Faculty

Evan Weber, PhD

faculty photo
Assistant Professor of Pediatrics
Department: Pediatrics
Graduate Group Affiliations

Contact information
Children's Hospital of Philadelphia
Colket Translational Research Building, Rm 10018
3501 Civic Center Blvd
Philadelphia, PA 19104
Philadelphia, PA 19104
Office: 267-425-5589
Lab: www.theweberlab.org
Education:
BS (Program in the Environment)
University of Michigan, College of Literature, Science and the Arts, 2008.
PhD (Immunology)
Northwestern University, Feinberg School of Medicine, 2016.
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Description of Research Expertise

A major factor limiting the efficacy of chimeric antigen receptor (CAR) T cell therapy is T cell exhaustion, wherein chronic CAR signaling via antigen-independent CAR aggregation or high tumor burden drives global transcriptional and epigenetic alterations, overexpression of immune inhibitory receptors (ex. PD-1), and diminished anti-tumor function. My postdoctoral research demonstrated that transient cessation of CAR signaling, or “rest”, in exhausted CAR-T cells via enforced oscillations in CAR surface expression or pharmacologic inhibition of CAR signaling (Weber et al., Blood Adv, 2019) restores anti-tumor functionality through epigenetic remodeling (Weber et al., Science, 2021). This work is foundational to my independent research program centered around endowing human CAR-T cells with exhaustion resistance and improved durability. Utilizing an array of pharmacologic, gene-editing, and bioengineering approaches, my lab will identify and modulate transcriptional and epigenetic pathways that redirect human T cells towards more therapeutic cell states. Multi-omics analyses on experimental and patient CAR-T cells will enable us to link epigenetic features (ex. global or site-specific histone modifications) to cell phenotype, function, and patient outcomes, thereby informing our T cell engineering efforts. Collectively, our work will uncover molecular programs that drive human CAR-T cell dysfunction, identify targets for therapeutic intervention, and inform universal strategies that improve CAR-T cell efficacy in cancer patients.

Selected Publications

Labanieh L, Majzner RG, Klysz D, Sotillo E, Fisher CJ, Vilches-Moure JG, Pacheco KZB, Malipatlolla M, Xu P, Hui JH, Murty T, Theruvath J, Mehta N, Yamada-Hunter SA, Weber EW, Heitzeneder S, Parker KR, Satpathy AT, Chang HY, Lin MZ, Cochran JR, Mackall CL.: Enhanced safety and efficacy of protease-regulated CAR-T cell receptors. Cell May 2022 Notes: doi: 10.1016/j.cell.2022.03.041. Epub 2022 Apr 27.

Gennert D.G., Lynn R.C., Granja J.M., Weber E.W., Mumbach M.R., Zhao Y., Duren Z., Sotillo E., Greenleaf W.J., Wong W.H., Satpathy A.T., Mackall C.L., Chang H.Y. : Dynamic chromatin regulatory landscape of human CAR T cell exhaustion. PNAS 118(30): e2104758118, Jul 2021.

Weber E.W., Parker K.R., Sotillo e., Lynn R.C., Anbunathan H., Lattin J., Good Z., Belk J.A., Daniel B., Klysz D., Malipatlolla M., Xu P., Bashti M., Heitzeneder S., Labanieh L., Vandris P., Majzner R.G., Qi Y., Sandor K., Chen L.C., Prabhu S., Gentles A.J., Wandless T.J., Satpathy A.T., Chang H.Y., Mackall C.L.: Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling Science 372(6537): eaba1786, April 2021.

Lamarche C., Novakovsky G.E., Qi C.N., Weber E.W., Mackall C.L., Levings M.K.: Repeated stimulation or tonic-signaling chimeric antigen receptors drive regulatory T cell exhaustion. bioRxiv 28(1): https://doi.org/10.1101, Jun 2020.

Majzner R.G., Rietberg S., Sotillo E., Dong R., Vachharajani V., Labanieh L., Myklebust J., Kadapakkam M., Weber E.W., Tousley A., Richards R., Heitzeneder S., Nguyen S., Wiebking V., Theruvath J., Lynn R.C., Xu P., Dunn A., Vale R.D., Mackall C.L.: Tuning the Antigen Density Requirement for CAR T Cell Activity. Cancer Discov. 10(5): 702-723, May 2020.

Weber E.W., Maus M.V., Mackall C.L.: The Emerging Landscape of Immune Cell Therapies. Cell 181(1): 46-62, April 2020.

Dalal P., Sullivan D.P., Weber E.W., Sacks D., Gunzer M., Grumbach I, Brown J.H., Muller. W.A.: Spatiotemporal Restriction of Calcium Signaling in Endothelial Cells during Leukocyte Transmigration. J Exp Med 218(1): e20192378, Jan 2020.

Lynn R.C., Weber E.W., Sotillo E., Gennert D., Xu P., Good Z., Anbunathan H., Lattin J., Jones R., Tieu V., Nagaraja S., Granja J., DeBourcy C., Majzner R., Satpathy A.T., Quake S.R., Chang H.Y., Mackall C.L.: c-Jun Overexpression in CAR T Cells Induces Exhaustion-Resistance. Nature 576(7786): 293-300, Dec 2019.

Weber E.W., Lynn R.C., Sotillo E., Lattin J., Xu P., Mackall C.L.: Pharmacologic Control of CAR T Cell Function Using Dasatinib. Blood Adv 3(5): 711-717, Mar 2019 Notes: Selected by Blood Adv as “Top Influential Article” in 2020.

Weber E.W. and Muller W.A.: Roles of Transient Receptor Potential Channels in Regulation of Vascular and Epithelial Barries. Tissue Barriers 5(2): e1331722, Apr 2017.

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Last updated: 06/30/2022
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