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.

CALM3 affects the prognosis of leukemia and hemorrhoids

“…CALM3 is underexpressed in leukemia, with lower levels associated with worse prognosis, while it is overexpressed in hemorrhoids, with higher levels associated with poorer outcomes. This provides new directions for future disease management and treatment [16,17] CALM3 is a gene that encodes the calmodulin protein, which plays a crucial regulatory role in intracellular calcium signaling processes [18] Calmodulin is a highly conserved protein found in all eukaryotes, including mammals. It regulates many different biological processes inside cells and is essential for maintaining the balance of calcium ions within cells.…”

Regulatory Mechanisms and Reversal of CD8+T Cell Exhaustion: A Literature Review

“…Eventually T cells will partial or complete lose T killing capacity, eventually causing CD8 + T cells to form a complex set of noncanonical hyporesponsive T EFF subsets [ 18 ]. This phenomenon has been seen in a variety of mouse and human tumor models, including melanoma [ 19 ], chronic myeloid leukemia [ 20 ], ovarian cancer [ 21 ], and chronic lymphocytic leukemia (CLL) [ 22 ].…”

In Vitro and In Vivo Modeling of Normal and Leukemic Bone Marrow Niches: Cellular Senescence Contribution to Leukemia Induction and Progression

“…In another approach, syngeneic models were developed using murine cell lines or virally-transduced murine HSC to express target genes that result in leukemia initiation. These models do not need a complex breeding process as the genetically modified mice strains do, they allow the study of the disease in immunocompetent hosts, and have become the most commonly used preclinical models for immunotherapy evaluation; however, syngeneic mice lack genomic and microenvironmental heterogeneity because of the limited number of cell lines that can be implanted in a restricted number of inbred strains of mice [148,152,153]. Recently, by using lentiviral vectors for simultaneously transducing an oncogenic mix into immunocompetent animals, it was possible to establish AML-like and CLL-like leukemic lines using syngeneic mice [154].…”