CBET Award Achievements
Notable Accomplishments from CBET Awards
 

CAREER: Vaccination Nodes for Cancer Immunotherapy

Darrell Irvine    Massachusetts Institute of Technology


Background:  Though a variety of experimental evidence supports the idea that the immune system is capable of limiting the occurrence of tumors, the weakly immunostimulatory nature of many cancers and genetic alterations in these cells can together lead to a failure of immune defense and cancer progression.  To overcome this failure of immunity, strategies for therapeutic vaccination that would boost the immune response and/or combat the immunosuppressive signals derived from tumors are a topic of much research interest.  To date, few treatment strategies can destroy large established tumors, the setting commonly faced in the clinic.  Recently, a number of potent therapeutics that stimulate the immune system, including cytokines (signaling molecules) such as IL-15, immunomodulatory drugs, and Toll-like receptor ligands (transmitters), have been shown to augment immunotherapy, but an ongoing challenge is to synergistically deliver these compounds to tumors (while avoiding systemic side effects), to enable the establishment of potent tumor-focused immune responses.

Results:  During the past year, the Irvine lab has developed an approach to apply concepts from the field of regenerative medicine to the problem of cancer immunotherapy.  An injectable hydrogel material was developed that allows a viscuous solution of cells and drug-loaded microparticles to be injected around tumor sites in vivo, where the liquid 'sets' to form a stable gel within a period of minutes.  The gel serves as a depot to sequester factors secreted by immune cells loaded into the gel (particularly immunity-inducing cells known as dendritic cells) and serves as a scaffold supporting immune cell attraction to the tumor site.  This 'vaccination node' generated by injection of dendritic cell-loaded gels strongly attracts host immune cells to the gel site (and adjacent tumors), and provides cues to the attracted cells to promote their antitumor activity.  This work grew directly out of the group's earlier findings under an NSF-funded CAREER award, and the new developments were also supported by NSF.

Darrell Irvine Image 1
 
Figure 1.  Using a Perkin-Elmer Piezorray, ~300 pL spots of strepavidin-cyanine5 (SA-Cy5) at 50mg/ml and two-fold dilutions were deposited onto a photonic crystal functionalized with an epoxysilane surface chemistry.  After a 24 hour incubation and subsequent wash, label-free and fluorescence images of the arrayed spots were taken.  The label-free image (a) demonstrates sensitive detection of the surface-bound molecules and excellent spatial resolution.  An enhanced fluorescence image (b) precisely registered to the label-free image provides 315x intensity enhancement, 45x signal-to-noise enhancement, and a detection limit reduced by nearly two orders of magnitude compared to a glass slide control.


Darrell Irvine Image 2
 
Figure 2.  [Left Panel]:  Injectable gels are formulated by mixing calcium-loaded gel microspheres with a solution of the polysaccharide alginate.  Diffusion of calcium ions from the gel particles into the surrounding alginate solution crosslinks the polysaccharide, forming a physical gell over a period of ~1 hour in vivo.

[Middle Panel]:  Reconstructed fluorescence image illustrating self-gelled alginate structure.  Green fluorescence denotes the alginate solution and nonfluorescent voids are locations of calcium-loaded microsphreres in the matrix.

[Right Panel]: Immune cells (green fluorescence) readily infiltrate the porous anginate matrix (purple fluorescence) after a few days following injection in vivo.

Credit for Figures 1 & 2:  Y. Hori and D.J. Irvine, Massachusetts Institute of Technology. Modified in part from figures in Hori et al. Acta Biomaterialia in press (DOI: 10.1016/j.actbio.2008.11.019)


This project addresses the NSF Strategic Outcome Goals, as described in the NSF Strategic Plan 2006-2011, as follows:

Primary Strategic Outcome Goal:      (1) Discovery:  This work involved the demonstration of new ways to augment immunotherapy by combining ideas from cancer immunotherapy with concepts from regenerative medicine/biomaterials.  This highly interdisciplinary study has extended knowledge both in the field of biomaterials and in the area of immunotherapy.  Ongoing studies suggest that this approach will lead to new understanding of how drug/cell delivery can be combined to promote anti-cancer therapy.

                                                     (1) Discovery Categories:
                                                           - CAREER: Faculty Early Career Program
                                                           - Engineering Research

Secondary Strategic Outcome Goal:  (2) Learning: and (3) Research Infrastructure: The research carried out here was an integral part of an ongoing PhD student's thesis, and involved two different undergraduates.  One of the undergraduates who recently completed her BS degree was accepted this past Fall to Stanford University for graduate studies, very likely in part based on two publications she contributed to significantly during her research in the laboratory.

                                                     (2) Learning and Research Infrastructure Categories:
                                                           - Undergraduate Education and Undergraduate Student Research
                                                           - Graduate Education and Graduate Student Research
                                                           - Other Infrastructure and Research Resources

In terms of Intellectual Merit, this outcome is notable.  By co-delivering dendritic cells (DCs) and drug-releasing microspheres embedded in injectable gels, a dramatic enhancement in the ability of DCs to recruit host immune cells to the gel site and nearby tumors was found.  For example, T-cell recruitment to the site is increased by 800-fold when DCs are injected in alginate gels compared to the injection of DCs alone.  This synergy appears to be the result of the local buildup of inflammatory factors secreted by the DCs, which bind to the biomaterial matrix.  Early tumor therapy studies with this system suggest that it allows a major enhancement of the immune response generated by dendritic cells or cytokines alone, by promoting T-cell recruitment and effector functions at tumor sites.  This approach may be broadly applicable to a number of cancer immunotherapy strategies currently in clinical trials.

In terms of Broader Impacts, this outcome is notable.  This work involved graduate students and undergraduate students working together throughout, and involved substantial peer-based mentoring by the senior graduate students.  Publications resulting from this research undoubtedly played a role in the acceptance of one of the undergraduates involved in this work (Amy Winans, second author on two papers) to Stanford University for graduate studies this past fall.

This research is Transformative by leading new understanding of how drug/cell delivery can be combined to promote anti-cancer therapy.

Existing or potential Societal Benefits of this research:  Immunotherapy offers great promise for the treatment of established cancer, but strategies to effectively harness the power of the immune system are still in development.  The approach described here, using biomaterials to control the delivery of cell-based and cytokine/drug-based immunotherapy treatments to tumors and locally alter the effects of these treatments could provide a means to amplify anti-cancer immune responses while limiting systemic side effects elicited by intravenous drug therapy.  This approach provides a strategy to substantially enhance the effects of dendritic cell vaccination, a cell-based therapy currently in clinical trials, by using clinically-relevant biomaterials.



     
Program Officer:
 
  Semahat Demir
CBET Program Director - Biomedical Engineering
     
NSF Award Number:   0348259
     
Award Title:
  CAREER: Colloidal Micelles as Multifunctional Vaccines
     
PI Name:
  Darrell Irvine
     
Institution Name:   Massachusetts Institute of Technology
     
Program Element:   7236, 7236
     
NSF Investments:
 
  - Understanding Complex Biological Systems (including the
      interfaces of life, physical, and computational sciences)
     
CBET Nugget:   FY 2009
     

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This Nugget was Updated on 24 July 2009.