TSCOT + Thymic Epithelial Cell-Mediated Sensitive CD4 Tolerance by Direct Presentation

Although much effort has been directed at dissecting the mechanisms of central tolerance, the role of thymic stromal cells remains elusive. In order to further characterize this event, we developed a mouse model restricting LacZ to thymic stromal cotransporter (TSCOT)-expressing thymic stromal cells (TDLacZ). The thymus of this mouse contains approximately 4,300 TSCOT+ cells, each expressing several thousand molecules of the LacZ antigen. TSCOT+ cells express the cortical marker CDR1, CD40, CD80, CD54, and major histocompatibility complex class II (MHCII). When examining endogenous responses directed against LacZ, we observed significant tolerance. This was evidenced in a diverse T cell repertoire as measured by both a CD4 T cell proliferation assay and an antigen-specific antibody isotype analysis. This tolerance process was at least partially independent of Autoimmune Regulatory Element gene expression. When TDLacZ mice were crossed to a novel CD4 T cell receptor (TCR) transgenic reactive against LacZ (BgII), there was a complete deletion of double-positive thymocytes. Fetal thymic reaggregate culture of CD45- and UEA-depleted thymic stromal cells from TDLacZ and sorted TCR-bearing thymocytes excluded the possibility of cross presentation by thymic dendritic cells and medullary epithelial cells for the deletion. Overall, these results demonstrate that the introduction of a neoantigen into TSCOT-expressing cells can efficiently establish complete tolerance and suggest a possible application for the deletion of antigen-specific T cells by antigen introduction into TSCOT+ cells

Rethinking Cancer Clinical Trial Conduct Induced by COVID-19: An Academic Center, Industry, Government, and Regulatory Agency Perspective

The COVID-19 pandemic brought about major changes in cancer clinical trials. In its aftermath, the community has an opportunity to incorporate some of these changes as part of the future of trial conduct to make it more patient centered

Impact of an evolving regulatory landscape on skin cancer drug development in the U.S.

Background: There has been a rapid proliferation of FDA-approved medications with labeled indications for skin cancer over the last decade, with particular growth over the last 5 years. Objective: We aimed to evaluate the impact of an evolving U.S. regulatory framework on drug development programs to better understand current trends and regulatory considerations when adjudicating drug approvals for patients with skin cancer. Methods: We reviewed publicly-available regulatory documents of all systemic medications with a labeled indication for skin cancer. Results: We identified 130 FDA approvals that resulted in a unique indication, usage, formulation, or dosage change in skin cancer since 1949. Limitations: Publicly available data from the mid-to-late 20th century is limited. Conclusions: The therapeutic landscape in skin cancer has changed greatly since the first approval in 1949. In concert, regulatory medicine has also evolved over the last 70 years with the aim of ensuring safe and effective medicines for a diverse array of patients

Development of human anti-murine T-cell receptor antibodies in both responding and nonresponding patients enrolled in TCR gene therapy trials

Purpose: Immune responses to gene-modified cells are a concern in the field of human gene therapy, as they may impede effective treatment. We conducted 2 clinical trials in which cancer patients were treated with lymphocytes genetically engineered to express murine T-cell receptors (mTCR) specific for tumor-associated antigens p53 and gp100. Experimental Design: Twenty-six patients treated with autologous lymphocytes expressing mTCR had blood and serum samples available for analysis. Patient sera wer