Abstract 3232: In vitro cell based cytotoxicity and T cell activation assays to assess safety and efficacy of engineered T cell therapies
| Autor: | Sophie Vermond, Jeroen Overman, Sanne Holt, Monique Hazenoot, Jamil Aarbiou, Jeroen DeGroot |
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| Rok vydání: | 2020 |
| Předmět: | |
| Zdroj: | Cancer Research. 80:3232-3232 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2020-3232 |
| Popis: | Chimeric antigen receptor (CAR) and T cell receptor (TCR) engineered T cells are part of a big wave of immunotherapies showing great promise in cancer clinical trials. With the first T cell based therapies targeting hematological malignances now approved, their next challenge is solid tumors. Solid tumors create an additional challenge due to the lack of tumor specific target antigens, posing significant safety risks, i.e. on-target on-tumor, on-target off-tumor and off-target toxicities. Toxic effects previously reported vary from mild-severe cytokine release syndrome (CRS) to neurotoxicity and death. We have developed in vitro assays utilizing primary human cells from healthy tissue and/or differentiated iPCS-derived cells to assess on-target off-tumor and/or off-target cytotoxicity for engineered T cell therapies. The presence of CAR-T cell mediated cytotoxicity was measured through co-culture with healthy human primary cells to assess unwanted CAR-T reactivity as well as a high target antigen expressing control cancer cell line to confirm CAR-T functionality. The human primary cell type was selected based on its potential safety risk by establishing low level protein expression of the target antigen. Readouts included IFNγ production determined by MesoScale Discovery platform as a measure of T cell activation and Hoechst/PI staining of target cells by flow cytometry. Our study generated high quality data of the CAR-T cell, confirming functionality by showing consistent T cell activation and killing against a positive control cell line. Moreover, we were able establish a clear absence of activity against the primary human cells thus providing insight into the safety of the CAR-T therapy. The developed safety assays provide a robust and rapid platform to assess on-target off-tumor and off-target effects within immuno-oncology therapies, either TCR or CAR-T cells, in both early stage development or late stage testing of the therapeutic product. Through inclusion of a wide range of human primary cells, both high risk tissues and major organs at risk of off-target toxicity, a clear safety profile can be generate in vitro for these novel T cell therapies. Safety risks associated with cell based IO-therapies is the biggest challenge for the success of these therapies, performing a thorough safety screen on healthy primary human tissues is therefore crucial. Citation Format: Sanne Holt, Sophie Vermond, Monique Hazenoot Hazenoot, Jeroen Overman, Jamil Aarbiou Aarbiou, Jeroen DeGroot DeGroot. In vitro cell based cytotoxicity and T cell activation assays to assess safety and efficacy of engineered T cell therapies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3232. |
| Databáze: | OpenAIRE |
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