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

Abstract

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.

Gene delivery for immunoengineering

“…Poly (beta-amino ester)s (PBAEs) are cationic, hydrolytically degradable polymers that have been used to deliver CpG ODNs, agonists of Toll-like receptor 9 (TLR-9), which upregulates production of proinflammatory cytokines [25], or CDN as a STING agonist [26] by local intratumoral delivery in mouse melanoma models. Another PBAE was also used to deliver pDNA encoding Complexation of virus with catonic polymer like PEI immune-stimulatory genes locally to tumors, resulting in slowed tumor progression and long-term survival in B16-F10 and MC38 models [27 ]. Smith et al further modified PBAE/pDNA nanoparticles by coating them with a targeting ligand, allowtransfection of T cells after intravenous injection.…”

Immunoengineering has arrived

“…For example, mRNA encoding tumor antigen can be intracellularly delivered in nanoparticles to dendritic cells that can induce cytotoxic T cells to kill triple‐negative breast cancer in a mouse model, and act in combination with CTLA‐4 immune checkpoint inhibition (Liu et al, 2018). In an alternative approach, the tumor microenvironment can also be reprogrammed in situ utilizing biodegradable nanoimmunomaterials to generate an antigen‐specific systemic cellular immune response without needing a priori knowledge of the cancer‐specific antigens (Tzeng et al, 2020). Cancer vaccines can also be designed based on stimulation of the innate arm of the immune system and immunoengineered nanoparticles can be utilized to dramatically boost potency.…”

Insights into Nanomedicine for Immunotherapeutics in Squamous Cell Carcinoma of the head and neck

“…These effects have been seen in 2 days after vaccination and the reductions of tumors were correlated with survival in murine B16F10-OVA tumor models. Recently, a combinatorial design of biodegradable polymeric DNA nanoparticles for local delivery in solid tumors has been developed [71]. This platform utilizes nonviral cargo poly (beta-amino ester)s (PBAE)-based nanoparticles to deliver DNA to tumor cells expressing MHC-I and ultimately, induces expression of the co-stimulatory molecule 4-1BBL and IL-12 secretion which leads to activation of cell-mediated cytotoxic immune responses.…”

“…These genetically reprogrammed tumor cells are therefore termed tumor-associated antigen-presenting cells. This approach can avoid the intrinsic immunogenicity or toxicity as commonly seen in vectors like viruses or lipid nanoparticles [71]. Additionally, various nanoparticles have been utilized for developing therapeutic T cells for adoptive therapies.…”