Tinagl1 Gene Therapy Suppresses Growth and Remodels the Microenvironment of Triple Negative Breast Cancer.

Triple negative breast cancer (TNBC) remains one of the most challenging subtypes of breast cancer to treat and is responsible for approximately 12% of breast cancer cases in the US per year. In 2019, the protein Tinagl1 was identified as a key factor for improved prognoses in certain TNBC patients. While the intracellular mechanism of action has been thoroughly studied, little is known about the role of Tinagl1 in the tumor microenvironment. In this study, we developed a lipid nanoparticle-based gene therapy to directly target the expression of Tinagl1 in tumor cells for localized expression. Additionally, we sought to characterize the changes to the tumor microenvironment induced by Tinagl1 treatment, with the goal of informing future choices for combination therapies including Tinagl1. We found that Tinagl1 gene therapy was able to slow tumor growth from the first dose and that the effects held steady for nearly a week following the final dose. No toxicity was found with this treatment. Additionally, the use of Tinagl1 increases the tumor vasculature by 3-fold but does not increase the tumor permeability or risk of metastasis. However, the increase in vasculature arising from Tinagl1 therapy reduced the expression of Hif1a significantly (p < 0.01), which may decrease the risk of drug resistance.

Nanomaterials for cancer immunotherapy.

Cancer immunotherapy is quickly growing to be the fourth most important cancer therapy, after surgery, radiation therapy, and chemotherapy. Immunotherapy is the most promising cancer management strategy because it orchestrates the body's own immune system to target and eradicate cancer cells, which may result in durable antitumor responses and reduce metastasis and recurrence more than traditional treatments. Nanomaterials hold great promise in further improving the efficiency of cancer immunotherapy - in many cases, they are even necessary for effective delivery. In this review, we briefly summarize the basic principles of cancer immunotherapy and explain why and where to apply nanomaterials in cancer immunotherapy, with special emphasis on cancer vaccines and tumor microenvironment modulation.

Local and transient gene expression primes the liver to resist cancer metastasis.

The liver is the primary site of metastasis for gastrointestinal cancers and is a location highly susceptible to the establishment of metastasis in numerous other primary cancers, including breast, lung, and pancreatic cancers. The current standard of care typically consists of primary tumor resection and systemic administration of potent but toxic chemotherapeutics, yielding a minimal improvement in the median survival rate. CXCL12, a chemokine, is a key factor for activating the migration/survival pathways of CXCR4+ cancer cells and for recruiting immunosuppressive cells to areas of inflammation. Therefore, reducing CXCL12 concentrations within the liver has the potential to decrease tumor and immunosuppressive cell activation/migration within the liver. However, because of off-target toxicities associated with systemic administration of anti-CXCL12 therapies, transient and liver-specific expression of a CXCL12 trap is necessary. To address this challenge, we developed a lipid calcium phosphate nanoparticle optimized for delivering plasmid DNA, encoding an engineered CXCL12 protein trap, to the nucleus of liver hepatocytes. This pCXCL12-trap formulation yielded transient (4 days) liver-specific expression, which greatly decreased the occurrence of liver metastasis in two aggressive liver metastasis models, including colorectal [CT-26(FL3)] and breast (4T1) cancers. Subsequent studies in an aggressive human colorectal liver metastasis model (HT-29) decreased the establishment of liver metastasis more effectively than did systemic administration of the CXCL12 protein trap and to a level comparable to a high-dose regimen of a potent CXCR4 antagonist (AMD3100).