Biology subjects

Seaman, S.

Publications and source records attributed to Seaman, S..

3 recordsLinked to original sources

bioRxiv2026

Engineering Functionality-Optimized Fully Human B7-H3 CAR T Cells for Enhanced Solid Tumor Therapy

B7-H3 is a cell surface protein overexpressed in many solid tumors and an attractive target for chimeric antigen receptor (CAR) T cell therapy. The most clinically advanced B7-H3 CARs are derived from murine monoclonal antibodies (mAbs) 376.96 and MGA271, which are now in phase 1/11 trials. However, non-human mAb sequences can provoke immune responses, leading to CAR T-cell rejection and therapeutic failure. Although scFv humanization reduces this risk, residual foreign residues within the variable domains remain. To overcome this limitation, we used in vitro phage display to generate fully human B7-H3-specific scFvs for CAR design. In pancreatic cancer, neuroblastoma, and glioblastoma xenograft models, CAR T cells incorporating the lead human binder Y111 were well tolerated and demonstrated superior antitumor activity compared with 376.96- and MGA271-based CARs. Y111 CAR treatment induced complete responses, tumor rejection, and significant survival benefits, identifying Y111 as a promising fully human B7-H3 CAR for solid tumors.

immunology↗

bioRxiv2023

Selective targeting of α4β7/MAdCAM-1 axis suppresses fibrosis progression in chronic liver disease

Integrin 4{beta}7+ T cells perpetuate tissue injury in chronic inflammatory diseases, yet their role in hepatic fibrosis progression remains poorly understood. Here we report increased accumulation of 4{beta}7+ T cells in the liver of people with cirrhosis relative to disease controls. Similarly, hepatic fibrosis in the established mouse model of CCl4-induced liver fibrosis was associated with enrichment of intrahepatic 4{beta}7+ CD4 and CD8 T cells. Monoclonal antibody (mAb)-mediated blockade of 4{beta}7 or its ligand mucosal addressin cell adhesion molecule (MAdCAM)-1 attenuated hepatic inflammation and prevented fibrosis progression in CCl4 treated mice. Improvement in liver fibrosis was associated with a significant decrease in the infiltration of 4{beta}7+ CD4 and CD8 T cells suggesting that 4{beta}7/MAdCAM-1 axis regulates both CD4 and CD8 T cell recruitment to the fibrotic liver, and 4{beta}7+ T cells promote hepatic fibrosis progression. Analysis of hepatic 4{beta}7+ and 4{beta}7-CD4 T cells revealed that 4{beta}7+ CD4 T cells enriched for markers of activation and proliferation demonstrating an effector phenotype. Notably, blockade of 4{beta}7 or MAdCAM-1 did not affect the recruitment of Foxp3+ regulatory T cells, demonstrating the specificity of 4{beta}7/MAdCAM-1 axis in regulating effector T cell recruitment to the liver. The findings suggest that 4{beta}7+ T cells play a critical role in promoting hepatic fibrosis progression, and mAb-mediated blockade of 4{beta}7 or MAdCAM-1 represents a promising therapeutic strategy for slowing hepatic fibrosis progression in chronic liver diseases.

immunology↗

bioRxiv2018

High-resolution structural genomics reveals new therapeutic vulnerabilities in glioblastoma

We investigated the role of 3D genome architecture in instructing functional properties of glioblastoma stem cells (GSCs) by generating the highest-resolution 3D genome maps to-date for this cancer. Integration of DNA contact maps with chromatin and transcriptional profiles identified specific mechanisms of gene regulation, including individual physical interactions between regulatory regions and their target genes. Residing in structurally conserved regions in GSCs was CD276, a gene known to play a role in immuno-modulation. We show that, unexpectedly, CD276 is part of a stemness network in GSCs and can be targeted with an antibody-drug conjugate to curb self-renewal, a key stemness property. Our results demonstrate that integrated structural genomics datasets can be employed to rationally identify therapeutic vulnerabilities in self-renewing cells.\n\nSIGNIFICANCEIn adult GBM, GSCs act as therapy-resistant reservoirs to nucleate tumor recurrence. New therapeutic approaches that target these cell populations hold the potential of significantly improving patient care and overall prognosis for this always-lethal cancer. Our work describes new links between 3D genome architecture and stemness properties in GSCs. In particular, through integration of multiple genomics and structural genomics datasets, we found an unexpected connection between immune-related genes and self-renewal programs in GBM. Among these, we show that targeting CD276 with knockdown strategies or specific antibody-drug conjugates achieve suppression of self-renewal. Strategies to target CD276+ cells are currently in clinical trials for solid tumors. Our results indicate that CD276-targeting agents could be deployed in GBM to specifically target GSC populations.\n\nHIGHLIGHTSO_LIWe generated high (sub-5 kb) resolution Hi-C maps for stem-like cells from GBM patients.\nC_LIO_LIIntegration of Hi-C and genomics datasets dissects mechanisms of gene regulation.\nC_LIO_LI3D genomes poise immune-related genes, including CD276, for expression.\nC_LIO_LITargeting CD276 curbs self-renewal properties of GBM cells.\nC_LI

cancer biology↗