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Resistance to Immunotherapy Can Be Present
at the Start of Treatment or Form Over Time
- Advances in immunotherapy have resulted in enhanced anti-tumor responses
- A significant challenge is the development of resistant disease and disease progression during or after therapy1,2
- As tumors evolve over time, they can influence the activation and composition of cells within the tumor microenvironment1,2
- Some tumors do not respond from the beginning of treatment with immunotherapies, and this is termed “primary resistance”3
- “Acquired resistance” describes tumors that initially respond to immunotherapies, but then fail to respond after a period of time3
- Primary resistance may occur because of an expression or repression of certain genes and pathways in tumor cells that prevent infiltration or function of immune cells within the tumor microenvironment4
- Such tumors are characterized as “cold” or noninflamed tumors3
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Reestablishing the fundamental stages that are impaired within noninflamed
tumors—presentation, infiltration, and elimination—is a key strategy in improving the broad potential of Immuno-Oncology (I-O) - Ongoing research aims to promote inflammation within tumors to increase susceptibility to antitumor immunity
- Acquired resistance may occur because of multiple factors, including the loss of T-cell function, lack of T-cell recognition by downregulation of tumor antigen presentation, and development of escape mutation variants in tumors3
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Cancer cells avoid destruction by the immune system by functionally silencing effector T cells
in a process called T-cell exhaustion5
- From a therapeutic point of view, it is essential to recognize the pathways and molecular signatures governing T-cell exhaustion to restore the antitumor immunity and overcome I-O resistance in some patients6
- Bristol-Myers Squibb is committed to understanding the tumor immune response and exploring mechanisms underlying primary and secondary acquired resistance
- Identification of mechanisms of immunotherapy resistance is an area of research that will inform appropriate treatment options for patients
- Bristol-Myers Squibb is committed to understanding the tumor immune response and exploring mechanisms underlying primary and secondary acquired resistance
- Basket trials test one or more drugs in multiple tumor types and are being used to evaluate the effect of a drug in a type of patient, in the hope of better identifying patients most responsive to the immunotherapy (eg, mutations, biomarkers)7-10
- Combination therapies are being studied, utilizing immunotherapy drugs with known activity, different mechanisms of actions11
- Predictive biomarkers are being identified to determine whether individuals are more likely to experience a favorable or unfavorable response to treatment11
References–I-O resistance
1. Bindea G, Mlecnik B, Tosolini M, et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity. 2013;39(4):782-795. 2. Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature. 2017;541(7637):321-330. 3. Sharma P,
6. Patil S, Rao RS, Majumdar B. T-cell exhaustion and cancer immunotherapy. J Int Oral Health. 2015;7(8):i-ii. 7. Day D, Siu LS. Approaches to modernize the combination drug development paradigm. Genome Med. 2016;8(1):115. doi:10.1186/s13073-016-0369-x. 8. Ferrara R, Pilotto S, Caccese M, et al. Do immune checkpoint inhibitors need new studies methodology? J Thorac Dis. 2018;10(suppl 13):S1564-S1580. 9. Ornes S. Basket trial approach capitalizes on the molecular mechanisms of tumors. Proc Natl Acad Sci U S A. 2016;113(26):7007-7008. 10. Redig AJ, Jänne PA. Basket trials and the evolution of clinical trial design in an era of genomic medicine. J Clin Oncol. 2015;33(9):975-977. 11. Yuan J, Hegde PS, Clynes R, et al. Novel technologies and emerging biomarkers for personalized cancer immunotherapy. J Immunother Cancer. 2016;4:3. doi:10.1186/s40425-016-0107-3.