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2026

Blood Cancer Discov . 2026 Feb 2:10.1158/2643-3230.BCD-25-0092. doi: 10.1158/2643-3230.BCD-25-0092. Online ahead of print.

Endogenous CD28 drives the persistent activity of CAR T cells in myeloma and lymphoma models

Mackenzie M Lieberman, Jason H Tong, Nkechi U Odukwe, Colin A Chavel, Gina G Bishara, Kimberly M Crasti, Megan M Herr, Payal Goala, Terence J Purdon, Rebecca Burchett, Bryan M Gillard, Craig M Brackett, Joseph D Tario, Spencer R Rosario, Aj Robert McGray, Jonathan L Bramson, Marco L Davila, Renier J Brentjens, Ehsan Malek, Kelvin P Lee, Scott H Olejniczak

Roswell Park Cancer Institute Buffalo, NY United States. Roswell Park Cancer Institute United States. Roswell Park Cancer Institute Buffalo, New York United States. McMaster University Hamilton, ON Canada. McMaster University Hamilton, Ontario Canada. University Hospitals Case Medical Center United States. Indiana University School of Medicine Indianapolis, Indiana United States.

Service type: Knockout mice

Abstract

Chimeric antigen receptor (CAR) T cell therapy has reshaped the therapeutic landscape for multiple myeloma (MM), yet most patients treated with BCMA-targeted CAR T cells experience disease relapse. Consequently, we sought to determine if inhibition of CD28 survival signaling could increase MM sensitivity to CAR T cell therapy. Contrary to expectations, blockade of CD28 interaction with CD80/86 accelerated tumor regrowth in preclinical MM and lymphoma CAR T therapy models. Knockout studies revealed that endogenous CD28 on 4-1BB co-stimulated CAR T cells prolonged in vivo activity, reprogrammed mitochondrial metabolism to maintain redox balance, and stimulated proliferation and release of tumor-model specific inflammatory cytokines in the tumor microenvironment. Intriguingly, transient CD28 blockade decreased levels of certain TME cytokines without significantly affecting survival of CAR T cell treated mice. Collectively, these data provide direct evidence that endogenous CD28 signaling modulates CAR T cell responses in multiple myeloma and lymphoma models.

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