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Biology subjects

Sawyer, W.

Publications and source records attributed to Sawyer, W..

4 recordsLinked to original sources
bioRxiv2026

Lymphoma response to chimeric antigen receptor T cell therapy is driven by endogenous tumor-reactive CD8⁺ T cells

CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy induces durable remissions in a subset of patients with relapsed or refractory large B-cell lymphoma; however, most patients fail to respond or eventually relapse. By integrating whole-genome and transcriptome profiling of 54 patients with functional assays, syngeneic models, and mathematical modeling, we demonstrate that durable CAR-T efficacy requires cooperation between CAR-T cells and endogenous CD8 (eCD8) T cells recruited to join the attack on malignant cells. Tumors with biallelic loss of MHC class I or CD58 exhibited high genomic complexity, increased neoantigen burden, and resistance to CAR-T therapy. MHC-I-deficient lymphomas showed suboptimal response in immunocompetent hosts compared to wild type. Importantly, sustained responses in mice occurred only in the presence of eCD8 cells, whereas all CD8-depleted mice relapsed after initial CAR-T-mediated tumor regression. Patients and murine ELISPOT assays confirmed enhanced endogenous T-cell activation post-CAR-T. These findings reveal that CAR-T therapy functions not only as a cytotoxic modality but also as a catalyst for endogenous anti-tumor immunity.

cancer biology↗
bioRxiv2026

Enhanced lung delivery of an immunostimulatory duplex RNA augments the antitumor activity by reshaping systemic cytokine pharmacodynamics

The organ-specific enrichment of drug delivery vehicles, such as lipid nanoparticles (LNPs), can be leveraged to concentrate drugs at disease sites to increase efficacy and limit toxicity. For immunostimulatory therapeutics, however, tissue accumulation beyond diseased sites may also shape drug activity by determining which organs and cell populations first sense the agonist and initiate downstream immune responses. Here, we show that the anticancer efficacy of an immunostimulatory duplex RNA (dsRNA) can be augmented using LNPs that are formulated to preferentially target the lung, which dictates the systemic pharmacodynamics of the cytokines it elicits. The immunostimulatory dsRNA was formulated into LNPs engineered for either enhanced liver-(LiverLNPs) or lung-(LungLNPs) based delivery, matched for size, encapsulation efficiency, and in vitro potency. In mice, delivery of dsRNA in LungLNPs enhanced uptake into endothelial, epithelial, and resident immune cells populations and induced substantially higher circulating levels of type I, type III interferons and proinflammatory cytokines than dsRNA formulated in LiverLNPs. This significant systemic response induced by lung-enhanced delivery required competent retinoic acid-inducible gene I and Toll-like receptor 7 signaling. Functionally, LNPs that preferentially targeted the lungs induced significantly greater suppression of tumor growth in both subcutaneous and metastatic models of melanoma. LungLNP/dsRNA also induced cytokine secretion and inhibited tumor cell proliferation in a human lung cancer-on-a-chip model. Together, these results establish that pulmonary exposure can alter systemic pharmacodynamics and therapeutic activity of immunostimulatory RNA.

bioengineering↗
bioRxiv2019

Two distinct mechanisms of small molecule inhibition of LpxA acyltransferase essential for lipopolysaccharide biosynthesis

The lipopolysaccharide biosynthesis pathway is considered an attractive drug target against the rising threat of multidrug-resistant Gram-negative bacteria. Here, we report two novel small-molecule inhibitors (compounds 1 and 2) of the acyltransferase LpxA, the first enzyme in the lipopolysaccharide biosynthesis pathway. We show genetically that the antibacterial activities of the compounds against efflux-deficient Escherichia coli are mediated by LpxA inhibition. Consistently, the compounds inhibited the LpxA enzymatic reaction in vitro. Intriguingly, using biochemical, biophysical, and structural characterization, we reveal two distinct mechanisms of LpxA inhibition; compound 1 is a substrate-competitive inhibitor targeting apo LpxA and compound 2 is an uncompetitive inhibitor targeting the LpxA-product complex. Compound 2 exhibited more favorable biological and physicochemical properties than compound 1, and was optimized using structural information to achieve improved antibacterial activity against wild type E. coli. These results show that LpxA is a promising antibacterial target and imply the advantages of targeting enzyme-product complexes in drug discovery.

biochemistry↗