Clinical Research Division, Fred Hutch
Dr. Martin A. “Mac” Cheever is an expert in the development of cancer immunotherapies and cancer vaccines. He directs the federally funded Cancer Immunotherapy Trials Network, or CITN. Through the network, researchers across the continent design and conduct novel, early phase trials of immunotherapy drugs. The goal of these trials is to provide proof of concept that helps advance the most promising new treatment regimens for patients by harnessing the power of the immune system. In his own research outside the CITN, Dr. Cheever has identified principles of T-cell therapy, discovered new targets for cancer therapies, and developed cancer vaccines.
Dr Cheever is a Member of Fred Hutchinson Cancer Research Center (FHCRC), a Professor of Medicine and Director of the NCI-funded Cancer Immunotherapy Trials Network (CITN). Dr. Cheever, and others in the field of cancer research, predicted a decade ago that within the next 10 years immunotherapy will provide the backbone for the majority of cancer therapy. The prediction is becoming reality and the Fred Hutchinson/University of Washington Cancer Consortium is poised to continue to lead the way. The development of cancer immunotherapy is both exciting and challenging. The development and testing of new immunotherapies to treat the common cancers is a pressing national and global need. Our team at FHCRC and UW is increasingly expert and accomplished in evaluating and developing the promise of new cancer immunotherapies beginning with preclinical work, early stage clinical trials and pivotal trials. The efforts of the consortium are contributing substantially to hasten the biotechnology and pharmaceutical industry’s development of cancer immunotherapy agents, drugs and therapy regimens.
Dr. Cheever’s own research expertise is in cancer immune therapy and cancer vaccine development. From 1987 to 1997 he served as Professor of Medicine at the UW and as a Member of Fred Hutchinson Cancer Research Center with a major focus on developing the principles of T cell therapy, cancer antigen discovery and development of cancer vaccines, especially for breast cancer. In 1994, he co-founded a biotech company, Corixa Corporation to develop cancer vaccines as therapeutic products. He served as Vice President of Clinical Research and Medical Affairs from 1997 to 2005. In this capacity, he gained extensive experience with the design and initiation of cancer vaccine trials; cancer antigen discovery and cancer vaccine development. The discoveries were done in collaboration with major pharmaceutical corporations as well as with the FDA.
Dr Cheever is currently the Principal Investigator and Director for the NCI-funded Cancer Immunotherapy Trials Network (CITN). The CITN has established a highly productive network of leading investigators from foremost cancer centers and universities in North America to implement, design and conduct novel biologic early phase trials using agents and combinations to demonstrate proof-of-concept essential to proceed to larger pivotal trials, and provide high quality immunogenicity and biomarker data that elucidates mechanisms of response. The CITN has 34 sites for immunotherapy trials in adults and 10 sites for pediatric trials. The CITN provides an organized effort to conduct early phase trials with a focus on trials likely to achieve the optimal/quickest route to (1) Proof of Concept, (2) Demonstration of patient benefit and (3) Regulatory approval.
The CITN strategy is to develop highly informative trials not otherwise possible, by combining (1) the best peer-reviewed concepts, with submissions open to everyone in the field, (2) optimal trial design by multidisciplinary Concept Working Groups overseen by the CITN Executive and Steering Committees; and (3) priority agents not generally available for academic investigator initiated trials. The agents designated for the initial focus of CITN trials were prioritized in NCI-sponsored workshops (in fact, the formation of the CITN largely evolved from the findings of these workshops [2-4]). The agents in CITN trials all augment processes central to an effective immune response. Agents in completed or ongoing trials include (with agents in parentheses) dendritic cell activators (anti-CD40 and poly ICLC), dendritic cell growth factor (Flt3-L), innate and T cell activator (IFN-gamma), T-cell growth factors (IL-15 and IL-7), vaccine adjuvants (Poly ICLC), inhibitors of T-cell checkpoint blockade (anti-PD1 and anti-PD-L1), inhibitors of immune- and cancer-cell–induced immune-suppression (anti-TGFß and IDO inhibitors).
Of note, CITN trials in orphan diseases have changed the standard in three diseases to date (Merkel Cell carcinoma, mycosis fungoides/Sezary syndrome and patients with HIV and advanced malignancy. Additional trials in orphan and ultra-orphan disease largely ignored by industry are ongoing or soon to begin including three trials in pediatric cancers.
Toward the major goal of having many priority immunotherapy agents with proven biologic function in addition to checkpoint inhibitors broadly available for cancer therapy, the CITN strategy focuses on (1) collaborative trials likely to achieve the optimal or quickest route to (a) proof of concept, (b) demonstrating patient benefit, and (c) regulatory approval; and (2) agents and formulations likely to achieve broad availability through commercialization. With this strategy, the CITN has been able to gain access to the top-ranked priority agents heretofore not available to the broad community—which is a key first and essential step.
CITN: Pre-CITN Background References
1. Cheever MA. Twelve immunotherapy drugs that could cure cancers. Immunol Rev. 2008;222:357-368.
2. Cheever MA, Creekmore SP. Immunotherapy Agent Workshop, July 12, 2007. http://citninfo.org/research/rationale.html#workshop_1. Accessed April 4, 2012
3. Cheever MA, Allison, JP, Ferris, AS, Finn OJ, Hastings, BM, Hecht, TT, Mellman I, Prindiville SA, Steinman, Viner JL, Weiner LM, Matrisian LM. The prioritization of cancer antigens: A National Cancer Institute pilot project for the acceleration of translational research. Clin Cancer Res. 2009;15(17):5323-5337.
4. Cheever MA, Matrisian LM. Report of the Immune Response Modifier Pathway Prioritization Working Group (IRMP WG), November 2009. http://deainfo.nci.nih.gov/advisory/ctac/workgroup/_IRM%20Prioritization%20Working%20Group%20FINAL%20REPORT.pdf. Accessed April 4, 2012
CITN: Orphan Disease Trial References
5. Nghiem PT, Bhatia S, Lipson EJ, Kudchadkar RR, Miller NJ, Annamalai L, Berry S, Chartash EK, Daud A, Fling SP, Friedlander PA, Kluger HM, Kohrt HE, Lundgren L, Margolin K, Mitchell A, Olencki T, Pardoll DM, Reddy SA, Shantha EM, Sharfman WH, Sharon E, Shemanski LR, Shinohara MM, Sunshine JC, Taube JM, Thompson JA, Townson SM, Yearley JH, Topalian SL, Cheever MA. PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma. N Engl J Med. 2016 Jun 30;374(26):2542-52. PubMed PMID: 27093365; PubMed Central PMCID: PMC4927341.
6. Nghiem P, Bhatia S, Lipson EJ, Sharfman WH, Kudchadkar RR, Brohl AS, Friedlander PA, Daud A, Kluger HM, Reddy SA, Boulmay BC, Riker AI, Burgess MA, Hanks BA, Olencki T, Margolin K, Lundgren LM, Soni A, Ramchurren N, Church C, Park SY, Shinohara MM, Salim B, Taube JM, Bird SR, Ibrahim N, Fling SP, Homet Moreno B, Sharon E, Cheever MA, Topalian SL. Durable Tumor Regression and Overall Survival in Patients With Advanced Merkel Cell Carcinoma Receiving Pembrolizumab as First-Line Therapy. J Clin Oncol. 2019 Feb 6:JCO1801896. PubMed PMID: 30726175.
7. Thomas S. Uldrick, Priscila H. Gonçalves, Maher Abdul-Hay, Alisa J. Claeys, Brinda Emu, Marc S. Ernstoff, Steven P. Fling, Lawrence Fong, Judith C. Kaiser, Andreanne M. Lacroix, Steve Y. Lee, Lisa M. Lundgren, Kathryn Lurain, Christopher H. Parsons, Sharavi Peeramsetti, Ramya Ramaswami, Elad Sharon, Mario Sznol, Chia-Ching (Jackie) Wang, Robert Yarchoan, and Martin A. Cheever, for the Cancer Immunotherapy Trials Network (CITN)-12 Study Team. Phase 1 Study of Pembrolizumab in Patients with HIV and Advanced Cancer. JAMA Oncology (In press for on-line publication June 2 2019)
8. Michael S Khodadoust, Alain H Rook, Pierluigi Porcu, Francine Foss, Alison J Moskowitz, Andrei Shustov, Satish Shanbhag, Lubomir Sokol, Steven P Fling, Nirasha Ramchurren, Robert Pierce, Asa Davis, Richard Shine, Shufeng Li, Sophia Fong, Jinah Kim, Yi Yang, Wendy M Blumenschein, Jennifer H Yearley, Biswajit Das, Rajesh Patidar, Vivekananda Datta, Erin Cantu, Justine N McCutcheon, Chris Karlovich, Mickey Williams, Priyanka B Subrahmanyam, Holden T Maecker, Steven M Horwitz, Elad Sharon, Holbrook E Kohrt, Martin A Cheever and Youn H Kim. Pembrolizumab in Relapsed and Refractory Mycosis Fungoides and Sézary Syndrome: a Multicenter Phase II Study (in press)
Professor of Medicine/Oncology
University of Washington
Cancer Immunotherapy Trials Network
Study Number: CITN-09
Study Number: CITN-12
Study Number: CITN-13
Study Number: CITN-14
Study Number: CITN-16
Study Number: Ped-CITN-01
Phase: Ib and Expansion Study
Study Number: Ped-CITN-02
Study Number: ION-01
Study Number: ION-02
Study Number: ION-03
Study Number: ION-04
Study Number: ION-05
— Dr. Martin Cheever
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