Browsing by Author "Brentjens, Renier J."

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    Endogenous CD28 drives CAR T cell responses in multiple myeloma
    (bioRxiv, 2024-04-09) Lieberman, Mackenzie M.; Tong, Jason H.; Odukwe, Nkechi U.; Chavel, Colin A.; Purdon, Terence J.; Burchett, Rebecca; Gillard, Bryan M.; Brackett, Craig M.; McGray, A. J. Robert; Bramson, Jonathan L.; Brentjens, Renier J.; Lee, Kelvin P.; Olejniczak, Scott H.; Medicine, School of Medicine
    Recent FDA approvals of chimeric antigen receptor (CAR) T cell therapy for multiple myeloma (MM) have reshaped the therapeutic landscape for this incurable cancer. In pivotal clinical trials B cell maturation antigen (BCMA) targeted, 4-1BB co-stimulated (BBζ) CAR T cells dramatically outperformed standard-of-care chemotherapy, yet most patients experienced MM relapse within two years of therapy, underscoring the need to improve CAR T cell efficacy in MM. We set out to determine if inhibition of MM bone marrow microenvironment (BME) survival signaling could increase sensitivity to CAR T cells. In contrast to expectations, blocking the CD28 MM survival signal with abatacept (CTLA4-Ig) accelerated disease relapse following CAR T therapy in preclinical models, potentially due to blocking CD28 signaling in CAR T cells. Knockout studies confirmed that endogenous CD28 expressed on BBζ CAR T cells drove in vivo anti-MM activity. Mechanistically, CD28 reprogrammed mitochondrial metabolism to maintain redox balance and CAR T cell proliferation in the MM BME. Transient CD28 inhibition with abatacept restrained rapid BBζ CAR T cell expansion and limited inflammatory cytokines in the MM BME without significantly affecting long-term survival of treated mice. Overall, data directly demonstrate a need for CD28 signaling for sustained in vivo function of CAR T cells and indicate that transient CD28 blockade could reduce cytokine release and associated toxicities.
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    Screening Clinical Cell Products for Replication Competent Retrovirus: The National Gene Vector Biorepository Experience
    (Elsevier, 2018-09-21) Cornetta, Kenneth; Duffy, Lisa; Feldman, Steven A.; Mackall, Crystal L.; Davila, Marco L.; Curran, Kevin J.; Junghans, Richard P.; Tang, Jean Yuh; Kochenderfer, James N.; O'Cearbhaill, Roisin; Archer, Gary; Kiem, Hans-Peter; Shah, Nirali N.; Delbrook, Cindy; Kaplan, Rosie; Brentjens, Renier J.; Rivière, Isabelle; Sadelain, Michel; Rosenberg, Steven A.; Medical and Molecular Genetics, School of Medicine
    Replication-competent retrovirus (RCR) is a safety concern for individuals treated with retroviral gene therapy. RCR detection assays are used to detect RCR in manufactured vector, transduced cell products infused into research subjects, and in the research subjects after treatment. In this study, we reviewed 286 control (n = 4) and transduced cell products (n = 282) screened for RCR in the National Gene Vector Biorepository. The transduced cell samples were submitted from 14 clinical trials. All vector products were previously shown to be negative for RCR prior to use in cell transduction. After transduction, all 282 transduced cell products were negative for RCR. In addition, 241 of the clinical trial participants were also screened for RCR by analyzing peripheral blood at least 1 month after infusion, all of which were also negative for evidence of RCR infection. The majority of vector products used in the clinical trials were generated in the PG13 packaging cell line. The findings suggest that screening of the retroviral vector product generated in PG13 cell line may be sufficient and that further screening of transduced cells does not provide added value.