We tackle the following challenges in clinical immunotherapies:
Immunotherapies (such as vaccines) rely on the immune systems of each individual patient to properly function. Modern genetics has identified 450 types of human primary immunodeficiencies – hereditary impaired or weakened immune systems that cannot respond normally to immunotherapies. Additionally, human immune systems are also subject to impairment due to aging and disease such as certain viral infections and cancers. Hence, restoring the damaged immune pathways is a prerequisite for effective administration.
Drug delivery poses several translational challenges for immunotherapies and vaccines. Efforts have primarily focused on the spatial distribution of drug – maintaining sufficient drug levels at the disease site while avoiding non-specific accumulation in healthy tissues – which is critical to therapeutic outcome. However, another aspect commonly overlooked is the temporal order of drug administration, especially for combination therapies that target multiple facets of the immune system.
More than a hundred distinct types of human cancer have been identified. In a single type of cancer, temporal variations in disease stage likewise contribute to tumor heterogeneity. Existing cancer vaccines are dominated by predefined cancer antigens like the gp100 in melanoma and the HER2 in breast cancer, which have demonstrated survival benefits in Phase I clinical trials. However, cancer can undergo antigen loss under such selective pressure and evolve adaptive resistance to treatment. Such evolving heterogeneity eventually leads to metastasis, which causes the vast majority of deaths of cancer patients.
We leverage interdisciplinary engineering in biology and chemistry to tailor immunotherapy to be more effective and broadly available for human patients.
To address host immune deficiencies, which are often caused by a single missing or mis-functioning mutant protein, we engineer bio-inspired protein signaling complexes to repair damaged signaling pathways or overcome inhibitory factors, ultimately develop personalized therapies for patients with deficient immune systems.
To precisely control the sequence and duration of drug release, we design tunable drug delivery platforms with stimuli-responsive, bio-compatible polymers. By adjusting the molecular architecture and charged groups of polymer chains, we can modulate the release profile of drug components to match the patients’ natural rhythm of immune signaling.
To tackle the heterogeneity of cancer, we leverage the potency of immune cells, such as T cells, NK cells, and dendritic cells. However, the primary functions of those cells evolved from the arms race with microbial infection. We need to repurpose the immune cells (for example, via genome editing) to recognize cancer cells as targets for elimination.
Our ultimate goal is to expand knowledge in the field of immunotherapy and develop translatable applications to benefit human health.
We restore impaired signaling by discovering non-canonical signaling pathways. For instance, during my PhD, I first demonstrated with my colleagues that the transmembrane domain (TM) of the STING protein was not indispensable to achieve signaling, based on which we elucidated an alternative STING signaling achieved through a tetrameric TM-deleted STING protein segment that is independent of Golgi translocation, a key departure from claims in prior seminal work.
Representative work: He et al. Sci Adv (2020)
We synthesize new polymers to control drug release. During my early PhD training in polymer chemistry, I devised a new strategy to lift off electrostatic layer-by-layer (LbL) drug films from microneedle skin patches using a pH-sensitive charge-invertible polymer. This results in a markedly improved release rate in comparison to conventional LbL films, which are “sticky” and take a long time to dissociate due to the electrostatic attraction between adjacent layers.
Representative work: He*, Hong* et al. ACS Nano (2018)
One strategy of overcoming tumor heterogeneity is to use the patient’s own tumor as a personalized source of antigens. During my postdoc, I developed an effective in situ cancer vaccine based on the TM-deleted STING platform and immune checkpoint blockade, eliminating 70%-100% established solid tumors in mouse melanoma and colon cancer models. We also reported on the surprisingly crucial role of CD4+ T cells in STING-mediated anti-tumor immunity that I’m thrilled to carry forward for more potential mechanism discoveries.
Representative work: He et al. Adv Healthcare Mat (2023)
We gratefully acknowledge the generous support of our funding agencies, whose contributions make our research possible:
