U01CA265706

Immunotherapy via Engineered Therapeutic Programs in Tumors Using RNA

Immunotherapy treatments, such as checkpoint blockade and chimeric antigen receptor T cell therapy, have demonstrated the power of the immune system to eradicate metastatic cancer. However, the efficacy of immunotherapies in solid tumors remains confined to a minority of patients. To achieve efficacy, a series of interlinked events are needed, including the induction of immunogenic tumor cell death, recruitment of immune cells to the tumor bed, and reversion of immunosuppressive cues in the tumor microenvironment (TME).

We have developed a therapeutic approach using intratumorally-administered synthetic lipid nanoparticles (LNPs) to deliver self-replicating (replicon) RNAs to tumors. These RNAs activate innate immune signaling pathways and potently express therapeutic payloads. Our recently published preliminary data has shown that this approach elicits profound anti-tumor immune responses in several tumor models, enabling tumor regression of both injected and distal non-injected tumors.

In this project, we aim to build on these initial findings and apply a synthetic biology toolkit to create next-generation LNP-replicon therapeutics. These therapeutics will combine multiple features to increase the safety and efficacy of the approach. These features include cell classifier circuits that allow replicon expression only in target cancer cells or immune cells, optimized multi-subgenomic promoter replicons that encode multiple payload genes expressed at tunable predefined expression levels, and small molecule-regulated replicons that allow two-stage therapeutic programs to be implemented following a single intratumoral injection.

To promote efficient transfection of desired target cell types in the TME, these engineered RNAs will be combined with optimized LNP formulations. We will apply this technology to treat lung cancer, the leading cause of cancer death, using a syngeneic mouse model of local intratumoral therapy in orthotopic and autochthonous lung cancer models that recapitulate the TME of human lung cancers.

Our specific aims are as follows:
1. Develop formulations for cell type-specific expression in cancer cells and T cells.
2. Create small molecule-regulated RNA circuits for cancer cells and T cells for programmable immunogenic cancer cell death and specific expression in T cells.
3. Therapeutic testing of optimized replicon circuits in orthotopic lung cancer models alone and in combination.

This proposal brings together a highly interdisciplinary team, combining cutting-edge concepts from synthetic biology and cancer immunotherapy. The goal is to achieve a more effective, safe, and scalable form of immunotherapy.

Massachusetts Institute Of Technology

TO DEVELOP THE MEANS TO CURE AS MANY CANCER PATIENTS AS POSSIBLE AND TO CONTROL THE DISEASE IN THOSE PATIENTS WHO ARE NOT CURED. CANCER TREATMENT RESEARCH INCLUDES THE DEVELOPMENT AND EVALUATION OF IMPROVED METHODS OF CANCER TREATMENT THROUGH THE SUPPORT AND PERFORMANCE OF BOTH FUNDAMENTAL AND APPLIED LABORATORY AND CLINICAL RESEARCH. RESEARCH IS SUPPORTED IN THE DISCOVERY, DEVELOPMENT, AND CLINICAL TESTING OF ALL MODES OF THERAPY INCLUDING: SURGERY, RADIOTHERAPY, CHEMOTHERAPY, AND BIOLOGICAL THERAPY INCLUDING MOLECULARLY TARGETED THERAPIES, BOTH INDIVIDUALLY AND IN COMBINATION. IN ADDITION, RESEARCH IS CARRIED OUT IN AREAS OF NUTRITIONAL SUPPORT, STEM CELL AND BONE MARROW TRANSPLANTATION, IMAGE GUIDED THERAPIES AND STUDIES TO REDUCE TOXICITY OF CYTOTOXIC THERAPIES, AND OTHER METHODS OF SUPPORTIVE CARE THAT MAY SUPPLEMENT AND ENHANCE PRIMARY TREATMENT. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.286 - Discovery and Applied Research for Technological Innovations to Improve Human Health

National Cancer Institute (NCI) [HHS - NIH]

National Institute of Biomedical Imaging and Bioengineering (NIBIB) [HHS - NIH]

Cambridge, Massachusetts 021394301 United States

Single Zip Code

Collaborative Approaches to Engineer Biology for Cancer Applications (U01 Clinical Trial Not Allowed) (RFA-CA-20-054)

Amendment Since initial award the total obligations have increased 1702% from $175,000 to $3,154,064.