Fig. 2.

Strategies of using antigen-specific receptors with different avidities for immunotherapy. a Natural T cell responses are polyclonal and mediated by TCRs of different avidities; while low avidity TCRs contribute to primary responses and generate T cell memory, selective expansion of high avidity TCRs leads to ‘avidity maturation’ of the population as a whole. High avidity TCRs, thus, dominate and ensure protection during recall responses. b Simultaneous application of CARs with different avidities could ‘re-build’ natural TCR repertoires. The infusion of a T cell product with higher doses of low avidity receptors may reduce the initial antigen load with less cytokine release, whereas enrichment of high avidity CARs over time would ensure robust protection and tumor clearance. c CARs with different avidities may be also applied sequentially with a similar effect, but may be easier to implement than the approach presented in (b)