The study’s conclusion drives home the point that researchers need to shift how they approach the evaluation of immunotherapies, said Padmanee Sharma, MD, PhD, an immunologist at the University of Texas MD Anderson Cancer Center in Houston. “As oncologists, we’ve been entrenched in the paradigm that a single biomarker such as a genetic mutation is how we should select patients for treatment. We think it predicts the drugs you should take because the drug was developed for that mutation. It’s a beautiful system when you think about it,” she said. “So, given the success of using single biomarkers to predict responses in genomic medicine, we expected the next breakthrough in oncology to follow the same logic, except it doesn’t.” 

Unlike patients’ genetic codes, their immune systems are dynamic and change daily. “It’s not something you can sequence today and get the exact same thing tomorrow,” said Dr Sharma, who is also a professor in the department of genitourinary medical oncology at MD Anderson. “We can’t use a single biomarker the same way we do in genomics, and that is what is throwing everyone off. We weren’t expecting that.”

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A better approach would be to search for multiple biomarkers, including markers of response gleaned from genomic and immune profiling assays, to determine which combination therapies might be appropriate for patients, according to Dr Sharma.

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Future research should focus on understanding the biological pathways and specific mechanisms that lead to tumor rejection. For example, other biomarkers of value might include the number of mutations within a tumor, as previous research has shown that patients with a higher “mutational load” were more likely to respond to anti–CTLA-4 or anti–PD-1 immune checkpoint therapies. “We can learn from the genomics field and say that tumors with certain mutations – plus tumors with high CD8 T cells or high IFN-gamma gene signature – will have better outcomes,” said Dr Sharma. “Identification of successful predictive biomarkers will depend on integrating the fields of genomic medicine and immunology to find combinatorial biomarkers that provide information about both the cancer cells and the patient’s immune response.”