Host Features Affecting CAR T Cell Therapy of Hematological Malignancies

Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising approach for the treatment of hematologic malignancies. CAR T cells are engineered to express constructs encoding an extracellular antigen-specific recognition sequence fused to a transmembrane domain and intracellular co-stimulatory domain(s) enabling recognition and cytotoxicity against antigen-expressing cells. Best responses to CAR T-cell therapy are associated with several parameters such as the quality of the circulating T cells used for manufacturing, rapid CAR T-cell expansion processes to avoid exhaustion before administration, the systemic level of homeostatic cytokine after lymphodepleting chemotherapy, and evidence of anti-tumor activity typically evaluated by PET-CT 30 days after infusion. Yet, the lack of robust pre-treatment biomarkers for patient stratification and monitoring remains a major challenge. The prognostic and predictive roles of the tumor microenvironment (TME) have been described for solid tumors, including for checkpoint inhibitors, but the systematic analysis of hematopoietic tumors and the role of systemic immune dysregulation in response to CAR T-cell therapy are still at an early stage.

Unlike other therapies, the efficacy of CAR T cell therapy is comparable across all subtypes of Large B-Cell Lymphoma (LBCL) as defined through conventional tumor-related prognostic markers from histological, cytogenetic, or molecular origins. However, recent publications suggest that the response to CAR-T cell therapy also associates with specific characteristics of the systemic immunity and of the tumor immune infiltrates before lymphodepletion. In addition, it is now well documented that both cancer-cell intrinsic and extrinsic features can modulate cancer immune responsiveness. Considering the immune mechanistic nature of the CAR T-cell intervention, host features such as functional status of tumor-infiltrating immune or stroma cells could enable the discovery of novel prognostic biomarkers or therapeutic strategies to improve patient response to CAR T cells. We thus propose to develop a Research Topic investigating the host features that can modulate the response of patients with hematological malignancies to CAR T cell therapy, including TME characteristics (immune tumor signature, DLBCL-activated fibroblastic reticular cells); TME evolution across chemotherapeutic lines; upregulation of circulating immunosuppressive cells; and germline genetic variants.

The Research Topic focuses on host-intrinsic features that can modulate the therapeutic response to CAR T-cells, including:

• functional characteristics of systemic immune cells (such as for example the presence of circulating M-MDSC that associates to therapeutic resistance) and tumor-infiltrating immune cells (including tumor IFN signaling; tumor immune contexture and evolution of TME composition across chemotherapeutic lines and consequences for response to CAR T cell therapeutic response);

• characterization and role of tumor-infiltrating stroma cells (DLBCL-activated fibroblastic reticular cells that hinder T cell migration and cytotoxicity in an antigen-specific manner);

• germline genetics of the tumor immune microenvironment of hematological cancers (LBCL) that may associated to response to CAR T cell therapy.

The use of novel technical approaches to investigate the TME, including but not only spatial transcriptomics and proteomics, and single cell transcriptomics, are of particular interest.


Please note: Manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are out of scope for this section and will not be accepted as part of this Research Topic.



Dr. Nathalie Scholler is Vice President of TORL Biotherapeutics, a biotech company that develops novel antibody-based therapeutics to treat cancer patients.