Use of TCR diversification in peripheral blood as a pharmacodynamic biomarker for immunomodulatory agents in oncology Craig B Davis*1, Shibing Deng1, Tao Xie1, Jadwiga Bienkoswka1, Will DeWitt2 Julie Rytlewski2, Erik Yusko2 1Pfizer Oncology, La Jolla, CA, USA; 2Adaptive Biotechnologies, Seattle, WA, USA *Corresponding Author
Selection of the optimal dose and schedule for immunomodulators in oncology would be facilitated by reliable pharmacodynamic biomarkers that can be measured non-invasively. Candidate biomarkers have included soluble proteins such as CXCL9 and CXCL10, as well as increase of lymphocyte activation markers such as Ki-67 and ICOS. In many circumstances, however, the correlation of circulating biomarkers with dose or subsequent clinical benefit is poor, and new approaches are needed. Targeted sequencing of the TCRB locus can generate a profile of the TCR repertoire at a given time point, thereby enabling assessment of the evolution of the TCR repertoire over time. Here we describe a new differential abundance method for determining whether frequencies of TCR clones in peripheral blood change over time. Building on the work by DeWitt et al. [1], the new method is based on the beta-binomial distribution, and includes a variance (dispersion) parameter to model typical biological variability. Using data derived from Adaptive Biotechnologies' immuneAccess® public database, the method has been applied to peripheral blood from normal donors and cancer patients treated with immuno-oncology agents to evaluate its performance. Analysis of the expansion of tumor-associated clones and their correlation with RECIST-derived clinical benefit showed that the new model likely increases specificity for therapeutically active clones. Further details on the potential utility of the approach for assessing differential pharmacodynamic efficacy of immunomodulators alone and in combination will be presented.
[1] DeWitt et al. Dynamics of the cyotoxic T cell response to a model of acute viral infection. J Virol. 2015; 89(8): 4517-4526.
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