A Platform Technology to Genetically Reprogram Cancer Cells for Enhanced Immunotherapy

Johns Hopkins University, Baltimore MD

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Abstract

PROJECT SUMMARY Advances in cancer immunotherapy have great potential for treating tumors that are refractory to conventional treatments, and T cells primed ex vivo by natural or artificial antigen-presenting cells (APCs) to target and kill cancer cells have been shown clinically to improve survival in patients with highly aggressive cancers. APCs normally prime T cells by presenting a tumor antigen-specific signal 1, consisting of a major histocompatibility complex (MHC) I molecule with a tumor antigen peptide; a co-stimulatory signal 2 that directs the action of the T cells upon recognition of the tumor; and a secreted signal 3 for recruitment and activation of immune cells. Instead of engineering the patient's APCs to direct a T-cell response against a tumor or fabricating artificial, synthetic APCs, both of which are costly, complex, and/or patient-specific processes, we propose to reprogram cancer cells themselves to become tumor-associated APCs (tAPCs). Because tumor cells already intrinsically express signal 1 (tumor antigen in the context of MHC I), they can be engineered in situ to express the other necessary signals and therefore act as APCs, directing cytotoxic T-cell responses against themselves. Tumor cells with low MHC I expression will stimulate natural killer (NK) cells to aid this purpose. We have designed synthetic, non-viral nanoparticles that can deliver DNA to cancer cells with high efficacy and specificity over healthy tissue, and we will inject these into a tumor mass to induce expression of signal 2 and signal 3, using two different in vivo orthotopic tumor models (melanoma and triple-negative breast cancer) and four in vitro tumor models as examples. Having optimized a nanoparticle formulation with anti-cancer efficacy after intratumoral injection in local and metastatic cancer models, we will further this strategy during the R37 extension period by co-delivering a gene cassette to locally express checkpoint inhibitor antibodies, following our discovery in the first phase of the R37 that our nanoparticles (1) synergize with systemic checkpoint inhibition and (2) prevent immunotoxicity of systemic immunotherapies by sequestering gene expression primarily to the local tumor. We will further discover new genetic pathways leading to susceptibility and resistance to this immunotherapy strategy via comparative transcriptomics across different tumor types, allowing us to apply the new knowledge to the development of even more successful immunomodulatory gene therapies. This extension remains within the initial scope of the project, which focused on local therapy and immunological analysis thereof, but broadens its goals by further innovating on the platform technology developed in the first phase. If successful, this could result in an affordable, fully synthetic, local, antigen-agnostic therapy that nevertheless leads to antigen-specific systemic immune rejection of a wide range of different tumor types.