Abstract 619: Functional evaluation of immuno-oncology drug candidates in customized and fine-tuned T cell bioassays to assess therapeutic potential

Abstract

Abstract Re-activation of tumor-reactive T cells with so-called immune checkpoint inhibitors (ICIs) has translated into significant clinical breakthroughs. Specifically, antibodies directed against CTLA-4 and PD-L1/PD-1 have yielded long-term remission and cure in many solid as well as hematological malignancies. However, as not all cancer types respond to current ICI therapies, the quest for novel strategies to re-enable anti-tumor immunity by blocking immune checkpoints or by activating prominent co-stimulatory receptors is crucial. The field of cancer immunology has developed rapidly over the past decades, with numerous studies adding up to the complexity of immune-related interactions taking place in the tumor microenvironment. Compounds or combinations of compounds designed to target traditional or novel pathways require early evaluation of effectiveness on in vitro assays using primary immune cells or representative mouse models. On top of classical T cell bioassays, expanding on current methods and the development novel strategies to assess the modulation of cancer-related immunological networks is a continuously important process. One classical approach is the functional evaluation of compounds in a mixed lymphocyte reaction (MLR). Here, the potency of drug candidates to promote physiological T cell responses can be evaluated. Antigen-specific immune responses can be further assessed in Cytomegalovirus (CMV) recall- or in Staphylococcal enterotoxin B (SEB) activation assays. Additionally, it might also be beneficial to generate tumor-associated antigen-specific T cell pools or clones to be used in functional assays. The classical MLR assay could be expanded on by e.g., inclusion of specific tumor cell populations or T regulatory (Treg) cells, as evaluating reduced cancer cell viability, or reversing loss of immune effector cell functionality can be of interest. Furthermore, real-time evaluation of cancer cell killing by T cells upon addition of drug candidates could also provide pivotal information on the compound’s functional dynamics. With our deepening understanding of cancer-related immunological networks it becomes clear that different drug candidates may require customized and fine-tuned T cell bioassays to assess their full therapeutic potential. Moreover, quality controlled primary immune cells are an essential factor for the robustness of these assays and to yield reproducible and consistent results. Collectively, taking in mind these aspects will ease decision making and accelerate the drug discovery pipeline. Citation Format: Thibaut J. Janss, Martijn Vlaming, Simon Lefevre, Johan Arnold, Ellen Boelen, Sofie Pattijn. Functional evaluation of immuno-oncology drug candidates in customized and fine-tuned T cell bioassays to assess therapeutic potential [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 619.