Development, validation and results from the impact of treatment evolution in non-small cell lung cancer (iTEN) model.

OBJECTIVES: Treatment of advanced NSCLC (aNSCLC) is rapidly evolving, as new targeted and immuno-oncology (I-O) treatments become available. The iTEN model was developed to predict the cost and survival benefits of changing aNSCLC treatment patterns from a Canadian healthcare system perspective. This report describes iTEN model development and validation. MATERIALS & METHODS: A discrete event patient simulation of aNSCLC was developed. A modified Delphi process using Canadian clinical experts informed the development of treatment sequences that included commonly used, Health Canada approved treatments of aNSCLC. Treatment efficacy and the timing of progression and death were estimated from published Kaplan-Meier progression free and overall survival data. Costs (2018 CDN$) included were: drug acquisition and administration, imaging, monitoring, adverse events, physician visits, best supportive care, and end-of-life. RESULTS AND CONCLUSION: Clinical validity of the iTEN model was assessed by comparing model survival predictions to published real-world evidence (RWE). Four RWE studies that reported the overall survival of patients treated with a broad sampling of common aNSCLC treatment patterns were used for validation. The validation coefficient of determination was R2 = 0.95, with the model generally producing estimates that were neither optimistic nor conservative. The model estimated that current Canadian practice patterns yield a median survival of almost 13 months, a five-year survival rate of 3% and a life-time per-treated-patient cost of $110,806. Cost and survival estimates are presented and were found to vary by aNSCLC subtype. In conclusion, the iTEN model is a reliable tool for forecasting the impact on cost and survival of new treatments for aNSCLC.

Blocking the attachment of cancer cells in vivo with DNA aptamers displaying anti-adhesive properties against the carcinoembryonic antigen.

The formation of metastatic foci occurs through a series of cellular events, initiated by the attachment and aggregation of cancer cells leading to the establishment of micrometastases. We report the derivation of synthetic DNA aptamers bearing anti-adhesive properties directed at cancer cells expressing the carcinoembryonic antigen (CEA). Two DNA aptamers targeting the homotypic and heterotypic IgV-like binding domain of CEA were shown to block the cell adhesion properties of CEA, while not recognizing other IgV-like domains of CEACAM family members that share strong sequence and structural homologies. More importantly, the pre-treatment of CEA-expressing tumour cells with these aptamers prior to their intraperitoneal implantation resulted in the prevention of peritoneal tumour foci formation. Taken together, these results highlight the effectiveness of targeting the cell adhesion properties of cancer cells with aptamers in preventing tumour implantation.

A short DNA aptamer that recognizes TNFα and blocks its activity in vitro.

Tumor necrosis factor-alpha (TNFα) is a pivotal component of the cytokine network linked to inflammatory diseases. Protein-based, TNFα inhibitors have proven to be clinically valuable. Here, we report the identification of short, single-stranded DNA aptamers that bind specifically to human TNFα. One such 25-base long aptamer, termed VR11, was shown to inhibit TNFα signaling as measured using NF-κB luciferase reporter assays. This aptamer bound specifically to TNFα with a dissociation constant of 7.0 ± 2.1 nM as measured by surface plasmon resonance (SPR) and showed no binding to TNFß. Aptamer VR11 was also able to prevent TNFα-induced apoptosis as well as reduce nitric oxide (NO) production in cultured cells for up to 24 h. As well, VR11, which contains a GC rich region, did not raise an immune response when injected intraperitoneally into C57BL/6 mice when compared to a CpG oligodeoxynucleotide (ODN) control, a known TLR9 ligand. These studies suggest that VR11 may represent a simpler, synthetic scaffold than antibodies or protein domains upon which to derive nonimmunogenic oligonucleotide-based inhibitors of TNFα.

Delivering cargoes into cancer cells using DNA aptamers targeting internalized surface portals.

Many evolving treatments for cancer patients are based on the targeted delivery of therapeutic cargoes to and into cancer cells. The advent of monoclonal antibodies and the use of peptide hormones, growth factors and cytokines have historically provided a spectrum of ligands needed to selectively target tumor-associated antigens on cancer cells. However, issues linked to the size, cost and immunogenicity of protein-based ligands have led to the search for alternate ligand families. The advent of short synthetic oligonucleotide ligands known as aptamers now provides a simple strategy to select for membrane-impermeant aptamers tailored to precisely target internalized surface markers present on cancer cells. Here we described how 25-base long, synthetic single-stranded DNA aptamers were derived to bind to known internalized tumor markers such as CD33, CEA, MUC1 and Tn antigens and are imported through these surface portals into cancer cells. The key consequence of using internalized aptamers is their ability to accumulate inside the cells, thus routing their therapeutic cargoes to intracellular sites relevant to their action. Internalized aptamers are discussed in the context of how such ligands have been used to create a range of guided therapeutic agents ranging from drug-based conjugates up to targeted nanoparticles.