Pan-B-Lineage Targeting with Adapter CAR-T Cells Controls Antigen-Heterogeneous Lymphoma
- 1Hopp Children's Cancer Center Heidelberg (KiTZ)
Abstract
Antigen heterogeneity and antigen-negative relapse represent major limitations to durable CAR-T cell efficacy in B-lineage malignancies. We previously developed the Adapter CAR-T cell (AdCAR-T) platform, which enables flexible redirection of engineered T cells to distinct surface antigens through biotinylated adapter molecules (AMs). In this study, AMs generated from an in-house-produced tafasitamab biosimilar (anti-CD19), commercial rituximab (anti-CD20), and an in-house-produced daratumumab biosimilar (anti-CD38) mediated potent, antigen-specific AdCAR-T cell cytotoxicity. While single-antigen targeting resulted in the selection of antigen-negative tumor populations, simultaneous targeting of CD19, CD20, and CD38 effectively controlled a defined heterogeneous Burkitt lymphoma model in vitro and induced sustained tumor control in vivo. Selective loss of the CD38+ AdCAR-T cell population after CD38-directed AM exposure was consistent with fratricide; however, the surviving CD38low population retained cytotoxic activity. These findings establish combinatorial AdCAR-T cell targeting as a flexible pan-B-lineage strategy for addressing pre-existing antigen heterogeneity and support further development of antibody-derived AM combinations for B-cell malignancies.
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BibTeX
@misc{krost2026panblineage,
title = {{Pan-B-Lineage Targeting with Adapter CAR-T Cells Controls Antigen-Heterogeneous Lymphoma}},
author = {S. Krost and A.-S. Mast and D. Atar and B. Kristmann and S. Scheuermann and C. M. Seitz},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.12.751171},
url = {https://www.biorxiv.org/content/10.64898/2026.09.12.751171v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Pan-B-Lineage Targeting with Adapter CAR-T Cells Controls Antigen-Heterogeneous Lymphoma
AU - S. Krost
AU - A.-S. Mast
AU - D. Atar
AU - B. Kristmann
AU - S. Scheuermann
AU - C. M. Seitz
PY - 2026
DA - 2026/09/12
PB - bioRxiv
DO - 10.64898/2026.09.12.751171
UR - https://www.biorxiv.org/content/10.64898/2026.09.12.751171v1
AB - Antigen heterogeneity and antigen-negative relapse represent major limitations to durable CAR-T cell efficacy in B-lineage malignancies. We previously developed the Adapter CAR-T cell (AdCAR-T) platform, which enables flexible redirection of engineered T cells to distinct surface antigens through biotinylated adapter molecules (AMs). In this study, AMs generated from an in-house-produced tafasitamab biosimilar (anti-CD19), commercial rituximab (anti-CD20), and an in-house-produced daratumumab biosimilar (anti-CD38) mediated potent, antigen-specific AdCAR-T cell cytotoxicity. While single-antigen targeting resulted in the selection of antigen-negative tumor populations, simultaneous targeting of CD19, CD20, and CD38 effectively controlled a defined heterogeneous Burkitt lymphoma model in vitro and induced sustained tumor control in vivo. Selective loss of the CD38+ AdCAR-T cell population after CD38-directed AM exposure was consistent with fratricide; however, the surviving CD38low population retained cytotoxic activity. These findings establish combinatorial AdCAR-T cell targeting as a flexible pan-B-lineage strategy for addressing pre-existing antigen heterogeneity and support further development of antibody-derived AM combinations for B-cell malignancies.
ER -