Inhibition of eIF4A to improve T cell efficacy (SJ-22-0012) 

St. Jude Reference #SJ-22-0012

Description

Researchers at St. Jude have developed a pharmacological treatment strategy to improve CAR T cell immunotherapy using the eIF4A inhibitor Silvestrol. The invention can be used during the process of CAR T cell generation to increase persistence of CAR T cells in patients.

Activated CD8+ T lymphocytes differentiate into heterogeneous subsets. Using super-resolution imaging, researchers at St. Jude found that prior to the first division, dynein-dependent vesicular transport polarized active TORC1 toward the microtubule-organizing center (MTOC) at the proximal pole. This active TORC1 was physically associated with active eIF4F, required for the translation of c-myc mRNA. As a consequence, c-myc-translating polysomes polarized toward the cellular pole proximal to the immune synapse, resulting in localized c-myc translation. Upon division, the TORC1-eIF4A complex preferentially sorted to the proximal daughter cell, facilitating asymmetric c-Myc synthesis. Transient disruption of eIF4A activity at first division skewed long-term cell fate trajectories to memory-like function. Using a genetic barcoding approach, we found that first-division sister cells often displayed differences in transcriptional profiles that largely correlated with c-Myc and TORC1 target genes. The findings provide mechanistic insights as to how distinct T cell fate trajectories can be established during the first division.

Keywords

Biologic, CAR T cell, immunotherapy, eIF4A inhibitor, Silvestrol, persistence, activation, promote memory function, efficacy, CD8(+) T cells, STED, STORM, asymmetric cell division, c-Myc, cell fate, eIF4A, polarization, scRNA-seq, translation

Granted patents or published applications

Pending patent application

Related scientific references

Diego A Rodriguez, Duygu Kuzuoğlu-Öztürk, Ao Guo, Katherine C Verbist, Jamshid Temirov, Mark J Chen, Davide Ruggero, Hui Zhang, Paul G Thomas, Douglas R Green, “Localization of a TORC1-eIF4F translation complex during CD8+ T cell activation drives divergent cell fate, ” Mol. Cell, Volume 82, Issue 13, 7 July 2022, Pages 2401-2414.e9. DOI: 10.1016/j.molcel.2022.04.016, https://pubmed.ncbi.nlm.nih.gov/35597236/

Licensing opportunities

We are currently seeking a partner to commercialize this  invention. Contact: chad.riggs@stjude.org

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