Shivani Srivastava, PhD

Shivani Srivastava, PhD

Institution: Fred Hutchinson Cancer Research Center

Project: Enhancing Effectiveness of CAR-T Cell Therapy for Lung Cancer

Grant(s): Lung Cancer Discovery Award

I started my lab at the Fred Hutchinson Cancer Center in November 2020, and funding from the ALA Lung Cancer Discovery Award has been critical in building my research program centered on developing more effective CAR-T cell therapies for lung cancer. The COVID-19 pandemic has added some strain to the start of research group in two main areas: 1) due to travel restrictions and halted research progress at many institutions around the country, hiring of new postdoctoral fellows has been particularly impacted and it has been difficult to attract talented postdoctoral fellows who are able to relocate to the Seattle area in the midst of a pandemic; 2) supply chain issues have significantly increased the cost and delayed shipment of basic lab supplies, causing significant delays to planned experiments and wasting of lab funds on increased costs for basic materials like plasticware. Nevertheless, our group has been able to hire several talented graduate students and research technicians and to execute experiments, enabling us to generate data that we have presented at national conferences and that we are preparing for publication.

Update: This project aims to understand the mechanisms by which overexpression of the AP-1 subunit cJun improves the activity of CAR-T cells in lung cancer, and to evaluate how durable this effect remains in an immunosuppressive, clinically relevant tumor microenvironment. We have demonstrated that a single infusion of cJun CAR-T cells significantly improves long-term survival in an aggressive genetically-engineered mouse model of non-small cell lung cancer. Interestingly, cJun CAR-T cells maintain higher levels of CAR expression in vivo. Mechanistically, this appears to be due to increased CAR transcription and faster recovery of surface CAR expression after ligand-induced downregulation and may facilitate greater sensitivity to antigen-low tumors. Finally, we found that tumor progression in cJun CAR-T-treated mice is associated with post-transcriptional downregulation of cJun and loss of CAR-T function. We are exploring strategies to preserve cJun expression that may prolong the anti-tumor activity of cJun CAR-T cells.

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