Preclinical Models in Chimeric Antigen Receptor–Engineered T-Cell Therapy

Abstract

Cancer immunotherapy has enormous potential in inducing long-term remission in cancer patients, and chimeric antigen receptor (CAR)-engineered T cells have been largely successful in treating hematological malignancies in the clinic. CAR-T therapy has not been as effective in treating solid tumors, in part due to the immunosuppressive tumor microenvironment. Additionally, CAR-T therapy can cause dangerous side effects, including off-tumor toxicity, cytokine release syndrome, and neurotoxicity. Animal models of CAR-T therapy often fail to predict such adverse events and frequently overestimate the efficacy of the treatment. Nearly all preclinical CAR-T studies have been performed in mice, including syngeneic, xenograft, transgenic, and humanized mouse models. Recently, a few studies have used primate models to mimic clinical side effects better. To date, no single model perfectly recapitulates the human immune system and tumor microenvironment, and some models have revealed CAR-T limitations that were contradicted or missed entirely in other models. Careful model selection based on the primary goals of the study is a crucial step in evaluating CAR-T treatment. Advancements are being made in preclinical models, with the ultimate objective of providing safer, more effective CAR-T therapy to patients.

Establishing a model system for evaluating CAR T cell therapy using dogs with spontaneous diffuse large B cell lymphoma

“…Humanized mouse and primate studies have been used in preclinical CAR T cell investigation; however, the former approach is hindered by disparate results between studies and technical challenges, whereas the latter is impeded by financial and ethical concerns. 4 Currently, no single system accurately recapitulates the variables associated with clinical response or mechanisms of resistance, thereby mandating the requirement for new, improved cancer immunotherapy models. 4,5 DLBCL is an aggressive and rapidly progressive disease that is commonly encountered as a spontaneous tumor in pet dogs.…”

“…4 Currently, no single system accurately recapitulates the variables associated with clinical response or mechanisms of resistance, thereby mandating the requirement for new, improved cancer immunotherapy models. 4,5 DLBCL is an aggressive and rapidly progressive disease that is commonly encountered as a spontaneous tumor in pet dogs. 6 Multi-agent CHOP-based chemotherapy is considered the standard of care for dogs with DLBCL and most dogs achieve remission after initial chemotherapy.…”

Mouse Models for Cancer Immunotherapy Research

“…Human xenograft models, using human cell lines injected into immunocompromised hosts such as athymic nude or severe combined immunodeficiency (SCID) animals, are one of the oldest models used to evaluate cytotoxic therapies against cancer. These models have particular relevance for the development of chimeric antigen receptor (CAR) therapies, which can utilize either human cell lines or patient-derived samples to generate xenografts for antitumor efficacy evaluation (35). One of the critical factors that determine the utility of human xenograft models for other immunotherapeutic applications is the degree of immunodeficiency of the murine host.…”

Pharmacologically upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of genetically-modified chimeric antigen receptor NK-92MI against colorectal cancer cells

“…Genetically-modified effector cells with a chimeric antigen receptor (CAR) were chosen with the intention of enhancing their reactivity against antigen-expressing tumour cells [ 15 – 17 ]. However, chimeric antigen receptor T-cell (CAR-T) treatments are associated with adverse events, mostly commonly eliciting Cytokine Release Syndrome (CRS), a systemic inflammatory response that can lead to widespread organ dysfunction and death [ 18 , 19 ]. NK cell lines may be alternative cytotoxic effectors for CAR-driven tumour cell-specific cytolysis [ 20 , 21 ].…”