Stock, S. | Search bioRxiv

bioRxiv2026

A CAR T cell-amplified suppressive B cell circuit in AML

Immunotherapy in acute myeloid leukemia (AML) is constrained by a hostile bone marrow niche. Here we identify atypical memory B cells (Batyp) as a suppressive population within this microenvironment. Across single cell and flow cytometry cohorts, Batyp were expanded in AML, and their molecular and phenotypic profiles resembled those of atypical B cells associated with chronic inflammatory conditions. Batyp were polarized within the AML microenvironment, and this was amplified by CAR T cell-AML interactions. Mechanistically, polarization was dependent on Toll-like receptor, interferon and CD70-CD27 signaling. Batyp suppressed T cell and CAR T cell responses via PD-1- and TGF-beta signaling, and were enriched in non-responding patients with AML and myeloma. CD180-directed CAR T cells, targeting an antigen shared by Batyp and AML blasts, resisted suppression in vitro and cleared disease in B cell-humanized xenografts while sparing hematopoietic stem cells, with B cell engagement further enhancing their expansion. CAR T cells thus reinforce their own suppressive niche through Batyp polarization, a constraint that can be relieved by dual blast- and B cell-targeting strategies.

immunology↗

bioRxiv2023

Mutation-specific CAR T cells as precision therapy for IGLV3-21R110 expressing high-risk chronic lymphocytic leukemia

The concept of precision cell therapy targeting tumor-specific mutations is appealing but requires surface-exposed neoepitopes, which is a rarity in cancer. B cell receptors (BCR) of mature lymphoid malignancies are exceptional in that they harbor tumor-specific-stereotyped sequences in the form of point mutations that drive self-engagement of the BCR and autologous signaling. Here, we used a BCR light chain neoepitope defined by a characteristic point mutation (IGLV3-21R110) for selective targeting of a poor-risk subset of chronic lymphocytic leukemia (CLL) with chimeric antigen receptor (CAR) T cells. We developed murine and humanized CAR constructs expressed in T cells from healthy donors and CLL patients that eradicated IGLV3-21R110 expressing cell lines and primary CLL cells, but not polyclonal healthy B cells. In vivo experiments confirmed epitope-selective cytolysis in xenograft models using engrafted IGLV3-21R110 expressing cell lines or primary CLL cells. We further demonstrate in two humanized mouse models lack of cytotoxicity towards human B cells. These data provide the basis for novel avenues of resistance-preventive and biomarker-guided cellular targeting of functionally relevant lymphoma driver mutations sparing normal B cells.

cancer biology↗