In situ genetic engineering of tumors for long-lasting and systemic immunotherapy

PNAS – Proceedings of the National Academy of Sciences of the United States
of America
[Accessed 8 Feb 2020]

Research Article
In situ genetic engineering of tumors for long-lasting and systemic immunotherapy

Stephany Y. Tzeng, Kisha K. Patel, David R. Wilson, Randall A. Meyer, Kelly R. Rhodes, and Jordan J. Green
There is an urgent need for improved cancer immunotherapies. The nanoparticles described here deliver genes to stimulate the immune system to specifically kill tumor cells. This synthetic, biodegradable system avoids the use of common gene delivery materials like viruses that can have safety concerns and manufacturing limitations. Local nanoparticle delivery evades adverse side effects stemming from systemic administration of immune-activating therapeutics. Importantly, this technology causes a tumor-targeting response but does not require prior knowledge of a particular patient’s gene expression profile; thus, it can serve as a platform to combat many different solid cancers. Moreover, local nanoparticle administration causes a systemic cellular immune response, which has the potential to lead to better outcomes in the context of recurrence or metastasis.
Cancer immunotherapy has been the subject of extensive research, but highly effective and broadly applicable methods remain elusive. Moreover, a general approach to engender endogenous patient-specific cellular therapy, without the need for a priori knowledge of tumor antigen, ex vivo cellular manipulation, or cellular manufacture, could dramatically reduce costs and broaden accessibility. Here, we describe a biotechnology based on synthetic, biodegradable nanoparticles that can genetically reprogram cancer cells and their microenvironment in situ so that the cancer cells can act as tumor-associated antigen-presenting cells (tAPCs) by inducing coexpression of a costimulatory molecule (4-1BBL) and immunostimulatory cytokine (IL-12). In B16-F10 melanoma and MC38 colorectal carcinoma mouse models, reprogramming nanoparticles in combination with checkpoint blockade significantly reduced tumor growth over time and, in some cases, cleared the tumor, leading to long-term survivors that were then resistant to the formation of new tumors upon rechallenge at a distant site. In vitro and in vivo analyses confirmed that locally delivered tAPC-reprogramming nanoparticles led to a significant cell-mediated cytotoxic immune response with systemic effects. The systemic tumor-specific and cell-mediated immunotherapy response was achieved without requiring a priori knowledge of tumor-expressed antigens and reflects the translational potential of this nanomedicine.