Technologies and approaches from the physical sciences and engineering can act as enabling partners with biology to find solutions to difficult problems in medicine. Because the immune system plays a critical role in disease, engineering approaches grounded in immunology may hold the key to the discovery and development of novel treatments for cancer, infectious disease, and autoimmunity. To this end, we take a materials science–centric engineering approach to create new therapies based in the controlled modulation of the immune system; we also use our materials chemistry expertise to create new experimental tools to better understand how the immune system functions in health and disease.
Our main efforts focus on the development of drug delivery materials designed to control the spatial and temporal delivery of cues to the immune system in vitro and in vivo, from antigens and adjuvant molecules to entire cells. Synthetic materials that precisely control delivery of signals to the immune system (targeting the correct tissue site, controlling entry into the cell, controlling the time evolution of these signals) can change the qualitative and quantitative nature of T- and B-cell responses to vaccines, bolster immune responses against cancer, and enhance the effectiveness of cell-based immune therapies.
Solving Challenges in Vaccine Design Using Smart Materials and Nanotechnology
Designing new materials for safe and effective subunit vaccines. A key goal of our laboratory is to advance methods for delivery of antigens and/or immunostimulatory cues to immune cells by using polymers, microparticles, or nanoparticles to create improved vaccines and immunotherapies. Control over the temporal sequence and physical form of antigen and immunostimulatory signals delivered to immune cells enables dramatic enhancements in T cell and B cell function and memory elicited by vaccination. In recent work, we have engineered stabilized lipid nanocapsules that co-package antigen and molecular adjuvants and deliver these vaccines to lymph nodes, where they form intranodal depots lasting several weeks and promote prolonged antigen presentation. This alteration in kinetics of antigen/adjuvant exposure lead to CD8+ T cell responses to protein vaccines comparable to recombinant viral vectors and durable, high-avidity B cell responses, addressing two challenges that have plagued the development of subunit vaccines. We have also developed strategies for using microneedles to rapidly deliver vaccines into the skin, forming micro-implants in the skin that controllably expose draining lymph nodes to vaccine components over days to weeks. These microneedle skin patch systems have been shown to promote immune responses to DNA vaccines comparable to in vivo electroporation, a complex process currently viewed as the gold standard for DNA vaccine delivery. We are applying these technologies to the development of vaccines against HIV, malaria, and cancer.
Chemotherapy for vaccines. Small-molecule drugs that very specifically modulate intracellular signaling pathways are a mainstay of cancer drug development, and several such targeted drugs have had a major clinical impact in cancer. We hypothesize that drugs targeting signaling pathways that control immunity could also be powerful adjuvants for prophylactic vaccines, but the application of small-molecule drugs as vaccine adjuvants faces two hurdles: (1) these drugs typically have short half-lives, requiring sustained or repeated intravenous infusion in the setting of cancer, and (2) systemic exposure is often accompanied by systemic toxicity that is acceptable in the treatment of advanced cancer but intolerable in prophylactic vaccines. We are developing strategies to deliver potent drugs through microparticles and nanoparticles that safely provide a tunable exposure of draining lymph nodes to these agents without leading to accumulation in the systemic circulation. Several candidate signaling pathways have been identified that can be manipulated by these chemotherapy adjuvants to boost T cell immunity, humoral immunity, or both. In addition, these controlled-release vaccines provide a powerful nongenetic strategy to probe the role of key signaling pathways in vaccine responses.
Designing New Approaches for Safe and Potent Cancer Immunotherapy
Safe and effective immunotherapy by using localized treatment driving disseminated immunity. Immunomodulatory agents are often limited by severe dose-limiting toxicity when administered systemically (e.g., interleukin-2), restricting the effectiveness of immunotherapy in cancer. We are studying strategies to harness the full potency of immunotherapy agents while eliminating systemic toxicity by designing strategies to control the biodistribution of these drugs. For example, anchoring immunomodulators (cytokines, antibodies, etc.) to nanoparticles can confine the biodistribution of these drugs to target tissue sites, and exposure in the systemic circulation can be drastically reduced while retaining the fully biological potency of the parent soluble molecules. Importantly, we have used this approach to show that even local treatment of accessible tumors can lead to systemic immune responses, with T cell–mediated elimination of distal untreated tumors (again, without toxicity). This approach provides a general strategy to fully exploit the potency of immunotherapy drugs without the side effects that typically restrain their use in the clinic.
Pharmacytes as living drug delivery agents for cancer therapy. Adoptive cell therapy (ACT) that uses patient-derived tumor-specific T cells is a promising approach for cancer treatment, but strategies to enhance the persistence and functionality of ACT T cells are still sought. Meanwhile, the use of synthetic nanoparticles as carriers to deliver anticancer drugs has become of increasing interest, with the goal of targeting drugs to tumor sites. We have developed a strategy combining these two approaches, which relies on stable chemical conjugation of drug-loaded nanoparticles (NPs) to the surfaces of live lymphocytes for ACT. We have demonstrated how ACT T cells carrying cytokine-loaded NPs (to permit pseudo-autocrine self-stimulation following transfer into tumor-bearing hosts) are capable of massive in vivo expansion and robust antitumor responses, enabled by minimal doses of cytokines that by comparison have no therapeutic effect when given in a soluble form systemically. In a second approach, we have used T cells as carriers to deliver chemotherapy agents to lymphoid tumors; the natural lymph node and bone marrow homing tropism of lymphocytes are employed to target drugs to sites of lymphoma dissemination. Together, these results suggest that the combination of nanotechnology approaches with cell therapy can dramatically enhance the efficacy of cancer immunotherapies.
Developing New Tools to Interrogate the Immune System
Regulation of immune cell migration. Chemokines are host proteins that regulate immune cell migration; in response to pathogens, chemokines direct dendritic cells (DCs; key initiators of adaptive immunity) and their precursors to sites of infection. We developed microspheres that release chemokines at predetermined rates, allowing gradients of chemokine to be created with tailored characteristics; each microsphere can act as a point source of attractant. These microparticles avidly chemoattract DCs, and loading of these attracting microspheres with antigen or other immunostimulatory molecules allows selective delivery of these compounds to attracted cells. We seek to use this system to determine how the recruitment of unique T cells and DC precursor cells by different chemokine signals alters immune responses in vivo. These materials may also form the basis of improved vaccines that mimic the cellular recruitment processes normally triggered during infections.
This work is also supported by the National Institutes of Health, the National Science Foundation, and the Department of Defense.
As of November 16, 2012