Work

Mitigating off target B cell transduction during in situ CAR T cell induction 3591

Year: 2025

Type: article

Abstract: Description Therapeutic in situ chimeric antigen receptor (isCAR) T cells can be generated by targeting activated T cells within a lymph node (LN) with retroviruses encoding CARs. While isCAR T cells are successfully generated by intradermal LN priming using adenovirus encoding allogeneic MHC in all mouse lines tested, differences in emerging therapeutic peripheral isCAR T cells are found in a strain dependent manner. Potentially harmful off target retroviral transduction of B cells with CARs is observed within the targeted LN. Here we report the blockade of B cell transduction using anti-CD20 antibody B cell depletion with the introduction of anti-CD19 chimeric antigen receptors into the activated CD8+ T cells. Lymphocytes were analyzed in blood and LN following isCAR T cell generation. When B cells were depleted by systemic administration of anti-CD20 antibodies during isCAR T cell induction, >97.5% systemic depletion of B cells was achieved. Whereas very small numbers of CAR transduced B cells were found in the blood of mice not treated with anti-CD20, none were observed in animals systemically depleted of B cells. In contrast, CAR B cells persisted in the LN of local anti-CD20 treated animals. However, animals expressing dominant CD8+ isCAR T cell populations eliminated LN B cells expressing CARs by week two. Furthermore, systemic treatment of lymphoma in animals with anti-CD20 antibody complemented anti-CD19 isCAR T therapy while blocking off target B cell transduction. Funding Sources Mayo Clinic Ventures Mayo Clinic Graduate School of Biomedical Sciences Mayo Clinic Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.1373