Leukemia's Next Top Model? Syngeneic Models to Advance Adoptive Cellular Therapy

Abstract

In recent years, there has been an emphasis on harnessing the immune system for therapeutic interventions. Adoptive cell therapies (ACT) have emerged as an effective option for B-cell derived hematological malignancies. Despite remarkable successes with ACT, immune dysregulation and the leukemia microenvironment can critically alter clinical responses. Therefore, preclinical modeling can contribute to the advancement of ACT for leukemias. Human xenografts, the current mainstay of ACT in vivo models, cannot evaluate the impact of the immunosuppressive leukemia microenvironment on adoptively transferred cells. Syngeneic mouse models utilize murine tumor models and implant them into immunocompetent mice. This provides an alternative model, reducing the need for complicated breeding strategies while maintaining a matched immune system, stromal compartment, and leukemia burden. Syngeneic models that evaluate ACT have analyzed the complexity of cytotoxic T lymphocytes, T cell receptor transgenics, and chimeric antigen receptors. This review examines the immunosuppressive features of the leukemia microenvironment, discusses how preclinical modeling helps predict ACT associated toxicities and dysfunction, and explores publications that have employed syngeneic modeling in ACT studies for the improvement of therapy for leukemias.

Keywords: adoptive cell immunotherapy; cell therapy; leukemia; leukemia microenvironment; syngeneic animal model.

Figure 1

Comparison of mouse models for Adoptive Cell Therapy (ACT). Brief overview of the leukemia source, timeline to propagate and test tumor model, and immune and stromal composition of each mouse model. Human is denoted by warm colors (yellow, orange, red) and murine is denoted by cool colors (blue and purple). Created with BioRender.com.