajorin DF, Bandlamudi C, Callahan MK, Funt SA, Hadrup SR, Holm JS, Rosenberg JE, Shah SP, Vázquez-García I, Weigelt B, Wu M, Zamarin D, Campitelli LF, Osborne EJ, Klinger M, Robins HS, Khincha PP, Savage SA, Balachandran VP, Wolchok JD, Hellmann MD, Merghoub T, Levine AJ, Łuksza M, Greenbaum BD*. Fundamental immune-oncogenicity trade-offs define driver fitness. Nature. 2022 Jun;606(7912):172–179. PMCID: PMC9159948
Łuksza M, Sethna ZM, Rojas LA, Lihm J, Bravi B, Elhanati Y, Soares K, Amisaki M, Dobrin A, Hoyos D, Guasp P, Zebboudj A, Yu R, Chandra AK, Waters T, Odgerel Z, Leung J, Kappagantula R, Makohon-Moore A, Johns A, Gill A, Gigoux M, Wolchok J, Merghoub T, Sadelain M, Patterson E, Monasson R, Mora T, Walczak AM, Cocco S, Iacobuzio-Donahue C, Greenbaum BD*, Balachandran VP*. Neoantigen quality predicts immunoediting in survivors of pancreatic cancer. Nature. 2022 Jun;606(7913):389–395. PMID: PMC35589842
Lyudovyk O, Kim JY, Qualls D, Hwee MA, Lin YH, Boutemine SR, Elhanati Y, Solovyov A, Douglas M, Chen E, Babady NE, Ramanathan L, Vedantam P, Bandlamudi C, Gouma S, Wong P, Hensley SE, Greenbaum BD*, Huang AC, Vardhana SA*. Impaired humoral immunity is associated with prolonged COVID-19 despite robust CD8 T cell responses. Cancer Cell. 2022 Jul;40(7):738-753.e5. PMCID: PMC9149241.
Lee CY, Shah MK, Hoyos D, Solovyov A, Douglas M, Taur Y, Maslak P, Babady NE, Greenbaum BD, Kamboj M, Vardhana SA. Prolonged SARS-CoV-2 infection in patients with lymphoid malignancies. Cancer Discov. American Association for Cancer Research (AACR); 2022 Jan;12(1):62–73. PMCID: PMC8758535
Porter RL, Sun S, Flores MN, Berzolla E, You E, Phillips IE, Kc N, Desai N, Tai EC, Szabolcs A, Lang ER, Pankaj A, Raabe MJ, Thapar V, Xu KH, Nieman LT, Rabe DC, Kolin DL, Stover EH, Pepin D, Stott SL, Deshpande V, Liu JF, Solovyov A, Matulonis UA, Greenbaum BD*, Ting DT*. Satellite repeat RNA expression in epithelial ovarian cancer associates with a tumor-immunosuppressive phenotype. J Clin Invest. 2022 Aug;132(16). PMCID: PMC9374379
Rajurkar M, Parikh AR, Solovyov A, You E, Kulkarni AS, Chu C, Xu KH, Jaicks C, Taylor MS, Wu C, Alexander KA, Good CR, Szabolcs A, Gerstberger S, Tran AV, Xu N, Ebright RY, Van Seventer EE, Vo KD, Tai EC, Lu C, Joseph-Chazan J, Raabe MJ, Nieman LT, Desai N, Arora KS, Ligorio M, Thapar V, Cohen L, Garden PM, Senussi Y, Zheng H, Allen JN, Blaszkowsky LS, Clark JW, Goyal L, Wo JY, Ryan DP, Corcoran RB, Deshpande V, Rivera MN, Aryee MJ, Hong TS, Berger SL, Walt DR, Burns KH, Park PJ, Greenbaum BD*, Ting DT*. Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer. Cancer Discov. 2022 Jun;12(6):1462–1481. PMCID: PMC9167735
Hoyos D, Greenbaum BD*. Perfecting antigen prediction. J Exp Med. 2022 Sep;219(9). PMCID: PMC9386507
Hoyos D, Greenbaum BD, Levine AJ. The genotypes and phenotypes of missense mutations in the proline domain of the p53 protein. Cell Death Differ. 2022 May(5):938–945. PMCID: PMC9090814
Bravi B, Balachandran VP, Greenbaum BD, Walczak AM, Mora T, Monasson R, Cocco S. Probing T-cell response by sequence-based probabilistic modeling. PLoS Comput Biol. 2021 Sep(9):e1009297. PMCID: PMC8476001
Roudko V, Cimen Bozkus C, Greenbaum BD, Lucas A, Samstein R, Bhardwaj N. Lynch Syndrome and MSI-H Cancers: From Mechanisms to “Off-The-Shelf” Cancer Vaccines. Front Immunol. 2021 Sep;12:757804. PMCID: PMC8498209.
Di Gioacchino A, Šulc P, Komarova AV, Greenbaum BD, Monasson R, Cocco S. The Heterogeneous Landscape and Early Evolution of Pathogen-Associated CpG Dinucleotides in SARS-CoV-2. Mol Biol Evol. 2021;38(6):2428-45. PMCID: PMC7928797
Solovyov A, Vabret N, Arora KS, Snyder A, Funt SA, Bajorin DF, Rosenberg JE, Bhardwaj N, Ting DT, Greenbaum BD*. Global Cancer Transcriptome Quantifies Repeat Element Polarization between Immunotherapy Responsive and T Cell Suppressive Classes. Cell Rep. 2018 Apr;23(2):512-521. PMCID: PMC6016853.
Łuksza M, Riaz N, Makarov V, Balachandran VP, Hellmann MD, Solovyov A, Rizvi NA, Merghoub T, Levine AJ, Chan TA, Wolchok JD, Greenbaum BD. A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy. Nature. 2017 Nov;551(7681):517-520. PMCID: PMC6137806.
Balachandran VP, Łuksza M, Zhao JN, Makarov V, Moral JA, Remark R, Herbst B, Askan G, Bhanot U, Senbabaoglu Y, Wells DK, Cary CIO, Grbovic-Huezo O, Attiyeh M, Medina B, Zhang J, Loo J, Saglimbeni J, Abu-Akeel M, Zappasodi R, Riaz N, Smoragiewicz M, Kelley ZL, Basturk O; Gönen M, Levine AJ, Allen PJ, Fearon DT, Merad M, Gnjatic S, Iacobuzio-Donahue CA, Wolchok JD, DeMatteo RP, Chan TA, Greenbaum BD, Merghoub T, Leach SD. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature. 2017 Nov;551(7681):512-516. PMCID: PMC6145146.
Tanne A, Muniz LR, Puzio-Kuter A, Leonova KI, Gudkov AV, Ting DT, Monasson R, Cocco S, Levine AJ, Bhardwaj N, Greenbaum BD*. Distinguishing the immunostimulatory properties of noncoding RNAs expressed in cancer cells. Proc Natl Acad Sci U S A. 2015 Dec;112(49):15154-9. PMCID: PMC4679042.
Greenbaum BD, Levine AJ, Bhanot G, Rabadan R. Patterns of evolution and host gene mimicry in influenza and other RNA viruses. PLoS Pathog. 2008 Jun;4(6):e1000079. PMCID: PMC2390760.
[* denotes Corresponding author]
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