Objective analysis of immunotherapy in cancer

Unfortunately, human nature, perhaps, or the principle of our democratic societies to earn as much money and fame as possible, have sometimes turned “precision medicine” into a farce that makes it difficult for doctors to explain the truth and the emotional state of patients who suffer from a deception when learning this truth.

Thus, Bishal Gyawali (MD, PhD) reveals the main deficiencies of the so-called precision medicine. Referring to immunotherapy, the author states: “However, I believe that the paradigms of immunotherapy and precision medicine have become antithetical to each other. We’ve let our precision medicine principle of «right dose for the right patient, right time» go out the window when it comes to immunotherapy”.

The deficiencies of immunotherapeutic treatment are⁽¹⁾:

We don’t have good biomarkers to predict a patient’s response to immunotherapy, nor do we have good biomarkers to predict toxicities.

The adjuvant trials (with immunotherapy) can run for 1-3 years, often with no overall survival data to reveal. That’s an enormous therapeutic burden on too many patients for an unproven benefit – at the same time, we use chemotherapy for a much shorter period.

I am convinced that we are giving our patients unnecessarily high doses of immunotherapy. Several studies have shown that there is no dose-response relationship with immunotherapy. For instance, peripheral receptors may become saturated at a dose of 0.3 mg/kg of nivolumab.

In the last 10 years, immunotherapy has taken a special lead in terms of its use in the treatment of cancer. This enthusiasm must be tempered because there is a relatively low percentage (<15%) of patients who present an effective immune response against cancer, and there is also an inability to accurately identify these patients. Quite recently, several existing or acquired characteristics have been shown to impact the efficacy of immune checkpoint inhibitors⁽²⁾.

The response to immune checkpoint blockade and its prediction are, undoubtedly, complex and multifactorial processes. It is obvious that a single biomarker will never be able to capture the complexity of the tumor and/or its microenvironment and, obviously, accurately predict the response to immunotherapy. A combination of multiple biomarkers will inevitably be required, as demonstrated by an increased performance of the combination of PD-L1 immunohistochemistry and T-cell infiltration or TMB assessment, compared to the three parameters taken together⁽³⁾.

Based on current knowledge, the combination of immune infiltration and TMB assessment with the more traditional PD-L1 tumor expression analysis appears to be the most feasible compromise, as it presents the best risk-time-cost/benefit ratio. Thus, PD-L1 expression as well as CD3+/CD8+ T-cell infiltration can be assessed on the same slide (or on serial tissue sections) and TMB can be determined using DNA extracted from the same biopsy, which is a considerable advantage for determining potential responding patients.

Integrative multi-omics analysis and algorithms/computing science (artificial intelligence) could also prove to be informative in the coming years.