Immunotherapeutic Spherical Nucleic Acids for Cancer: Rational Design of Vaccines for Stimulating Immune Responses to Attack Cancer
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.
Engineered Spherical Nucleic Acids for Advanced T-Cell Therapy
Melanoma is the most dangerous and deadly type of skin cancer. It develops when unrepaired DNA damage to skin cells (melanocytes) triggers genetic mutations that lead the skin cells to multiply rapidly, forming malignant tumors. In 2019, The American Cancer Society estimated over 90,000 new cases of melanoma will be reported. Immunotherapies, such as those based on spherical nucleic acids (SNAs), show promise for eradicating this devastating disease.
The objective of this research project is to develop a novel cellular-based therapy for treating established solid tumors (primarily melanoma) by using immunostimulatory SNAs (IS-SNAs) to program tumor-specific cytotoxic CD8+T-cells to home to and kill tumors.
Mint: A Targeted Approach Enabling Immunologic Eradication of Advanced Cancer
Cancer cell growth and immune system function are intimately linked with cholesterol metabolism. Currently, there are no targeted therapies that potently and simultaneously modulate cellular cholesterol in cancer and immune cells. Our lab has developed myeloid inactivating nanoparticle therapy (MINT) that exquisitely targets and reduces cellular cholesterol as a new treatment for cancer that simultaneously activates a robust anti-tumor adaptive immune response.
The objective of this research project is to develop a treatment regimen of MINT and traditional immunotherapies for cancers that do not respond to either therapy alone. We believe that by rational tuning of the cholesterol-mediated pathway connecting cancer and immune cells, we will reveal potent new cancer therapies with reduced side effects.
Gene-Regulatory Spherical Nucleic Acids for Glioblastoma
Malignant brain tumors are aggressive and considered one of the deadliest of all human cancers. Treatment options are limited and at best offer temporary relief from progressive tumor growth. Brain tumors are comprised of many cell subpopulations that confer the tumor with an astonishing ability to overcome nearly any radiation and/or chemotherapy treatment. This characteristic is due, in part, to a complex intratumoral landscape of genetic and epigenetic changes. Informed by the tumor’s genetic and epigenetic makeup, several ‘targeted’ pharmacologicals have been approved for the treatment of brain cancers, foremost inhibitors of known cancer-associated enzymatic activities. While initial response rates were observed in a small fraction of brain tumor patients, tumor recurrence is nearly universal.
The overarching goals of this project are the development of gene-regulatory spherical nucleic acids (SNAs) targeted to the glioma oncogene IDH1, combined with small molecule-based IDH1 inhibitors to regulate cellular metabolism of glioma cells. Prior studies from the Stegh laboratory identified IDH1 as a critical glioma oncogene that promotes glioma progression (Calvert et al, 2017, Cell Reports).
Spherical Nucleic Acids as Multiantigen Immunotherapeutic Vaccines
Immunotherapy is a powerful emerging treatment for a variety of malignancies. Specifically, the use of cancer vaccines within the field of immunotherapy has revitalized interest in potentiating targeted antitumor immune responses. Using an immune system activator and an immune system target, these vaccines can drive the immune system to seek out and kill tumor cells.
Spherical nucleic acids (SNAs), nanostructures that are now part of four human clinical trials, take advantage of structure-activity relationships to press the immune system’s “gas pedal” and deliver the appropriate antigen for cancer immunotherapy.
We present two new strategies for strengthening antitumor immune responses that target more than one peptide antigen sequence or protein, to hasten the clinical translation of these nanostructures for treatment of metastatic castrate-resistant prostate cancer (mCRPC). We seek to induce responses towards a broad variety of prostate cancer (PCa) specific immunogenic peptides. To do this, we propose to design an SNA vaccine capable of delivering multiple epitopes. We will also utilize a new class of SNA, the protein SNA (ProSNA), where the core is a PCa tumor-associated protein, as a vaccine.
By enhancing the delivery of whole tumor-associated proteins to antigen-presenting cells, we will enable the cells to develop antigens internally which can elicit broader and more potent antitumor immune responses. The pursuit of these strategies will contribute to rational vaccine design, and their investigation in both transgenic mouse tumor models and human PCa patient samples will allow for facile clinical translation. This new project is funded in part by a Polsky Urologic Cancer Institute Research Award.