Leyuan Ma, PhD
Assistant Professor of Pathology and Laboratory MedicinePerelman School of Medicine at the University of Pennsylvania
Contact InformationChildren's Hospital of Philadelphia
CTRB 10-200, Ma Lab
Colket Translational Research Building
3501 Civic Center Blvd
Philadelphia, PA 19104
Office: 774-208-4271
Itmat Expertise
W 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.
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.
Education
BS (Biosciences and Bioengineering), Shandong Normal University, China, 2008
PhD (Molecular, Cell and Cancer Biology), University of Massachusetts Medical School, 2016
Specialty Certification
Postgraduate Training
Postdoctoral Fellow, Immune Engineering, Howard Hughes Medical Institute, Massachusetts Institute of Technology, 2016-2021
Awards and Honors
First Class Award, Shandong Normal University, 2005
Excellent Student, Shandong Normal University, 2005
Outstanding Bachelor’s Degree Thesis, Shandong Province, 2008
Sigma Xi Grant-in-Aid of Research, 2014
Dean’s Award for most insightful mid-thesis research, 2015
Chinese Government Award for Outstanding Self-Financed Students Abroad, 2016
American Cancer Society Postdoctoral Fellowship Award, 2019
Koch Institute Marlena Felter Bradford Research Travel Fellowship, 2019
CGTC seed grant/CHOP, 2022-2024
TAPITMAT Transdisciplinary Award/Penn, 2022-2024
NIAID New Innovators Awards/DP2, 2022-2027
Junior faculty mentored pilot grant, 2022-2024
The Distinguished Scientist Award/Sontag Foundation, 2023-2028
The Ben & Catherine Ivy Foundation Translational Adult Glioma Award, 2023-2025
SITC Young Investigator Abstract Travel Award/SITC, 2023
W.W. Smith Charitable Trust award, 2023-2024
Neuroblastoma neoantigen vaccine U01 (co-I), 2023-2028
I3H pilot grant/Penn, 2023-2024
Melanoma research Alliance Young Investigator Award, 2023-2026
Mesothelioma Research Grant Award, 2023-2025
SPORE career development program award/Penn, 2024-2026
Memberships and Professional Organizations
Sigma Xi, The Scientific Research Society, 2014 - 2018
Biomedical Engineering Society (BMES), 2018 - Present
American Society of Gene & Cell Therapy, 2022 - Present
Society for Immunotherapy of Cancer, 2023 - Present
American Association of immunologists, 2023 - Present
American Association for Cancer Research, 2023 - Present
Web Links
Selected Publications
Directed evolution-based discovery of ligands for in vivo restimulation of CAR-T cells
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., bioRxiv 1(): , 2024, PMID:38659938
Crosstalking with Dendritic Cells: A Path to Engineer Advanced T Cell Immunotherapy
Schafer, S., Chen, K., Ma, L., Front Syst Biol 4(): , 2024
ALK inhibitors increase ALK expression and sensitize neuroblastoma cells to ALK.CAR-T cells
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., Cancer Cell 41(12): 2100-2116 e10, 2023
Cooperative phagocytosis of solid tumours by macrophages triggers durable anti-tumour responses
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., Nat Biomed Eng 7(9): 1081-1096, 2023
Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity
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., Cell 186(15): 3148-3165 e20, 2023
Engineering enhanced chimeric antigen receptor-T cell therapy for solid tumors
Neeser, A., Ramasubramanian, R., Wang, C., Ma, L., Immunooncol Technol 19(): 100385, 2023
STING agonist delivery by tumour-penetrating PEG-lipid nanodiscs primes robust anticancer immunity
Dane, E. L., Belessiotis-Richards, A., Backlund, C., Wang, J., Hidaka, K., Milling, L. E., Bhagchandani, S., Melo, M. B., Wu, S., Li, N., Donahue, N., Ni, K., Ma, L., Okaniwa, M., Stevens, M. M., Alexander-Katz, A., Irvine, D. J., Nat Mater 21(6): 710-720, 2022
Supporting the Next Generation of Scientists to Lead Cancer Immunology Research
Alspach, E., Chow, R. D., Demehri, S., Guerriero, J. L., Gujar, S., Hartmann, F. J., Helmink, B. A., Hudson, W. H., Ho, W. J., Ma, L., Maier, B. B., Maltez, V. I., Miller, B. C., Moran, A. E., Parry, E. M., Pillai, P. S., Rafiq, S., Reina-Campos, M., Rosato, P. C., Rudqvist, N. P., Ruhland, M. K., Sagiv-Barfi, I., Sahu, A. D., Samstein, R. M., Schurch, C. M., Sen, D. R., Thommen, D. S., Wolf, Y., Zappasodi, R., Cancer Immunol Res 9(11): 1245-1251, 2021
CAR-T cell-induced cytokine release syndrome is rapidly alleviated by tripterygium glycosides
Zuqiong Xu, Fang Tian, Biqing Chen, Xiangtu Kong, Xingbin Dai, Jiang Cao, Pengjun Jiang, Jianxin Tan, Lu Lu, Xiachang Wang, Qi Lv, Di Kang, Miao Xu, Yingying Hu, Aiping Yang, Qian Wang, Zhong-Fa Yang, Xuemei Sun, Leyuan Ma, Lihong Hu, Xuejun Zhu, MedRxiv, 2020
Immunotherapy (Chapter 3.2)
Wang C*, Silva M*, Ma L*, Bioengineering Innovative Solutions for Cancer, 2019
