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.