Biology subjects

Weiss, G. J.

Publications and source records attributed to Weiss, G. J..

3 recordsLinked to original sources

bioRxiv2022

Open spaced ridged hydrogel scaffolds containing TiSAMP surface chemistry promotes regeneration and recovery following spinal cord injury.

The spinal cord has poor ability to regenerate after injury, which may be due to cell loss, cyst formation, inflammation, and scarring. A promising approach to treat spinal cord injury (SCI) is the use of biomaterials. We have developed a novel hydrogel scaffold fabricated from oligo(poly(ethylene glycol) fumarate) (OPF) as a 0.08 mm thick sheet containing polymer ridges and a cell-attractive surface chemistry on the other side. When the cells are cultured on OPF with the chemical patterning, the cells attach, align, and deposit ECM along the direction of the pattern. Animals implanted with the rolled scaffold sheets had greater hindlimb recovery compared to the multichannel scaffold control, likely due to the greater number of axons growing across. Inflammation, scarring, and ECM deposits were equal across conditions. Overall, the results suggest that the scaffold sheets promote axon outgrowth that can be guided across the scaffold, thereby promoting hindlimb recovery.

neuroscience↗

bioRxiv2022

Glypican-3 (GPC3) is associated with MCPyV-negative status and impaired outcome in Merkel Cell Carcinoma

BackgroundMerkel cell carcinoma (MCC) is an aggressive skin cancer, related to the Merkel Cell Polyomavirus (MCPyV) in 80% of cases. Immune checkpoint inhibitors provide sustained benefit in about half of MCC patients with advanced disease. Glypican-3 (GPC3) is an oncofetal tumor antigen that is an attractive target for chimeric antigen receptor T cell therapy due to its highly restricted expression on normal tissue and high prevalence in several solid tumors. GPC3 was previously found to be expressed in MCC but its association with tumor characteristics or prognosis has not been reported. ObjectivesTo investigate the expression of GPC3 in MCC by immunohistochemistry (IHC) and its association with tumor characteristics, MCPyV status, and patient outcome. MethodsThe GC33 antibody clone was validated for GPC3 IHC staining of tumor specimens in comparison to an established GPC3 IHC antibody. A tissue microarray of tumors collected from an ongoing cohort of MCC patients was stained for GPC3 by IHC using GC33 antibody. Association of GPC3 positivity with baseline characteristics, MCPyV status (quantitative PCR) and outcome (death from MCC, recurrence) were assessed by Fishers exact tests and Cox regression analysis. ResultsAmong 62 tumors from 59 patients, 42 samples (67.7%) were GPC3-positive. GPC3 expression was more frequently observed in females (p=0.048) and MCPyV-negative tumors (p=0.021). In the multivariate analysis, GPC3 expression was associated with increased death from disease (CSS) (hazard ratio [HR] 4.05, 95% CI 1.06-15.43), together with advanced age (HR 4.85, 95% CI 1.39-16.9) and male gender (HR 4.64, 95% CI 1.31-16.41). ConclusionsGPC3 expression is frequently expressed in MCC tumors, especially MCPyV-negative cases, and is associated with increased risk of death. The high prevalence of surface GPC3 makes it a putative drug target.

cancer biology↗

bioRxiv2021

BOXR1030, an anti-GPC3 CAR with exogenous GOT2 expression, shows enhanced T cell metabolism and improved antitumor activity

PurposeThe solid tumor microenvironment (TME) drives T cell dysfunction and inhibits the effectiveness of immunotherapies such as chimeric antigen receptor-based T cell (CAR T) cells. Early data has shown that modulation of T cell metabolism can improve intratumoral T cell function in preclinical models. Experimental DesignWe evaluated GPC3 expression in human normal and tumor tissue specimens. We developed and evaluated BOXR1030, a novel CAR T therapeutic co-expressing glypican-3 (GPC3)-targeted CAR and exogenous glutamic-oxaloacetic transaminase 2 (GOT2) in terms of CAR T cell function both in vitro and in vivo. ResultsExpression of tumor antigen GPC3 was observed by immunohistochemical staining in tumor biopsies from hepatocellular carcinoma, liposarcoma, squamous lung cancer, and Merkel cell carcinoma patients. Compared to control GPC3 CAR alone, BOXR1030 (GPC3-targeted CAR T cell that co-expressed GOT2) demonstrated superior in vivo efficacy in aggressive solid tumor xenograft models, and showed favorable attributes in vitro including an enhanced cytokine production profile, a less-differentiated T cell phenotype with lower expression of stress and exhaustion markers, an enhanced metabolic profile and increased proliferation in TME-like conditions. ConclusionsTogether, these results demonstrated that co-expression of GOT2 can substantially improve the overall antitumor activity of CAR T cells by inducing broad changes in cellular function and phenotype. These data show that BOXR1030 is an attractive approach to targeting select solid tumors. To this end, BOXR1030 will be explored in the clinic to assess safety, dose- finding, and preliminary efficacy (NCT05120271).

cancer biology↗