Leyuan Ma

faculty photo
Assistant Professor of Pathology and Laboratory Medicine
Assistant Professor of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine
Department: Pathology and Laboratory Medicine
Graduate Group Affiliations

Contact information
CTRB, 10-200, Ma Lab
Office: 267-425-0133
Lab: 2674255594
BS (Biosciences and Bioengineering)
Shandong Normal University, China, 2008.
PhD (Molecular, Cell and Cancer Biology)
University of Massachusetts Medical School, 2016.
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Description of Research Expertise

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.

​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.

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).

Our research comprises three inter-connected themes:
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.

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.

We are also interested in engineering immune cells using surface chemistry to achieve spatial-temporal modulation of their activities and functionalities.

2) ImmunoSensing. Genetic engineering and synthetic immunology to create intelligent cells that integrate environmental cues for decision making.

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.

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.

3) ImmunoTherapy. Protein engineering to develop safe and potent immune-modulatory proteins and nanostructures.

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.

Selected Publications

Elisa Bergaggio, Wei-Tien Tai, Andrea Aroldi, Carmen Mecca, Elisa Landoni, Manuel Nüesch, Ines Mota, Jasna Metovic, Luca Molinaro, Leyuan Ma, Diego Alvarado, Chiara Ambrogio, Claudia Voena, Rafael B Blasco, Tongqing Li, Daryl Klein, Darrell J Irvine, Mauro Papotti, Barbara Savoldo, Gianpietro Dotti, Roberto Chiarle: ALK inhibitors increase ALK expression and sensitize neuroblastoma cells to ALK. CAR-T cells. Cancer Cell Dec 2023.

Dooling, L.J.*; Andrechak, J.A.*; Hayes, B.H.; Kadu, S.; Zhang, W.; Pan, R.; Vashisth, M.; Irianto, J.; Alvey, C.M.; Ma, L.; Discher, D.E.: Cooperative phagocytosis underlies macrophage immunotherapy of solid tumours and initiates a broad anti-tumour IgG response. Nature BME Sep 2023.

L. Ma#, A Hostetler, D Morgan, L Maiorino, I Sulkaj, CA Whittaker, A Neeser, I Pires, P. Yousefpour, J Gregory, K Qureshi, J Dye, W Abraham, H Suh, N Li, C. Love, D. J. Irvine#. : Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity. Cell Jul 2023.

A. Neeser*, R. Ramasubramanian*, Chao W, L.Ma#: Engineering enhanced CAR T cell therapy for solid tumors. IOTECH May 2023.

L. Ma, D Morgan, I Sulkaj, P. Yousefpour, W Abraham, N Li, C. Love, D. J. Irvine.: Eradication of tumors with pre- existing antigenic heterogeneity by vaccine-mediated co-engagement of CAR T and endogenous T-cell. BioRxiv Oct 2022.

E Dane, A Belessiotis-Richards, C Backlund, J Wang, K Hidaka, L Milling, S Bhagchandani, M Melo, NA Li, N Donahue, K Ni, L Ma, M Okaniwa, M Stevens, A Alexander-Katz, D. J. Irvine: Delivery of STING agonists using tumor-penetrating PEGylated lipid nanodiscs primes sustained anti-cancer immunity. Nat Materials May 2022.

2. E. Alspach, R. D. Chow, S. Demehri, J. L. Guerriero, S. Gujar, F. J. Hartmann, B. A. Helmink, W. H. Hudson, W. J. Ho, L. Ma, B. B. Maier, V. I. Maltez, B. C. Miller, A. E. Moran, E. M. Parry, P. S. Pillai, S. Rafiq, M. Reina-Campos, P. C. Rosato, N.-P. Rudqvist, M. K. Ruhland, I. Sagiv-Barfi, A. D. Sahu, R. M. Samstein, C. M. Schürch, D. R. Sen, D. S. Thommen, Y. Wolf, R. Zappasod: Supporting the next generation of scientists to lead cancer immunology research. Cancer Immunol Res Nov 2021.

Wang C*, Silva M*, Ma L*: Immunotherapy (Chapter 3.2). Bioengineering Innovative Solutions for Cancer. Ladame S and Chang J (eds.). Elsevier, Academic Press, Page: 221-244, Nov 2019 Notes: *Equal contribution https://doi.org/10.1016/B978-0-12-813886-1.09989-7.

Ma L, Dichwalkar JYH, Chang B, Cossette D, Garafola A, Zhang Q, Fichter M, Wang C, Liang S, Silva M, Kumari S, Mehta NK, Abraham W, Thai N, Li N, K. D. Wittrup KD, Irvine DJ: Enhanced CAR–T cell activity against solid tumors by vaccine boosting through the chimeric receptor. Science 365(6449): 162-168, July 2019 Notes: Editorial highlight “A boost for CAR–T cells” Science, 2019 “Amph-Ligand Vaccine Enhances CAR-T Cell Activity against Solid Tumors” Cancer discovery, 2019 Comment “Boosting engineered T cells” Science, 2019 Featured “CAR T cells get a boost inside lymph nodes” ACIR, 2019

Momin N, Mehta HN, Bennett NR*, Ma L*, Palmieri JR, Chinn MM, Lutz EA, Kang B, Irvine DJ, Spranger S, Wittrup KD.: Anchoring of intratumorally administered cytokines to collagen safely potentiates systemic cancer immunotherapy. Sci Transl Med 11(498): eaaw2614, June 2019 Notes: * Equal contribution DOI: 10.1126/scitranslmed.aaw2614.

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Last updated: 07/20/2024
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