Evan Weber, PhD

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Assistant Professor of Pediatrics (Oncology)
Assistant Professor, University of Pennsylvania, Perelman School of Medicine, Department of Pediatrics, Division of Oncology
Member, Abramson Cancer Center, University of Pennsylvania
Member, Center for Cellular Immunotherapies, University of Pennsylvania
Member, Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia
Member, Center for Childhood Cancer Research, Children's Hospital of Philadelphia
Member, Institute for Immunology, University of Pennsylvania
Principal Investigator, Cell and Gene Therapy Collaborative, Children's Hospital of Philadelphia
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
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

Larmarche C., Ward-Hartstonge K., Mi T., Lin D.T.S., Huang Q., Brown A., Edwards K., Novakovsky G.E., Qi C.N., Kobor M.S., Zebley C.C., Weber E.W., Mackall C.L., Levings M.K. : Tonic-signaling chimeric antigen receptors drive human regulatory T cell exhaustion. PNAS 120(14), April 2023.

Tousley A.M., Rotiroti M.C., Labanieh L., Rysavy L.W., Kim W.J., Lareau C., Sotillo E., Weber E.W., Rietberg S.P., Dalton G.N., Yin Y., Klysz D., Xu P., de la Serna E.L., Dunn A.R., Satpathy A.T., Mackall C.L., Majzner R.G. : Coopting T cell proximal signaling molecules enables Boolean logic-gated CAR T control. Nature 615(7952): 507-516, Mar 2023.

Yingqin Hou, Jaroslav Zak, Yujie Shi, Isaraphorn Pratumchai, Brandon Dinner, Wenjian Wang, Ke Qin, Evan Weber, John R. Teijaro, Peng Wu: Transient EZH2 suppression by Tazemetostat during in vitro expansion maintains T cell stemness and improves adoptive T cell therapy. bioRxiv February 2023.

Freitas KA, Belk JA, Sotillo E, Quinn PJ, Ramello MC, Malipatlolla M, Daniel B, Sandor K, Klysz D, Bjelajac J, Xu P, Burdsall KA, Tieu V, Duong VT, Donovan MG, Weber EW, Chang HY, Majzner RG, Espinosa JM, Satpathy AT, Mackall CL.: Enhanced T cell effector activity by targeting the Mediator kinase module. Science 378(6620), Nov 2022 Notes: doi: 10.1126/science.abn5647. Epub 2022 Nov 11.

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.

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Last updated: 06/09/2023
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