Pre-Clinical Models for CAR T-Cell Therapy for Glioma

Abstract

Immunotherapy represents a transformative shift in cancer treatment. Among myriad immune-based approaches, chimeric antigen receptor (CAR) T-cell therapy has shown promising results in treating hematological malignancies. Despite aggressive treatment options, the prognosis for patients with malignant brain tumors remains poor. Research leveraging CAR T-cell therapy for brain tumors has surged in recent years. Pre-clinical models are crucial in evaluating the safety and efficacy of these therapies before they advance to clinical trials. However, current models recapitulate the human tumor environment to varying degrees. Novel in vitro and in vivo techniques offer the opportunity to validate CAR T-cell therapies but also have limitations. By evaluating the strengths and weaknesses of various pre-clinical glioma models, this review aims to provide a roadmap for the development and pre-clinical testing of CAR T-cell therapies for brain tumors.

Keywords: CAR T-cell therapy; glioma; immunotherapy; pre-clinical models; solid tumors.

Figure 1

Overview of the pre-clinical models discussed in this review. (Figure created with BioRender.com (accessed on 3 April 2024)).

Figure 2

The four murine models most frequently used in CAR T-cell therapy development. The syngeneic model uses an immunocompetent mouse with a functional murine immune system implanted with a tumor of murine origin; this tumor holds a murine TAA, which is targeted with murine CAR T cells. The transgenic model utilizes an immunocompetent mouse genetically engineered to express a human TAA, which is targeted with human CAR T cells. Xenograft and humanized models both use immunoincompetent mice, with NSG mice being the most widely used. In the xenograft model, in vitro cultured human tumor cells or patient-derived human cells are implanted into mice lacking a functional immune system, and the mice are, thereafter, treated with human CAR T cells. In the humanized model, (a part of) the functional human immune system is engrafted into the mouse, human tumor cells are implanted and the mouse is treated with human CAR T cells. (Abbreviations: TAA = tumor-associated antigen) (Figure created with BioRender.com (accessed on 1 April 2024)).