Dougan Lab

Overview

The Dougan lab is focused on understanding the relationship between effective antitumor immunity and immune-related toxicities. Immunotherapy targeting the immune checkpoint receptors CTLA-4, PD-1 and PD-L1 has transformed the treatment landscape for a diverse range of human cancers, inducing durable remissions in tumors that were previously uniformly fatal. Yet by disabling key immune regulatory circuits, immunotherapy also induces a broad array of inflammatory toxicities. These toxicities, which often involve the gastrointestinal tract, are a window into mucosal immune regulation more generally. Using a variety of modern genomics techniques, mechanism-based clinical trials, and animal models, my group strives to define the cellular and molecular mechanisms controlled by the CTLA-4 and PD-1/PD-L1 pathways in the gut, and to use this information, paired with a detailed understanding of antitumor immunity to design new therapeutic approaches to uncouple productive antitumor responses from treatment-limiting toxicities. Insights from these experiments may also have broader implications for autoimmune disease.

COVID-19

During the COVID-19 pandemic, our group shifted its focus to developing effective treatments for this devastating disease. Realizing that many patients who became critically ill with COVID-19 generated insufficient endogenous immune responses, we worked in collaboration with Eli Lilly and Company to perform first in human testing of monoclonal antibodies against the SARS-CoV-2 spike protein. Working on these antibodies from Phase 1 through Phase 3 testing, we established that monoclonal antibody therapy for SARS-CoV-2 is safe and if given early in disease can decrease the risk of hospitalization and death by 80%.

Key Publications

1. Dougan M*, Nirula A*, Azizad M, Mocherla B, Gottlieb RL, Chen P, Hebert C, Perry R, Boscia J, Heller B, Morris J, Crystal C, Igbinadolor A, Huhn G, Cardona J, Shawa I, Kumar P, Adams AC, Van Naarden J, Custer KL, Durante M, Oakley G, Schade AE, Holzer TR, Ebert PJ, Higgs RE, Kallewaard NL, Sabo J, Patel DR, Dabora MC, Klekotka P, Shen L, Skovronsky DM; BLAZE-1 Investigators. Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19. N Engl J Med. 2021 Jul 14. doi: 10.1056/NEJMoa2102685.
2. Luoma AM, Suo S, Williams HL, Sharova T, Sullivan K, Manos M, Bowling P, Hodi FS, Rahma O, Sullivan RJ, Boland GM, Nowak JA, Dougan SK, Dougan M*, Yuan GC, Wucherpfennig KW*. Molecular Pathways of Colon Inflammation Induced by Cancer Immunotherapy. Cell. 2020 Jun 25:S0092-8674(20)30688-7. doi: 10.1016/j.cell.2020.06.001.
3. Abu-Sbeih H, Faleck DM, Ricciuti B, Mendelsohn RB, Naqash AR, Cohen JV, Sellers MC, Balaji A, Ben-Betzalel G, Hajir I, Zhang J, Awad MM, Leonardi GC, Johnson DB, Pinato DJ13, Owen DH, Weiss SA, Lamberti G, Lythgoe MP, Manuzzi L, Arnold C, Qiao W, Naidoo J, Markel G, Powell N, Yeung SJ, Sharon E, Dougan M*, Wang Y*. Immune Checkpoint Inhibitor Therapy in Patients With Preexisting Inflammatory Bowel Disease. J Clin Oncol. 2019 Dec 4:JCO1901674. doi: 10.1200/JCO.19.01674. [Epub ahead of print].

Additional Publications

1. Chen P, Datta G, Li YG, Chien J, Price K, Chigutsa E, Brown-Augsburger P, Poorbaugh J, Fill J, Benschop RJ, Rouphael N, Kay A, Mulligan MJ, Saxena A, Fischer WA, Dougan M, Klekotka P, Nirula A, Benson C. First in Human Study of Bamlanivimab in a Randomized Trial of Hospitalized Patients with COVID-19. Clin Pharmacol Ther. 2021 Aug 28. doi: 10.1002/cpt.2405. Online ahead of print.
2. Pisuchpen N, Durbin SM, Mooradian MJ, Fintelmann FJ, Reynolds KL, Dougan M, Kambadakone A. Multi-detector computed tomography (MDCT)-based severity score as a prognostic tool in patients with suspected immune checkpoint inhibitor therapy associated colitis. Eur Radiol. 2021 Jun 3. doi: 10.1007/s00330-021-07925-7.
3. Roehle K, Qiang L, Ventre KS, Heid D, Ali LR, Lenehan P, Heckler M, Crowley SJ, Stump CT, Ro G, Godicelj A, Bhuiyan AM, Yang A, Quiles Del Rey M, Biary T, Luoma AM, Bruck PT, Tegethoff JF, Nopper SL, Li J, Byrne KT, Pelletier M, Wucherpfennig KW, Stanger BZ, Akin JJ, Mancias JD, Agudo J, Dougan M, Dougan SK. cIAP1/2 antagonism eliminates MHC class I-negative tumors through T cell-dependent reprogramming of mononuclear phagocytes. Sci Transl Med. 2021 May 19;13(594):eabf5058. doi: 10.1126/scitranslmed.abf5058.
4. Heckler M, Ali LR, Clancy-Thompson E, Qiang L, Ventre KS, Lenehan P, Roehle K, Luoma A, Boelaars K, Peters V, McCreary J, Boschert T, Wang ES, Suo S, Marangoni F, Mempel TR, Long HW, Wucherpfennig KW, Dougan M, Gray NS, Yuan GC, Goel S, Tolaney SM, Dougan SK. Inhibition of CDK4/6 promotes CD8 T-cell memory formation. Cancer Discov. 2021 May 3:candisc.1540.2020. doi: 10.1158/2159-8290.
5. Fajnzylber J, Regan J, Coxen K, Corry H, Wong C, Rosenthal A, Worrall D, Giguel F, Piechocka-Trocha A, Atyeo C, Fischinger S, Chan A, Flaherty KT, Hall K, Dougan M, Ryan ET, Gillespie E, Chishti R, Li Y, Jilg N, Hanidziar D, Baron RM, Baden L, Tsibris AM, Armstrong KA, Kuritzkes DR, Alter G, Walker BD, Yu X, Li JZ; Massachusetts Consortium for Pathogen Readiness. SARS-CoV-2 viral load is associated with increased disease severity and mortality. Nat Commun. 2020 Oct 30;11(1):5493. doi: 10.1038/s41467-020-19057-5.
6. Fernandes RA, Su L, Nishiga Y, Ren J, Bhuiyan AM, Cheng N, Kuo CJ, Picton LK, Ohtsuki S, Majzner RG, Rietberg SP, Mackall CL, Yin Q, Ali LR, Yang X, Savvides CS, Sage J, Dougan M, Garcia KC. Immune receptor inhibition through enforced phosphatase recruitment. Nature. 2020 Oct 21. doi: 10.1038/s41586-020-2851-2. Online ahead of print.
7. Stone JH, Frigault MJ, Serling-Boyd NJ, Fernandes AD, Harvey L, Foulkes AS, Horick NK, Healy BC, Shah R, Bensaci AM, Woolley AE, Nikiforow S, Lin N, Sagar M, Schrager H, Huckins DS, Axelrod M, Pincus MD, Fleisher J, Sacks CA, Dougan M, North CM, Halvorsen YD, Thurber TK, Dagher Z, Scherer A, Wallwork RS, Kim AY, Schoenfeld S, Sen P, Neilan TG, Perugino CA, Unizony SH, Collier DS, Matza MA, Yinh JM, Bowman KA, Meyerowitz E, Zafar A, Drobni ZD, Bolster MB, Kohler M, D'Silva KM, Dau J, Lockwood MM, Cubbison C, Weber BN, Mansour MK; BACC Bay Tocilizumab Trial Investigators. Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N Engl J Med. 2020 Oct 21. doi: 10.1056/NEJMoa2028836. Online ahead of print
8. Durbin SM, Mooradian MJ, Fintelmann FJ, Zubiri L, Chute DF, Kambadakone A, Pisuchpen N, Reynolds KL, Dougan M. Diagnostic utility of CT for suspected immune checkpoint inhibitor enterocolitis. J Immunother Cancer. 2020 Oct;8(2):e001329.

9. Sacks CA*, Dougan M*, McCoy TH Jr, Zheng A, Buonomo G, North CM, Metlay JP, Walensky RP. he Association between Symptoms and COVID-19 Test Results among Healthcare Workers. Ann Surg. 2020 Sep 15. doi: 10.1097/SLA.0000000000004483.
10. Cohen JV, Dougan M, Zubiri L, Reynolds KL, Sullivan RJ, Misdraji J. Liver biopsy findings in patients on immune checkpoint inhibitors. Mod Pathol. 2020 Sep 3. doi: 10.1038/s41379-020-00653-1. Online ahead of print.
11. Badran Y, Shih A, Leet D, Mooradian MJ, Coromilas A, Chen J, Kem M, Zheng H, Borowsky J, Misdraji J, Mino-Kenudson M, Dougan M. Immune Checkpoint Inhibitor-Associated Celiac Disease. J Immunother Cancer. 2020 Jun;8(1):e000958. doi: 10.1136/jitc-2020-000958.
12. Grover S*, Dougan M*, Tyan K, Giobbie-Hurder A, Blum SM, Ishizuka J, Qazi T, Elias R, Vora KB, Ruan AB, Martin-Doyle W, Manos M, Eastman L, Davis M, Gargano M, Haq R, Buchbinder EI, Sullivan RJ, Ott PA, Hodi FS, Rahma OE. Vitamin D Intake Is Associated With Decreased Risk of Immune Checkpoint Inhibitor-Induced Colitis. Cancer. 2020 Jun 22. doi: 10.1002/cncr.32966.
13. Mooradian MJ, Wang DY, Coromilas A, Lumish M, Chen T, Giobbie-Hurder A, Johnson DB, Sullivan RJ*, Dougan M*. Mucosal inflammation predicts response to systemic steroids in immune checkpoint inhibitor colitis. J Immunother Cancer. 2020 May;8(1). pii: e000451. doi: 10.1136/jitc-2019-000451.
14. Xie YJ, Dougan M, Ingram JR, Pishesha N, Fang T, Momin N, Ploegh HL. Improved anti-tumor efficacy of chimeric antigen receptor T cells that secrete single-domain antibody fragments. Cancer Immunol Res. 2020 Feb 4. pii: canimm.0734.2019. doi: 10.1158/2326-6066.CIR-19-0734. [Epub ahead of print]
15. Crowley SJ, Bruck PT, Bhuiyan MA, Mitchell-Gears A, Walsh MJ, Zhangxu K, Ali LR, Jeong HJ, Ingram JR, Knipe DM, Ploegh HL, Dougan M, Dougan SK. Neoleukin-2 enhances anti-tumour immunity downstream of peptide vaccination targeted by an anti-MHC class II VHH. Open Biol. 2020 Feb;10(2):190235.
16. Hughes MS, Molina GE, Chen ST, Zheng H, Deshpande V, Fadden R, Sullivan RJ, Dougan M. Budesonide treatment for microscopic colitis from immune checkpoint inhibitors. J Immunother Cancer. 2019 Nov 7;7(1):292.
17. Badran YR, Cohen JV, Brastianos PK, Parikh AR, Hong TS, Dougan M. Concurrent therapy with immune checkpoint inhibitors and TNFα blockade in patients with gastrointestinal immune-related adverse events. J Immunother Cancer. 2019 Aug 22;7(1):226.
18. Zhang ML, Neyaz A, Patil D, Chen J, Dougan M, Deshpande V. Immune-Related Adverse Events in the Gastrointestinal Tract: Diagnostic Utility of Upper Gastrointestinal Biopsies. Histopathology. 2019 Jul 30. doi: 10.1111/his.13963. [Epub ahead of print]
19. Xie YJ, Dougan M, Jailkhani N, Ingram J, Fang T, Kummer L, Momin N, Pishesha N, Rickelt S, Hynes RO, Ploegh H. Nanobody-based CAR T cells that target the tumor microenvironment inhibit the growth of solid tumors in immunocompetent mice. Proc Natl Acad Sci U S A. 2019 Apr 1. pii: 201817147.
20. Silva DA, Yu S, Ulge U, Spangler JB, Jude KM, Labao-Almeida C, Ali LR, Quijano-Rubo A, Ruterbusch M, Leung I, Biary T, Crowley S, Marco E, Walkey CD, Weitzner BD, Pardo-Avila F, Carter L, Stewart L, Riddell S, Pepper M, Bernardes GJL, Dougan M, Garcia KC, Baker D. De novo design of potent and selective mimics of IL-2/IL-15. Nature. 2019 Jan;565(7738):186-191.
21. Krall JA, Reinhardt F, Mercury OA, Pattabiraman DR, Brooks MW, Dougan M, Lambert AW, Bierie B, Ploegh HL, Dougan SK, Weinberg RA. The systemic response to surgery triggers the outgrowth of distant immune-controlled tumors in mouse models of dormancy. Sci Transl Med. 2018 Apr 11;10(436).
22. Ingram JR, Blomberg OS, Rashidian M, Ali L, Garforth S, Fedorov E, Fedorov AA, Bonanno JB, Le Gall C, Crowley S, Espinosa C, Biary T, Keliher EJ, Weissleder R, Almo SC, Dougan SK, Ploegh HL*, Dougan M*. Anti-CTLA-4 therapy requires an Fc domain for efficacy. Proc Natl Acad Sci USA. 2018.
23. Dougan M*, Ingram JR*, Jeong HJ, Mosaheb MM, Bruck PT, Ali L, Pishesha N, Blomberg O, Tyler PM, Servos MM, Rashidian M, Nguyen QD, von Andrian UH, Ploegh HL, Dougan SK. Targeting cytokine therapy to the pancreatic tumor microenvironment using PD-L1 specific VHHs. Cancer Immunol Res. 2018.
24. Clancy-Thompson E, Ali L, Bruck PT, Exley MA, Blumberg RS, Dranoff G, Dougan M*, Dougan SK. IAP antagonists enhance cytokine production from mouse and human iNKT cells. Cancer Immunol Res. 2017 Nov 29.
25. Ingram JR*, Dougan M*, Rashidian M, Knoll M, Keliher EJ, Garrett S, Garforth S, Blomberg OS, Espinosa C, Bhan A, Almo SC, Weissleder R, Lodish H, Dougan SK, Ploegh HL. PD-L1 is an activation-independent marker of brown adipocytes. Nat Commun. 2017 Sep 21;8(1):647.
26. Rashidian M*, Ingram JR*, Dougan M*, Dongre A, Whang KA, LeGall C, Cragnolini JJ, Bierie B, Gostissa M, Gorman J, Grotenbreg GM, Bhan A, Weinberg RA, Ploegh HL. Predicting the response to CTLA-4 blockade by longitudinal noninvasive monitoring of CD8 T cells. J Exp Med. 2017 Aug 7;214(8):2243-2255.
27. Sockolosky JT*, Dougan M*, Ingram JR, Ho CC, Kauke MJ, Almo SC, Ploegh HL, Garcia KC. Durable antitumor responses to CD47 blockade require adaptive immune stimulation. Proc Natl Acad Sci U S A. 2016 May 10;113(19):E2646-54.
28. Dougan M, Li D, Neuberg D, Mihm M, Googe P, Wong K, Dranoff G. A Dual Role for the Immune Response in a Mouse Model of Inflammation Associated Lung Cancer. Journal of Clinical Investigation. 121, 2436-2446 (2011)
29. Dougan M, Dougan S, Slisz J, Firestone B, Vanneman M, Draganov D, Goyal G, Li W, Neuberg D, Blumberg R, Hacohen N, Porter D, Zawel L, Dranoff G. IAP Inhibitors Enhance Co-Stimulation to Promote Tumor Immunity. Journal of Experimental Medicine. 207, 2195-2206 (2010)

Group Members

Michael Dougan, MD, PhD
Assistant Professor

Keri Sullivan
Clinical Research Coordinator

Elizabeth Keleher
Clinical Research Coordinator

Kevin Zhangxu
Laboratory Technician

Courtney Stump
Laboratory Technician

Lestat Ali
Harvard Medical Student

Yousef Badran, MD
Gastroenterology Fellow