art I of this article, published in the February 2021 issue of Global Forum, provided a brief overview of the clinical successes and currently remaining challenges in the field of immune-oncology. The second part of the article discusses considerations for navigating the road ahead in this rapidly evolving field.

Navigating the Road Ahead

The goal of cancer immunotherapy is to initiate or reiterate a self-sustaining cycle of cancer immunity, enabling it to amplify and propagate an anticancer response. The most effective approaches therefore will involve selectively targeting the rate-limiting step(s) operating in any given patient. Thus, the foundation of any precision immune-oncology implementation is the availability of validated biomarkers that allow us to holistically identify the roadblocks and the underlying biology responsible for immune surveillance evasion at the individual patient level to inform appropriate therapeutic intervention(s).

In the field of targeted anticancer therapy, where the drug mechanism of action lies in the direct interference with an established oncogenic driver (such as human epidermal growth factor receptor 2 [Her2] expression), single analyte biomarkers that directly measure the presence or absence of the drug target on tumor cells have traditionally been used in the clinic to identify the patient subset that would likely benefit from the targeted treatment (2).

However, predictive biomarkers for immunotherapy differ from the traditional biomarkers used for targeted therapies, because the complexity of the immune response and tumor biology requires a more holistic approach than the use of a single analyte biomarker.

In addition, as opposed to the mutated genes in tumors, which remain largely constant, the immune response is dynamic and changes temporally and spatially. Therefore, the issue facing the field of cancer immunotherapy is how to measure an evolving immune response, to recognize the immune response that contributes to a clinical benefit, and to drive every patient’s immune response in that direction through appropriate treatments (2).

Thanks to rapid advances in technology, today we can measure the multi-facet factors affecting the cancer-immune interaction by using technology platforms that simultaneously measure different types of potentially informative analytes (DNA, RNA, and proteins) in different tissues (such as tumor samples, peripheral blood circulating cells, and sera) (2).

Recognizing New Challenges

Specifically, before a candidate biomarker and/or new technology can be used in a clinical setting, several steps are necessary to demonstrate its performance characteristics:

• Analytical validation (assessment of basic assay performance): The assay’s ability to accurately and reliably measure the analyte of interest in the clinical laboratory and in specimens representative of the population of interest (3).
• Clinical validation (assessment of assay performance with regard to its intended use): The ability of the biomarker assay to separate a population into two or more distinct groups with different biological characteristics or clinical outcomes (4).
• Clinical utility assessment: An assay’s ability to significantly improve clinical outcomes (i.e., the use of the biomarker results in patient benefit or adds value to patient management decision-making compared to current practices?) (4).

This process requires significant investment of resources and time from both the diagnostic as well as pharmaceutical companies involved. It is also associated with numerous challenges, including strategic business risks (e.g., drug failure), logistical and regulatory complexities (e.g., coordination of high interconnected co-development programs), and financial demands which are particularly high for complex molecular tests. Current diagnostic reimbursement policies do not tend to support the development of high-value molecular tests, as reimbursement of these tests has typically been based on a assay cost, not value or potential value of the assay results.

However, given the importance of biomarker development for the advancement of cancer immunotherapy, there is a tremendous need to identify, develop, and validate molecular diagnostics in this space.

Due to the ever-growing sophistication and cost of correlative science for immunotherapy clinical trials, together with the need for large data-sets, many stakeholders (including major academic centers, government agencies, and federal funding sources, philanthropic foundations, and pharmaceutical/biotech and diagnostic companies) have recognized that, despite potential competing interests, any significant advance in the field does require broad and sustained pre-competitive efforts. The same stakeholders also recognize that these efforts need to focus on the discovery and assessment of biomarkers through appropriately designed clinical trials. In these trials the evaluation of the biomarker must be one of the primary objectives of the study, testing large number of appropriately collected and clinically annotated patient samples and using standardized high throughput assay platforms and advanced validated bioinformatic tools (5).

These ongoing efforts, together with an unprecedented scientific capacity at our disposal, will result in the next transformational wave of progress toward a precision immune-oncology reality for the ultimate benefit of our patients.