Efficacy-related pharmacodynamic (PD) biomarkers

The deficit of many prior immunotherapy trials is the lack of effective PD-biomarker analysis. Without this, the patient is a black box. If a given drug fails to exert any clinical effect, or the effect is suboptimal, there is no way to find out what has gone wrong and how things could be improved in a rational manner. Therefore, the IACT project encompasses the development of validated and harmonized assays for effective measurement of PD-biomarkers. This is a critical requirement for the proper evaluation of the clinical studies discussed above and any future trial.

Analysis of systemic PD-biomarkers such as serum cytokine/chemokine levels and antigen-specific immune responses, although until recently a neglected area of clinical trials, is now commonly performed. The IACT program goes beyond this state-of-the-art by selecting clinical settings that allow monitoring of efficacy-related biomarkers (immune cell infiltration, immune cell activation status and antigen-specific reactivity, tumor cell viability/death) in the tumor microenvironment. The validated whole slide ‘Immunomap’ procedure developed by the IACT partners University Hospital Heidelberg and German Cancer Research Center, will be used to evaluate and quantitate the immune  cell  density  and  heterogeneity  across  the  tissue  section,  to  avoid  human  observer-biased outcomes and take into account the notion that immune cell infiltration can differ greatly between areas within the same tumor.

With respect to the clinical studies in HPV16+ HNSCC, detailed ex vivo analysis of the HPV16 -specific T-cell responses will be performed using standardized and validated protocols that make use of synthetic peptide arrays as previously developed and applied in clinical vaccination studies by two of the IACT partners (University Hospital Southampton & University Hospital Heidelberg). Notably, these partners are long-time members of CIMT, the European Association of Cancer Immunotherapy, and participants in the CIMT Immunoguiding Program (CIP) that is aimed at promoting the validation and harmonization of immunomonitoring assays.