Prof. Chad A. Mirkin
Prof. Andrew Lee
This project is aimed at developing spherical nucleic acid (SNA) nanostructures as a technology for the immunotherapeutic treatment of cancer. SNAs are chemically well-defined and modular structures that we have adapted to raise antigen-specific, anti-tumor immune responses. Our study of SNAs as cancer immunotherapy has demonstrated the importance of rational design in the development of cancer vaccines. We can improve vaccine performance and control the way in which SNAs stimulate anti-cancer immune responses through the systematic and rational variation in their chemical composition and structure (i.e., molecular placement/presentation, component linkages). Previous work has established this idea, as structurally different SNAs with the identical compositions of immunostimulatory oligonucleotides and peptide antigens demonstrated varying responsivities of generated adaptive immunities, a cause of the different levels of tumor-specific cytotoxic T cells. Our systematic assessment between structural changes and downstream immune responses has given us mechanistic insights into the way in which SNAs are taken up and processed by immune system cells, and ultimately allows us to define a structure-function relationship that enhances vaccine development.
SNA technology has made critical advances in the clinic. Studies performed by Exicure, a biotechnology company spun out of Northwestern University based on initial work completed in the Mirkin lab, have shown that SNAs formulated with immunostimulatory DNA are safe and capable of stimulating cellular immune responses in a Phase 1 clinical trial. The efficacy of such SNAs is currently under evaluation in a Phase 1b/2 trial in patients with inoperable tumors (cutaneous squamous cell carcinoma, melanoma, Merkel cell carcinoma) across five clinical sites with SNAs delivered by intra-tumoral injection. These developments point to the importance of this research and show the potential of SNA technology to enhance the potency and specificity of immune responses to attack cancer.
Outcomes of this project are well-defined, tuned, and molecularly precise SNA structures and an understanding for how each aspect of SNA structure (i.e., oligonucleotide sequence, density, chemical linkage, peptide antigen, peptide-conjugation chemistry, chemistry of the nanoparticle core) contributes to downstream generated tumor-specific cytotoxic T cells and subsequent adaptive immune responses. Such structures will be capable of advancing to clinical evaluation for specific cancers (e.g., prostate cancer), but will also set the stage for their development as a platform to improve patient immune responses to other types of cancer (via choice or addition of different tumor-associated antigens) and address other aspects of anti-tumor immune responses (e.g., combination therapy with checkpoint blockade inhibitors).
The accomplishments of the current period of research are centered upon 1) improving the potency of anti-tumor T cell responses through the application of SNA vaccines to clinically relevant models; 2) understanding the cellular trafficking of SNAs to manipulate structure and enhance potency; and 3) improving immune responses through SNAs that target tumor resistance to checkpoint inhibitors.