Publications by authors named "Khloe S Gordon"

Chimeric antigen receptor therapies have demonstrated potent efficacy in treating B cell malignancies, but have yet to meaningfully translate to solid tumors. Here, we utilize our pooled screening platform, CARPOOL, to expedite the discovery of CARs with anti-tumor functions necessary for solid tumor efficacy. We performed selections in primary human T cells expressing a library of 1.

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The anti-tumor function of engineered T cells expressing chimeric antigen receptors (CARs) is dependent on signals transduced through intracellular signaling domains (ICDs). Different ICDs are known to drive distinct phenotypes, but systematic investigations into how ICD architectures direct T cell function-particularly at the molecular level-are lacking. Here, we use single-cell sequencing to map diverse signaling inputs to transcriptional outputs, focusing on a defined library of clinically relevant ICD architectures.

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Article Synopsis
  • CAR-T therapy shows promise for treating B-cell malignancies, but many patients experience relapses due to mechanisms like loss of CAR-T cells and antigen escape.* ! -
  • Researchers used CRISPR-Cas9 in a mouse model of B-ALL to discover that IFNγR/JAK/STAT signaling and antigen processing pathways contribute to resistance against CAR-T therapy.* ! -
  • The study found that increased expression of these pathways in relapsed tumors is linked to poor outcomes in B-ALL patients, highlighting the role of the tumor microenvironment, including natural killer cells, in inducing resistance mechanisms.* !
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While immune checkpoint blockade results in durable responses for some patients, many others have not experienced such benefits. These treatments rely upon reinvigorating specific T cell-antigen interactions. However, it is often unknown what antigens are being recognized by T cells or how to potently induce antigen-specific responses in a broadly applicable manner.

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The immunostimulatory intracellular domains (ICDs) of chimaeric antigen receptors (CARs) are essential for converting antigen recognition into antitumoural function. Although there are many possible combinations of ICDs, almost all current CARs rely on combinations of CD3𝛇, CD28 and 4-1BB. Here we show that a barcoded library of 700,000 unique CD19-specific CARs with diverse ICDs cloned into lentiviral vectors and transduced into Jurkat T cells can be screened at high throughput via cell sorting and next-generation sequencing to optimize CAR signalling for antitumoural functions.

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