Faculty

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Leyuan Ma, Ph.D.

Assistant Professor of Pathology and Laboratory Medicine

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Department: Pathology and Laboratory Medicine

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1f Graduate Group Affiliations 8

46 Contact information
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CHILDREN'S HOSPITAL OF PHILA
21 3501 CIVIC CENTER BOULEVA
1c CTRB, 10-200, Ma Lab
39 COLKET TRANSL RES BLDG
PHILADELPHIA, PA 19104

2e Office: 267-425-0133
3d Lab: 2674255594
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Email:
Leyuan.Ma@Pennmedicine.upenn.edu

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13 Education:
21 7 BS 2b (Biosciences and Bioengineering) c
3a Shandong Normal University, China, 2008.
21 8 PhD 2f (Molecular, Cell and Cancer Biology) c
43 University of Massachusetts Medical School, 2016.
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Links
83 CHOP Lab Page
78 Center for cellular immunotherapy website
5c External lab website
68 CHOP PI Profile
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5 3 3 92 Permanent link
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b6 > Perelman School of Medicine > Faculty > Details a

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Description of Research Expertise

17e The immune system plays a central role in maintaining tissue homeostasis. Immune dysregulation results in many disorders, such as cancer, autoimmunity, and chronic infections. A systematic understanding and controlled intervention of immune cell signaling in lymphoid and peripheral tissues hold great promise for addressing these outstanding biomedical challenges.
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161 At Ma Laboratory For Immune Engineering, we employ a combination of genetic, chemistry, engineering and computational tools to decode the molecular and cellular crosstalk between immune cells and their microenvironment, and leverage these crosstalk mechanisms to engineer novel biomaterials, protein, and cell-based precision immunotherapies.
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1e9 We have recently developed a novel biomaterial-based synthetic vaccine to specifically stimulate and re-invigorate CAR T cells with enhanced anti-tumor activity (Ma et al, Science, 2019). We further engineered a yeast surface display platform to screen for surrogate peptide ligand for any CAR of interest, enabling us to rapidly develop a customized synthetic vaccine for a desired CAR T product enabling CAR T in vivo manufacturing and tumor targeting in tandem (In preparation).
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3c Our research comprises three inter-connected themes:
c4 1) ImmunoModulation. Chemical and biomaterials engineering to dissect and manipulate immune cell-cell and cell-tissue crosstalk to enhance cellular therapy and promote vaccine development.
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256 Building on the synthetic vaccine platform we recently developed for CAR T cells, we aim to elucidate the optimal design rules of this synthetic vaccine. This project will leverage high-throughput library screening, genomics and chemistry to dissect immune cell crosstalk at the single-cell level and its impact on vaccination outcomes. This project will guide the design of a robust major histocompatibility complex (MHC)-independent vaccination strategy applicable to any adoptive T cell therapy(e.g., CAR T, Treg, and TIL therapy), potentially redefining therapeutic T cell vaccination.
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a3 We are also interested in engineering immune cells using surface chemistry to achieve spatial-temporal modulation of their activities and functionalities.
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99 2) ImmunoSensing. Genetic engineering and synthetic immunology to create intelligent cells that integrate environmental cues for decision making.
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1af Targeting malignant cells via cell surface antigens using CAR T therapy has proven highly effective in controlling certain blood cancers. However, loss of surface antigen became one of the major mechanisms of resistance to CAR T therapy, and many solid tumors often do not possess unique surface antigens, making it challenging to generalize cellular immunotherapy via this surface antigen-based tumor-targeting mechanism.
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16c An alternative and complementary strategy could be engineering therapeutic cells to specifically sense and respond to features associated with the tumor microenvironment (TME). This project will employ multi-omics, synthetic biology, and viral engineering to define and create genetic circuits enabling immune cells to distinguish tumor from normal tissue.
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78 3) ImmunoTherapy. Protein engineering to develop safe and potent immune-modulatory proteins and nanostructures.
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266 Therapeutic applications of highly potent immune-modulatory proteins, such as cytokines, often need to overcome two major hurdles, specificity and toxicity. Our recent work on matrix-anchoring fusion cytokines (e.g., Lumican-IL12) presents an alternative strategy via sustained local release within the tumor microenvironment. Along this line, we aim to harness protein fusions, directed evolution and chemical modification to engineer proteins with desired trafficking profile, release kinetics, enhanced or completely new functions for immunotherapy in situ or as therapeutic payload for engineered cells.
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Selected Publications

1ff T Grzywa, A Neeser, R Ramasubramanian, N.K. Mehta, B Cossette, D.M. Morgan, I Sukaj, E Bergaggio, S Kadauke, R.M. Myers, L Paruzzo, G Ghilardi, A Cozzone, SJ. Schuster, N Frey, L Zhang, P Yousefpour, W Abraham, H Suh, M Ruella, S.A. Grupp, R Chiarle, K.D Wittrup, L Ma#, D.J. Irvine#. : Directed evolution-based discovery of ligands for in vivo restimulation of CAR-T cells. Nat. Biomed. Eng August 2025 Notes: [# co-corresponding author.

220 J Domagala, T. M Grzywa, I Baranowska, M Justyniarska, R Tannir, A Graczyk-Jarzynka, Al Kusowska, M Lecka, M Poreba, K Fidyt, K Marhelava, Z Pilch, L. K Picard, T. Wegierski, K. Jastrzebski, M Krawczyk, M Klopotowska, M Granica, D Urlaub, S Hajduk, A Neeser, S Moros, P Kozlowski, M Bobrowicz, M Miaczynska, L Ma, C Watzl, M Winiarska: Ammonia Suppresses the Antitumor Activity of Natural Killer Cells and T Cells by Decreasing Mature Perforin. Cancer Research July 2025.

182 Wenqun Zhong, Zhiyuan Qin, Ziyan Yu, Jingbo Yang, Dongdong Yan, Nils W Engel, Neil C Sheppard, Yi Fan, Ravi Radhakrishnan, Xiaowei Xu, Leyuan Ma, Serge Y Fuchs, Carl H June, Wei Guo: Overcoming extracellular vesicle-mediated fratricide improves CAR T cell treatment against solid tumors. Nature Cancer April 2025.

127 R. Tannir, L. Chan, S. Kaha, C.Wang, A. Neeser, A. Cozzone, L Ma#. : Chemistry-enabled lentivirus attachment as a generic approach to promote efficient gene delivery to mammalian cells. BioRxiv, Mol Ther. in revision 2025.

26d Grzywa, T., Mehta, N., Cossette, B., Romanov, A., Paruzzo, L., Ramasubramanian, R., Cozzone, A., Morgan, D., Sukaj, I., Bergaggio, E., Tannir, R., Kadauke, S., Myers, R., Yousefpour, P., Ghilardi, G., Schuster, S., Neeser, A., Frey, N., Goncalves, B., Zhang, L., Abraham, W., Suh, H., Ruella, M., Grupp, S., Chiarle, R., Wittrup, K. D., Ma, L., Irvine, D. J.: Directed evolution-based discovery of ligands for in vivo restimulation of CAR-T cells. bioRxiv 1, October 2024 Notes: [Preprint] DOI: 10.1101/2024.04.16.589780.

db Schafer, S., Chen, K., Ma, L.: Crosstalking with Dendritic Cells: A Path to Engineer Advanced T Cell Immunotherapy. Front Syst Biol 4, April 2024.

205 Bergaggio, E., Tai, W. T., Aroldi, A., Mecca, C., Landoni, E., Nuesch, M., Mota, I., Metovic, J., Molinaro, L., Ma, L., Alvarado, D., Ambrogio, C., Voena, C., Blasco, R. B., Li, T., Klein, D., Irvine, D. J., Papotti, M., Savoldo, B., Dotti, G., Chiarle, R.: ALK inhibitors increase ALK expression and sensitize neuroblastoma cells to ALK.CAR-T cells. Cancer Cell 41(12): 2100-2116 e10, December 2023 Notes: DOI: 10.1016/j.ccell.2023.11.004.

169 Dooling, L. J., Andrechak, J. C., Hayes, B. H., Kadu, S., Zhang, W., Pan, R., Vashisth, M., Irianto, J., Alvey, C. M., Ma, L., Discher, D. E.: Cooperative phagocytosis of solid tumours by macrophages triggers durable anti-tumour responses. Nat Biomed Eng 7(9): 1081-1096, September 2023.

1e0 Ma, L., Hostetler, A., Morgan, D. M., Maiorino, L., Sulkaj, I., Whittaker, C. A., Neeser, A., Pires, I. S., Yousefpour, P., Gregory, J., Qureshi, K., Dye, J., Abraham, W., Suh, H., Li, N., Love, J. C., Irvine, D. J.: Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity. Cell 186(15): 3148-3165 e20, July 2023 Notes: DOI: 10.1016/j.cell.2023.06.002.

121 Neeser, A., Ramasubramanian, R., Wang, C., Ma, L.: Engineering enhanced chimeric antigen receptor-T cell therapy for solid tumors. Immunooncol Technol 19: 100385, May 2023 Notes: DOI: 10.1016/j.iotech.2023.100385.

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