Researchers are making bold strides in revolutionizing cancer therapy. While some patients experience potent and durable clinical responses to these breakthrough immunotherapies, response rates are highly variable, and these treatments are often associated with side effects that differ from those of cytotoxic chemotherapy. As a result, researchers and clinicians are in search of tools that help them identify which patients are most likely to benefit from specific immunotherapies.
There is a critical need for standardized and validated biomarkers that yield actionable insights into immunotherapy efficacy at every stage of development. In addition to helping identify patients who could benefit from available therapies, biomarkers may be useful for monitoring treatment response. These indicators also have the potential to shed light on a treatment’s mechanism of action, which would provide important insight for optimizing treatment approaches and defining rational combination therapies. However, the intrinsic characteristics of malignant tumors, such as their heterogeneity, plasticity, and diversity, pose challenges to biomarker development.
We consider the following four trends like the most important to watch as researchers continue to make headway in the development of biomarkers for cancer immunotherapy.
Using state of the art technologies for biomarker development
Only a tiny fraction of the tens of thousands of identified biomarkers have been developed into validated genomic biomarkers for FDA-approved drugs, and none have become in vitro companion diagnostics. New genomic and proteomic technologies, combined with advanced bioinformatics tools, enable the simultaneous analysis of thousands of biological molecules. These cutting-edge techniques help enable the discovery of new tumor signatures, which are critical for making the leap to precision medicine and personalized cancer therapy.
Validating PD-L1 as a biomarker of response
Programmed death ligand-1 (PD-L1) a transmembrane protein expressed on a variety of cell types, including dendritic cells. PD-L1 binding inhibits the normal function of activated T-cells. By expressing PD-L1, tumor cells can co-opt the PD-1/PD-L1 regulatory mechanism and inhibit T-cell activation, allowing cancer cells to bypass the immune system.
In clinical studies, immunohistochemistry has been used to detect PD-L1 protein expression by tumor cells and evaluate it for correlation with response to PD-1 and PD-L1 immune checkpoint inhibitors. Currently, the only FDA-approved companion diagnostic is PD-L1 IHC 22C3 pharmDx, which is used to select patients for treatment with pembrolizumab, a PD-1 inhibitor marketed as Keytruda®.
Linking tumor mutation burden to response rate
Tumor mutation burden (TMB), a measure of the mutations carried by tumor cells, has been studied to evaluate its association with response to immuno-oncology therapy. DNA sequencing is used to determine the number of acquired mutations in a tumor, and TMB is generally reported as the number of mutations in a specific area of genetic material. The theory behind TMB as a biomarker is that tumor cells with high TMB may have more neoantigens, cell-surface molecules produced by DNA mutations that are unique to cancer cells. These neoantigens can be recognized by T-cells to stimulate an anti-tumor immune response in the tumor microenvironment. Consequently, a high TMB may correlate positively with the likelihood of responding to immunotherapy.
Leveraging the tumor microenvironment to direct therapeutic development
The tumor microenvironment comprises the cellular environment in which a tumor exists, including surrounding vasculature, immune cells, fibroblasts, inflammatory cells, signaling molecules, and the extracellular matrix. Recent investigations into the tumor microenvironment seek to determine whether genetic changes can guide the design of cancer immunotherapeutics. Unlike predictive or prognostic biomarkers, immune targets may not correlate with treatment response, but may help direct the development of new cancer therapies.
In conclusion, immunotherapies still represent a paradigm shift in cancer treatment and are expanding the therapeutic landscape for cancer patients. However, as a clinical research site we believe that researchers are closer to make big discoveries in the area, and meanwhile Althian is committed to keep searching for the most innovative protocols with immunotherapy approaches for our patients.