Contusugene ladenovec(Introgen Therapeutics, Inc.)

Head and neck squamous cell carcinoma (HNSCC) has an estimated annual global death rate of approximately 300,000. Despite advances in surgical techniques, the advent of efficient radiation delivery methods, and the introduction of newer chemotherapeutic agents, the survival rate for HNSCC has alarmingly remained unchanged for the past 50 years. However, there have been some promising developments in this field recently. Tumor protein 53 (TP53)-based gene therapeutics such as Gendicine^® and Advexin^®, and oncolytic viral therapeutics such as ONYX-015 and H101 have shown encouraging results and are gaining momentum. Cetuximab, the first US Food and Drug Administration-approved targeted therapeutic in HNSCC, although had a promising run initially, failed to garner enough attention subsequently due to its poor results in locally advanced HNSCC. Currently, its major utility is in palliation of recurrent and/or metastatic HNSCC as a part of the EXTREME regimen alongside cisplatin/carboplatin and fluorouracil. Of late, immunotherapeutics are evolving rapidly in HNSCC by demonstrating satisfactory effectiveness and acceptable tolerance both in locally advanced and recurrent tumors, and both as monotherapy and in combination with other agents. Recent accelerated approval of two immune checkpoint receptor blockers, pembrolizumab and nivolumab, has rejuvenated enthusiasm among clinicians and researchers by opening up a new domain for targeted and co-targeted therapeutics. The interim results of many ongoing trials and the latest updates of previous landmark trials such as KEYNOTE and CheckMate show promising trends in this regard. Immunotherapeutic agents belonging to different classes, such as durvalumab, epacadostat, motolimod, and T4 immunotherapy, are all being investigated presently in various therapeutic roles. Human papilloma virus (HPV)-based vaccines are now understood to have both a preventive and therapeutic role in HNSCC. Phase I/II trials are underway evaluating the safety profile, tolerable limits, and therapeutic efficacy of several therapeutic vaccines against HPV-driven HNSCC. Similarly, co-targeting therapeutics and precision medicine concepts are exploring newer and effective options including individuating the therapy based on particular tumor's molecular makeup and so on, the results of which are expected to change the landscape of HNSCC.

Hypertrophic scarring is a serious fibrotic skin disease, and the abnormal activation of hypertrophic scar fibroblasts (HSFs) intensifies its pathogenesis. Our previous studies have demonstrated that the dysregulation of autophagy in HSFs is associated with fibrosis. However, knowledge regarding the regulation of HS fibrosis by p53-modulated autophagy is limited. Here, we investigated the effect of p53-modulated autophagy on HS fibrosis. The overexpression of wtp53 (Adp53) promoted autophagic capacity and inhibited collagen and α-SMA expression in HSFs. In contrast, LC3 (AdLC3) overexpression did not suppress Col 1, Col 3, or α-SMA expression, but LC3 (shLC3) knockdown downregulated collagen expression. Adp53-modulated autophagy altered Bcl-2 and Bcl-xL expression, but AdLC3 affected only Bcl-xL expression. Silencing Bcl-xL suppressed collagen expression, but autophagy was also inhibited. Flow cytometry showed that the silencing of Bcl-2 (sibcl-2), Bcl-xL (sibcl-xL), and Adp53 significantly increased apoptosis in the HSFs. Therefore, wtp53 inhibited fibrosis in the HSFs by modulating autophagic HSF apoptosis; moreover, the inhibition of autophagy by sibcl-xL had antifibrotic effects. In addition, treatment with Adp53, AdLC3, shLC3, sibcl-2, and sibcl-xL reduced scar formation in a rabbit ear scar model. These data confirm that wtp53-modulated autophagy and autophagic HSF apoptosis can serve as potential molecular targets for HS therapy.