Chimeric Antigen Receptor T Cells for the Treatment of Cancer and the Future of Preclinical Models for Predicting their Toxicities

Abstract

CAR-T cell therapy has achieved highly promising results in clinical trials, particulary in B-cell malignancies. However, reports of Serious adverse events (SAE) including a number of patient deaths has raised concerns about safety of this treatment.Presently available pre-clinical models are not designed for predicting toxicities seen in human patients. Besides choosing the right animal model, careful considerations must be taken in CAR T-cell design and the amount of T-cells infused. The development of more sophisticated in vitro models and humanized mouse models for preclinical modeling and toxicity tests will help us to improve the design of clinical trials in cancer immunotherapy.

ROR1-CAR T cells are effective against lung and breast cancer in advanced microphysiologic 3D tumor models

“…A problem is that conventional preclinical test models do not reflect the unique attributes and challenges that solid tumors impose. In the majority of preclinical studies, the potency of CAR T cells is probed against singularized cells of established solid tumor cell lines in vitro at effector/target cell ratios that cannot be achieved in humans, and in murine xenograft models, where tumor cell lines are ectopically inoculated and form tumor lesions that do not resemble the architecture and phenotype of primary human tumors (18). Therefore, we set out to develop an alternative test system that incorporates physical and immunologic barriers of solid tumors more realistically and focused on lung and breast cancer as the 2 most prevalent cancers in men and women.…”

“…We and others have shown in previous work that, for example, the choice of targeting domain, spacer design, and signaling module affect tumor cell recognition and antitumor function of CAR T cells (5, 11,30). However, there is presently no consensus on whether a single assay or a combination of in vitro and in vivo assays constitutes a "gold standard" for evaluating CARs and for predicting safety and efficacy in humans (18). It seems plausible, however, to assume that conventional 2D (in vitro) test systems may be more useful for assessing "short-term" CAR T cell effector functions, such as cytolytic activity and cytokine secretion, whereas animal models (in vivo) may provide a "long-term" readout of overall CAR T cell performance, including engraftment and proliferation.…”

Safety Strategies of Genetically Engineered T Cells in Cancer Immunotherapy

“…A local route including intratumoral (IT) and intraperitoneal (IP) administration of engineered T cells has demonstrated improved safety and feasibility in clinical studies [ 63 ]. It is also important to test therapies in an appropriate mouse model to rule out unwanted severe side effects before initiating a clinical trial [ 64 ].…”

Potential lung attack and lethality generated by EpCAM-specific CAR-T cells in immunocompetent mouse models

“…Currently available preclinical xenograft mouse models can be used to evaluate CAR-T cells’ anti-tumor efficacy, but are poorly predictive of their potential toxicity due to these animals’ incomplete immune system. 13 , 14 Monocytes and macrophages are necessary for CRS induction, while the development and maturation of these cells are defective in NOD mice. 11 The IL2Rγ mutation present in NSG mice also impairs IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 cytokine signaling, 15 – 17 which negatively impacts T cell differentiation, proliferation, and cell growth.…”