Immunotherapy and Immunoengineering

Dysfunction of the immune system plays an important role in many diseases, ranging from inflammation to cancer, autoimmunity, and transplant rejection. Our immune systems consist of many molecules, cells, and tissues that normally protect against disease by identifying and killing foreign pathogens and cancer cells. The human immune system has the capability to learn how to recognize components of foreign agents more efficiently with multiple exposures, a process referred to as adaptive immunity, and this creates immunological memory which is the basis of vaccination. However, disease can result when this system does not function appropriately. Cancer is an example of what happens when the immune system is incapable or prevented from recognizing new molecular targets in our own diseased cells. On the opposite extreme, if the immune system is overly aggressive, attacking and destroying normal cells in the body, autoimmune disease results. Millions of Americans suffer from these diseases, which are often chronic, debilitating, and life-threatening. New immunomodulatory therapies and engineering strategies are clearly needed to treat these diseases.

Biomaterial vaccines for immunomodulation in-situ:

Our laboratory is developing strategies to quantitatively control immune cells and their signaling to both strengthen our understanding of the immune system and to develop new immunotherapies. Our approach targets dendritic cells (DCs) and T cells as a key mediator of adaptive immunity. DCs function as sentinels– continuously migrating through tissues and sampling their contents for foreign agents (i.e., antigens) before migrating to the lymph nodes to present the antigens they find to T cells. Here, we exploit the natural migratory and sampling function of DCs using biomaterials which actively recruits DCs migrating through tissues and encourages them to take up residence in the biomaterial scaffold. The scaffold provides a highly tunable microenviroment. The biomaterial-resident DCs are programmed via exposure to tolerizing or danger signals in concert with the antigen that will be used to induce a destructive or tolerizing immune response. Then, the DCs migrate from the biomaterial scaffold to the lymph nodes, to alter the immune response (Fig. 1). We are actively investigating how lymph nodes and particular immune cell subsets respond to biomaterial-based vaccination, and how they can be controlled to strengthen immunotherapies.

Biomaterial vaccine immunodulation

Figure 1. General strategy to use biomaterial systems to recruit and reprogram cells for immune therapies. Image taken from (Wang, et al., Nature Materials, 2018).

T-cell immunoengineering and manufacturing:

A substantial effort in the lab has been made on tuning T cell biology directly in vivo and ex vivo. T cells, especially CD8+ T cells, play a critical role in killing pathogenic and cancerous cells. Recently, we developed a cell-mimetic biomaterial system that presents activating cues to T cells in a similar manner to how these cues are naturally presented in the body – enabling several-fold greater expansion of primary T cells than widely-used clinical expansion systems (Fig. 2). This ex vivo approach has immediate implications in the expanding field of adoptive cell transfer (i.e., genetically-engineered, chimeric antigen receptor (CAR) T cells). We are currently developing similar technologies, with a particular interest in using materials to tune T cell responses in vivo.

antigen presenting cell-mimetic scaffold

Figure 2. Schematic representation of antigen presenting cell-mimetic biomaterial system for the production of therapeutic T cells, including autologous engineered CAR-T cells, allogeneic T cells, or TILs, and neoantigen-specific T cells. Image taken from (Zhang, et al., Nature Protocols, 2020).

Metabolic glycoengineering for cancer-targeted immunotherapy:

Metabolic glycoengineering with unnatural sugars provides a powerful tool to label cell membranes with chemical tags for subsequent targeted conjugation of molecular cargos via efficient chemistries. We are exploring this technology for cancer labelling and targeting. We are rationally designing unnatural sugars to enable preferential labelling of cancer  and immune cells, or to specifically deliver to cancerous tissues. We have shown that DCs concentrated by a biomaterial can be metabolically labelled with azido groups in situ, which allows for their subsequent tracking and targeted modulation over time to prime T cells and improve antitumour efficacy. We are also extending this technology to engineer cell-surface chemical tags on other cell types that can also enable targeted conjugation of immunomodulatory molecules including adjuvants, cytokines, and antibodies to modulate the interaction between tumour and immune cells (Fig. 3).

metabolic glycoengineering

Figure 3. Metabolic glycoengineering for targeted modulation of cancer and immune cells. Image taken from (Hua, et al., Nature Chemistry, 2020).

Overall, our research suggests significant potential in using biomaterials to govern aspects of the immune response for the treatment of cancer, and other immune-related ailments.

Relevant review articles in this area

  1. Wang, H., Mooney, D.J. Biomaterial-assisted targeted modulation of immune cells in cancer treatment. Nature Mater 17, 761–772 (2018). https://doi.org/10.1038/s41563-018-0147-9
  2. Wang, H., Mooney, D.J. Metabolic glycan labelling for cancer-targeted therapy. Nat. Chem. 12, 1102–1114 (2020). https://doi.org/10.1038/s41557-020-00587-w
  3. Gu L, Mooney DJ. Biomaterials and emerging anticancer therapeutics: engineering the microenvironment. Nat Rev Cancer. 2015;16(1):56-66. doi:10.1038/nrc.2015.3.

Representative research publications in this area

  1. Shah, N.J., Najibi, A.J., Shih, TY. et al. A biomaterial-based vaccine eliciting durable tumour-specific responses against acute myeloid leukaemia. Nat Biomed Eng 4, 40–51 (2020). https://doi.org/10.1038/s41551-019-0503-3
  2. Wang, H., Sobral, M.C., Zhang, D.K.Y. et al. Metabolic labeling and targeted modulation of dendritic cells. Nat. Mater. 19, 1244–1252 (2020). https://doi.org/10.1038/s41563-020-0680-1
  3. Li WA, Sobral MC, Badrinath S, et al. A facile approach to enhance antigen response for personalized cancer vaccination. Nat Mater. 2018. doi: 10.1038/s41563-018-0028-2.
  4. Cheung AS, Zhang DKY, Koshy ST, Mooney DJ. Scaffolds that mimic antigen-presenting cells enable ex vivo expansion of primary T cells. Nat Biotechnol. 2018;36(2):160-169. doi: 10.1038/nbt.4047.
  5. Bencherif SA, Warren Sands R, Ali OA, et al. Injectable cryogel-based whole-cell cancer vaccines. Nat Commun. 2015;6:7556. doi:10.1038/ncomms8556.
  6. Ali OA, Huebsch N, Cao L, Dranoff G, Mooney DJ. Infection-mimicking materials to program dendritic cells in situ. Nat Mater. 2009;8(2):151-158. doi:10.1038/nmat2357.