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Yan Leyfman: Rewiring CAR T-Cell Signaling to Overcome Immune Suppression in Solid Tumors
Yan Leyfman/LinkedIn

Yan Leyfman: Rewiring CAR T-Cell Signaling to Overcome Immune Suppression in Solid Tumors

Yan Leyfman, Medical Oncologist, Co-Founder and Executive Director of MedNews Week, shared a post on LinkedIn:

“Rewiring CAR T-Cell Signaling to Overcome Immune Suppression in Solid Tumors.

CAR T-cell therapy has transformed the treatment of hematologic malignancies, but its success in solid tumors has been limited by the immunosuppressive tumor microenvironment and intrinsic signaling deficiencies within CAR T cells.

In this study, investigators developed a novel PD-1–LAT (PLAT) chimeric switch scaffold that converts inhibitory PD-1/PD-L1 interactions into activating signals. Rather than simply blocking PD-1, PLAT recruits the LAT (linker for activation of T cells) signalosome, restoring signaling pathways that are naturally engaged by T-cell receptors (TCRs) but are often absent in conventional CAR constructs.

Key findings:

  • PLAT enhanced LAT phosphorylation and downstream signaling following PD-L1 engagement.
  • The engineered CAR T cells formed a more physiologic, TCR-like immune synapse, improving signal organization.
  • Stronger calcium signaling and NFAT/NF-κB activation translated into greater cytotoxicity, sustained proliferation, and improved resistance to T-cell exhaustion during chronic antigen exposure.
  • Compared with PD-1–CD28 switch receptors and dominant-negative PD-1 strategies, PLAT demonstrated superior functional durability and improved antitumor activity in preclinical models.

Rather than simply removing inhibitory signals, this approach repurposes immune checkpoint engagement into productive T-cell activation, addressing one of the fundamental signaling limitations of CAR T-cell therapy.

Although clinical validation is still needed, PLAT represents a promising next-generation engineering strategy that could improve CAR T-cell persistence and efficacy in solid tumors.”

Title: Chimeric switch scaffold protein augments CAR synapse formation and signaling networks

Authors: Cho I. Park, Segi Kim, Hwanyong Shim, Minh Ha Nguyen, Won-ki Cho, Chan Hyuk Kim

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Yan Leyfman

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cancer cancer immunotherapy Cancer research CAR T-CELL CAR T-cell therapy Cellular Therapy Chan Hyuk Kim Cho I. Park Hwanyong Shim Immune Checkpoint immuno-oncology immunotherapy Minh Ha Nguyen next-generation CAR-T OncoDaily Oncology PD-1 PD-L1 Precision Oncology Preclinical Research Segi Kim solid tumors T-cell engineering T-Cell Signaling translational research tumor microenvironment Won-ki Cho Yan Leyfman