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Understanding – and Fighting Against – Immunotherapy Resistance in Cancer Treatments

May 4, 2021
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Every patient has an immune system, which exists to protect the body from infection. We generally think about the immune system protecting us from threats like influenza, pertussis, or most recently, the SARS-CoV-2 virus. But a number of years ago, researchers came to the realization that traditional cancer therapies – which include chemotherapy, radiation, and surgery – might also gain help from the body’s immune response.

Specifically, they recognized the power of an individual’s self-defense system to fight cancer cells in a way that could guarantee a more precise and robust response than traditional modalities. This served as the foundation of modern-day immunotherapy.

Immunotherapy has saved many lives, but challenges remain. One of the most significant is the issue of treatment resistance, whether due to primary or acquired resistance by tumor cells. When this occurs, tumors do not respond to therapy and fail to regress. There has even been talk of hyperprogression, a proposed state of an increased rate of tumor progression, although more research is needed for clarification.

Dr. Siwen Hu-Lieskovan, Director of Solid Tumor Immunotherapy at the Huntsman Cancer Institute at the University of Utah, studies the characterization of immunotherapy resistance mechanisms. Her research is funded in collaboration with the National Cancer Institute and SWOG Cancer Research Network. She also oversees the sub-study portfolio for iMatch, a precision medicine trial for biomarker stratification.

Research by Dr. Hu-Lieskovan and others has led to greater understanding of immune evasion by cancer cells and the development of personalized treatment strategies for oncology patients. While traditional cancer therapies attack a tumor extrinsically, immunotherapy targets endogenous mechanisms of immunosuppression characteristic of tumor cells, based on a roadmap of the patient’s individual immune system. Early breakthroughs utilized checkpoint inhibitors, which activate immunogenicity to elicit cytotoxic effects. Additional options now exist, with even more in development.

Dr. Hu-Lieskovan notes that primary resistance is difficult to study from a genomics standpoint, due to baseline heterogeneity among participants. It is easier to study acquired resistance, which can be observed longitudinally in an individual. There are currently no diagnostic tests to predict immunotherapy resistance and treatment response, but certain biomarkers are approved for this purpose. Microsatellite instability, for example, can help predict immunotherapy resistance, as can measuring tumor mutational burden. PD-L1 expression is somewhat controversial in its use as a predictive biomarker, but nonetheless remains in use. Biomarkers can be very important to a patient’s treatment outcomes, as research trial participation and therapeutic course may depend on their presence or absence.

There is still a long way to go for those working to understand immunotherapy and treatment resistance. However, the future is bright. Better patient outcomes are often observed when biomarker data is used as part of a combined therapeutic approach, targeting the specific mechanisms that contribute to unregulated tumor growth.

Read our Q&A with Dr. Hu-Lieskovanto learn more about her research and the future of immunotherapy.


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