Proceedings of a Workshop
THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001
This activity was supported by Contract No. 75D30121D11240 (Task Order Nos. 75D30121F00002 and 75D30123F00024) with the Centers for Disease Control and Prevention; Contract No. HHSN263201800029I (Task Order Nos. HHSN26300007, HHSN26300008, 75N98023F00019, and 75N98023F00020) with the National Institutes of Health (National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, and Office of Science Policy); and Grant No. 1R13FD007302-01 with the U.S. Food and Drug Administration. This activity was also supported by the American Association for Cancer Research; American Cancer Society; American College of Radiology; American Society of Clinical Oncology; Amgen Inc.; Association of American Cancer Institutes; Association of American Medical Colleges; Association of Community Cancer Centers; AstraZeneca; Biogen; Bristol Myers Squibb; Burroughs Wellcome Fund; Cancer Support Community; Critical Path Institute; Eli Lilly & Co.; FasterCures, Milken Institute; Flatiron Health; Foundation for the National Institutes of Health; Friends of Cancer Research; Johnson & Johnson; Medable, Inc.; Merck; National Comprehensive Cancer Network; National Patient Advocate Foundation; New England Journal of Medicine; Novartis Oncology; Oncology Nursing Society; Partners in Health; Pfizer Inc; Sanofi; and Society for Immunotherapy of Cancer. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project.
International Standard Book Number-13: 978-0-309-71626-0
International Standard Book Number-10: 0-309-71626-8
Digital Object Identifier: https://doi.org/10.17226/27517
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Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2024. Addressing treatment resistance in the development of cancer immune modulator therapeutics: Proceedings of a workshop. Washington, DC: The National Academies Press. https://doi.org/10.17226/27517.
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PLANNING COMMITTEE1
SAMIR N. KHLEIF (Co-Chair), Georgetown University
GEORGE J. WEINER (Co-Chair), University of Iowa
GIDEON BLUMENTHAL, Merck
CHRIS BOSHOFF, Pfizer Inc.
TOM CURRAN, Children’s Mercy Kansas City
NANCY E. DAVIDSON, Fred Hutchinson Cancer Center; University of Washington
JULIE R. GRALOW, American Society of Clinical Oncology
ROY S. HERBST, Yale University
HEDVIG HRICAK, Memorial Sloan Kettering Cancer Center
SCOTT M. LIPPMAN, University of California, San Diego
W. KIMRYN RATHMELL, Vanderbilt University Medical Center
MARC THEORET, Oncology Center of Excellence, U.S. Food and Drug Administration
Project Staff
ANNA ADLER, Senior Program Assistant (from September 2023)
FRANCIS AMANKWAH, Program Officer (through August 2022)
LORI BENJAMIN BRENIG, Research Associate (through May 2023)
TORRIE BROWN, Program Coordinator
CHIDINMA CHUKWURAH, Senior Program Assistant
GRACE McCARTHY, Christine Mirzayan Science and Technology Policy Graduate Fellow (March–May 2023)
EMMA WICKLAND, Research Associate (from September 2023)
JULIE WILTSHIRE, Senior Finance Business Partner
JENNIFER ZHU, Associate Program Officer (from January 2023)
CAROLYN SHORE, Director, Forum on Drug Discovery, Development, and Translation
ERIN BALOGH, Co-Director, National Cancer Policy Forum
SHARYL NASS, Co-Director, National Cancer Policy Forum; Senior Director, Board on Health Care Services
___________________
1 The National Academies of Sciences, Engineering, and Medicine’s planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteurs and the institution.
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NATIONAL CANCER POLICY FORUM1
ROBERT A. WINN (Chair), Virginia Commonwealth University
PETER C. ADAMSON, Sanofi
JUSTIN E. BEKELMAN, University of Pennsylvania
SMITA BHATIA, The University of Alabama at Birmingham
GIDEON BLUMENTHAL, Merck
CHRIS BOSHOFF, Pfizer Inc.
OTIS W. BRAWLEY, Johns Hopkins University
HILLARY CAVANAGH, Centers for Medicare & Medicaid Services
CHRISTINA CHAPMAN, Baylor College of Medicine; Michael E. DeBakey VA Medical Center
GWEN DARIEN, National Patient Advocate Foundation
CRYSTAL DENLINGER, National Comprehensive Cancer Network
JAMES H. DOROSHOW, National Cancer Institute
S. GAIL ECKHARDT, Baylor College of Medicine
CHRISTOPHER R. FRIESE, University of Michigan
STANTON L. GERSON, Case Western Reserve University
SCARLETT LIN GOMEZ, University of California, San Francisco
JULIE R. GRALOW, American Society of Clinical Oncology
ROY S. HERBST, Yale University; American Association for Cancer Research
HEDVIG HRICAK, Memorial Sloan Kettering Cancer Center
CHANITA HUGHES-HALBERT, University of Southern California
ROY A. JENSEN, University of Kansas; Association of American Cancer Institutes
RANDY A. JONES, University of Virginia
BETH Y. KARLAN, University of California, Los Angeles
SAMIR N. KHLEIF, Georgetown University; Society for Immunotherapy of Cancer
SCOTT M. LIPPMAN, University of California, San Diego
ELENA MARTINEZ, University of California, San Diego
LARISSA NEKHLYUDOV, Brigham and Women’s Hospital; DanaFarber Cancer Institute; Harvard Medical School
___________________
1 The National Academies of Sciences, Engineering, and Medicine’s forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteurs and the institution.
RANDALL A. OYER, University of Pennsylvania; Penn Medicine Lancaster General Health; Association of Community Cancer Centers
CLEO A. RYALS, Flatiron Health
RICHARD L. SCHILSKY, ASCO TAPUR Study; University of Chicago
JULIE SCHNEIDER, Oncology Center of Excellence, U.S. Food and Drug Administration
SUSAN M. SCHNEIDER, Duke University
LAWRENCE N. SHULMAN, University of Pennsylvania
HEIDI SMITH, Novartis Pharmaceuticals
KATRINA TRIVERS, Centers for Disease Control and Prevention
ROBIN YABROFF, American Cancer Society
Forum Staff
ANNA ADLER, Senior Program Assistant
TORRIE BROWN, Program Coordinator
CHIDINMA CHUKWURAH, Senior Program Assistant
EMMA WICKLAND, Research Associate
JULIE WILTSHIRE, Senior Finance Business Partner
JENNIFER ZHU, Associate Program Officer
ERIN BALOGH, Co-Director, National Cancer Policy Forum
SHARYL NASS, Co-Director, National Cancer Policy Forum; Senior Director, Board on Health Care Services
FORUM ON DRUG DISCOVERY, DEVELOPMENT, AND TRANSLATION1
GREGORY SIMON (Co-Chair), Kaiser Permanente Washington Health Research Institute; University of Washington
ANN TAYLOR (Co-Chair), Retired
BARBARA E. BIERER, Harvard Medical School; Brigham and Women’s Hospital
LINDA BRADY, National Institute of Mental Health, NIH
JOHN BUSE, University of North Carolina, Chapel Hill School of Medicine
LUTHER T. CLARK, Merck
BARRY S. COLLER, The Rockefeller University
TAMMY R.L. COLLINS, Burroughs Wellcome Fund
TOM CURRAN, Children’s Mercy, Kansas City
RICHARD DAVEY, National Institute of Allergy and Infectious Diseases, NIH
KATHERINE DAWSON, Biogen
JAMES H. DOROSHOW, National Cancer Institute, NIH
JEFFREY M. DRAZEN, New England Journal of Medicine
STEVEN K. GALSON, Retired
CARLOS O. GARNER, Eli Lilly & Company
SALLY L. HODDER, West Virginia University
TESHEIA JOHNSON, Yale School of Medicine
LYRIC JORGENSON, Office of Science Policy, NIH
ESTHER KROFAH, FasterCures, Milken Institute
LISA M. LaVANGE, University of North Carolina
ARAN MAREE, Johnson & Johnson
CRISTIAN MASSACESI, AstraZeneca
ROSS McKINNEY JR., Association of American Medical Colleges
JOSEPH P. MENETSKI, Foundation for the National Institutes of Health
ANAEZE C. OFFODILE II, University of Texas MD Anderson Cancer Center
SALLY OKUN, Clinical Trials Transformation Initiative
___________________
1 The National Academies of Sciences, Engineering, and Medicine’s forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteurs and the institution.
ARTI RAI, Duke University School of Law
KLAUS ROMERO, Critical Path Institute
JONI RUTTER, National Center for Advancing Translational Sciences, NIH
SUSAN SCHAEFFER, The Patients’ Academy for Research Advocacy
ANANTHA SHEKHAR, University of Pittsburgh School of Medicine
ELLEN V. SIGAL, Friends of Cancer Research
MARK TAISEY, Amgen Inc.
AMIR TAMIZ, National Institute of Neurological Disorders and Stroke, NIH
PAMELA TENAERTS, Medable Inc.
MAJID VAKILYNEJAD, Takeda
JONATHAN WATANABE, University of California Irvine School of Pharmacy and Pharmaceutical Sciences
ALASTAIR WOOD, Vanderbilt University
CRIS WOOLSTON, Sanofi
JOSEPH C. WU, Stanford University School of Medicine
Forum Staff
CAROLYN SHORE, Forum Director
KYLE CAVAGNINI, Associate Program Officer
BRITTANY HSIAO, Associate Program Officer (as of September 2023)
MAYA THIRKILL, Associate Program Officer (until April 2023)
NOAH ONTJES, Research Associate
MELVIN JOPPY, Senior Program Assistant
CLARE STROUD, Senior Director, Board on Health Sciences Policy
Reviewers
This Proceedings of a Workshop was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published proceedings as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the charge. The review comments and draft manuscript remain confidential to protect the integrity of the process.
We thank the following individuals for their review of this proceedings:
Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the content of the proceedings nor did they see the final draft before its release. The review of this proceedings was overseen by DANIEL R. MASYS, University of Washington. He was responsible for making certain that an independent examination of this proceedings was carried out in accordance with standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the rapporteurs and the National Academies.
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Acknowledgments
The National Cancer Policy Forum is grateful for the support of our many annual sponsors. Federal sponsors include the Centers for Disease Control and Prevention and the National Cancer Institute/National Institutes of Health. Non-federal sponsors include the American Association for Cancer Research, American Cancer Society, American College of Radiology, American Society of Clinical Oncology, Association of American Cancer Institutes, Association of Community Cancer Centers, Bristol Myers Squibb, Cancer Support Community, Flatiron Health, Merck & Co., Inc., National Comprehensive Cancer Network, National Patient Advocate Foundation, Novartis Oncology, Oncology Nursing Society, Partners in Health, Pfizer Inc., Sanofi, and Society for Immunotherapy of Cancer.
The Forum on Drug Discovery, Development, and Translation is also appreciative of the support from our many annual sponsors. Federal sponsors include the National Institutes of Health (National Cancer Institute, National Institute on Allergy and Infectious Diseases, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, and Office of Science Policy) and the U.S. Food and Drug Administration. Non-federal sponsors include Amgen Inc.; Association of American Medical Colleges; AstraZeneca; Biogen; Burroughs Wellcome Fund; Critical Path Institute; Eli Lilly & Co.; FasterCures, Milken Institute; Foundation for the National Institutes of Health; Friends of Cancer Research; Johnson & Johnson; Medable Inc.; Merck; New England Journal of Medicine; and Sanofi.
The Forums wish to express their gratitude to the expert speakers whose presentations and discussions helped inform efforts to counter resistance and
advance meaningful progress in the development of immune modulator therapies for cancer treatment. The Forums also wish to thank the members of the planning committee for their work in developing an excellent workshop agenda.
Contents
SCIENTIFIC INNOVATIONS TO ADVANCE CANCER CARE
History of Immunotherapy Development
Clinical Trial Challenges and Opportunities
CRITERIA TO MOVE SINGLE AGENTS INTO CLINICAL TRIALS
Anti-Lymphocyte Activation Gene-3 (LAG-3) Antibodies
Chimeric Antigen Receptor T-Cell (CAR T) Resistance
Opportunities and Challenges to Advance the Development of Single Agents
SELECTION OF EXPERIMENTAL AGENTS IN COMBINATION THERAPY
Understanding the Effects of Combination Immunotherapy
Clinical Trials for Patients with Anti-PD-1/L1 Refractory Cancers
Opportunities to Improve Selection and Development of Combination Therapies
BIOMARKERS AND SURROGATE ENDPOINTS
Regulatory Considerations for Biomarkers in Cancer Immunotherapy
Surrogate Endpoint Development
THE ROLE OF DATA AND COMPUTATIONAL TOOLS
Regulatory and Access Considerations in Mining Big Data
Data-Driven Approaches for Modeling Response and Resistance
Leveraging Real-World Data to Characterize Immune-Related Adverse Events (irAEs)
AI, Data Science, and Big Data Approaches
Assessing the Contributions of Individual Components
Incorporating Pharmacodynamics
Boxes and Figures
BOXES
FIGURES
3 Clinical trial design for combination studies with two active agents
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Acronyms and Abbreviations
| AhR | aryl hydrocarbon receptor |
| AI | artificial intelligence |
| CAR T | chimeric antigen receptor T cell |
| CD | cluster of differentiation |
| COE | contribution of effect |
| COVID-19 | coronavirus disease of 2019 |
| ctDNA | circulating tumor DNA |
| CTLA-4 | cytotoxic T-lymphocyte-associated protein 4 |
| dMMR | deficient mismatch repair |
| EHR | electronic health record |
| FDA | U.S. Food and Drug Administration |
| FNIH | Foundation for the National Institutes of Health |
| GITR | glucocorticoid-induced tumor-necrosis-factor-related gene |
| ICI | immune checkpoint inhibitor |
| IDO1 | indoleamine 2,3-dioxygenase-1 |
| irAE | immune-related adverse event |
| JAK | Janus kinase |
| LAG-3 | lymphocyte activation gene-3 |
| LungMAP | Lung Cancer Master Protocol |
| mCODE | Minimal Common Oncology Data Elements |
| ML | machine learning |
| MRD | minimal residual disease |
| MRI | magnetic resonance imaging |
| MSI-H | microsatellite instability-high |
| NCI | National Cancer Institute |
| NLP | natural language processing |
| ORIEN | Oncology Research Information Exchange Network |
| pCR | pathological complete response |
| PD-1 | programmed cell death receptor 1 |
| PD-L1 | programmed cell death ligand 1 |
| PET | positron emission tomography |
| RECIST | Response Evaluation Criteria in Solid Tumors |
| RNA | ribonucleic acid |
| SCNA | somatic copy number alteration |
| TCR | T-cell receptor |
| TMB-H | tumor mutational burden-high |
