scholarly journals Local radiotherapy and E7 RNA-LPX vaccination show enhanced therapeutic efficacy in preclinical models of HPV16+ cancer

2021 ◽  
Author(s):  
Nadja Salomon ◽  
Abderaouf Selmi ◽  
Christian Grunwitz ◽  
Anthony Kong ◽  
Eliana Stanganello ◽  
...  
Keyword(s):  
Radiation Dose ◽  
Therapeutic Efficacy ◽  
Neck Region ◽  
Standard Of Care ◽  
Hpv Infection ◽  
Dose Fractionation ◽  
Therapeutic Effects ◽  
Two Phase ◽  
Hpv16 E6 ◽  
Hpv E6

AbstractHuman papilloma virus (HPV) infection is a causative agent for several cancers types (genital, anal and head and neck region). The HPV E6 and E7 proteins are oncogenic drivers and thus are ideal candidates for therapeutic vaccination. We recently reported that a novel ribonucleic acid lipoplex (RNA-LPX)-based HPV16 vaccine, E7 RNA-LPX, mediates regression of mouse HPV16+ tumors and establishes protective T cell memory. An HPV16 E6/E7 RNA-LPX vaccine is currently being investigated in two phase I and II clinical trials in various HPV-driven cancer types; however, it remains a high unmet medical need for treatments for patients with radiosensitive HPV16+ tumors. Therefore, we set out to investigate the therapeutic efficacy of E7 RNA-LPX vaccine combined with standard-of-care local radiotherapy (LRT). We demonstrate that E7 RNA-LPX synergizes with LRT in HPV16+ mouse tumors, with potent therapeutic effects exceeding those of either monotherapy. Mode of action studies revealed that the E7 RNA-LPX vaccine induced high numbers of intratumoral-E7-specific CD8+T cells, rendering cold tumors immunologically hot, whereas LRT primarily acted as a cytotoxic therapy, reducing tumor mass and intratumor hypoxia by predisposing tumor cells to antigen-specific T cell-mediated killing. Overall, LRT enhanced the effector function of E7 RNA-LPX-primed T cell responses. The therapeutic synergy was dependent on total radiation dose, rather than radiation dose-fractionation. Together, these results show that LRT synergizes with E7 RNA-LPX and enhances its anti-tumor activity against HPV16+ cancer models. This work paves into a new translational therapy for HPV16+ cancer patients.

scholarly journals Identification of High-Risk Human Papillomavirus DNA, p16 and E6/E7 Oncoproteins in Laryngeal and Hypopharyngeal Squamous Cell Carcinomas

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1008
Author(s):  
Andrejs Lifsics ◽  
Valerija Groma ◽  
Maksims Cistjakovs ◽  
Sandra Skuja ◽  
Renars Deksnis ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
High Risk ◽  
Squamous Cell ◽  
Surrogate Marker ◽  
Hpv Infection ◽  
Hpv16 E6 ◽  
Hpv Dna ◽  
Molecular Virology ◽  
Hpv E6 ◽  
E6 And E7

Human papillomavirus (HPV) was proven to play a significant role in cancer development in the oropharynx. However, its role in the development of laryngeal (LSCC) and hypopharyngeal squamous cell carcinoma (HPSCC) remains to be clarified. High-risk HPV (HR-HPV) viral proteins E6 and E7 are considered to be pertinent to HPV-related carcinogenesis. Hence, our aim was to estimate LSCC and HPSCC for HR-HPV DNA, p16, and E6/E7 oncoprotein status by using molecular virology and immunohistochemistry methods. The prevalence of HPV16 infection was 22/41 (53.7%) and 20/31 (64.5%) for LSCC and HPSCC, accordingly. The majority of HPV16+ tumor samples were stage III or IV. In most samples, the presence of either HPV16 E6 or HPV16 E7 viral protein in dysplastic or tumor cells was confirmed using immunohistochemistry. Our results suggest a high prevalence of HPV16 as a primary HR-HPV type in LSCC and HPSCC. The lack of HPV E6/E7 oncoproteins in some tumor samples may suggest either the absence of viral integration or the presence of other mechanisms of tumorigenesis. The utilization of p16 IHC as a surrogate marker of HR-HPV infection is impractical in LSCC and HPSCC.

Bezlotoxumab: Could This be the Answer for Clostridium difficile Recurrence?

2017 ◽  
Vol 51 (9) ◽  
pp. 804-810 ◽  
Author(s):  
Ryan W. Chapin ◽  
Tiffany Lee ◽  
Christopher McCoy ◽  
Carolyn D. Alonso ◽  
Monica V. Mahoney
Keyword(s):  
Monoclonal Antibody ◽  
Clostridium Difficile ◽  
English Language ◽  
Adverse Drug Events ◽  
Data Extraction ◽  
Standard Of Care ◽  
Phase Iii ◽  
Relative Reduction ◽  
Two Phase ◽  
Mesh Terms

Objective: To review the pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of bezlotoxumab (BEZ), a novel monoclonal antibody against Clostridium difficile toxin B. Data Sources: A PubMed search was conducted for data between 1946 and April 2017 using MeSH terms bezlotoxumab, MK-6072, or MDX-1388 alone and the terms Clostridium difficile combined with monoclonal antibody or antitoxin. Study Selection and Data Extraction: The literature search was limited to English-language studies that described clinical efficacy, safety, and pharmacokinetics in humans and animals. Abstracts featuring prepublished data were also evaluated for inclusion. Data Synthesis: BEZ is indicated for adult patients receiving standard-of-care (SoC) antibiotics for C difficile infection (CDI) to prevent future recurrence. Two phase III trials—MODIFY I (n = 1452) and MODIFY II (n = 1203)—demonstrated a 40% relative reduction in recurrent CDI (rCDI) with BEZ compared with placebo (16.5% vs 26.6%, P < 0.0001). The most common adverse drug events associated with BEZ were mild to moderate infusion-related reactions (10.3%). Conclusions: In patients treated with SoC antibiotics, BEZ is effective in decreasing rCDI. BEZ has no apparent effect on treatment of an initial CDI episode. In light of increasing rates of CDI, BEZ is a promising option for preventing recurrent episodes. The greatest benefit has been demonstrated in high-risk patients, though the targeted patient population is yet to be defined.

HPV Infection of the Head and Neck Region and Its Stem Cells

2015 ◽  
Vol 94 (11) ◽  
pp. 1532-1543 ◽  
Author(s):  
A.N. Pullos ◽  
R.M. Castilho ◽  
C.H. Squarize
Keyword(s):  
Stem Cells ◽  
Head And Neck ◽  
Neck Region ◽  
Hpv Infection ◽  
Head And Neck Region

P–802 The fate and regenerative efficiency of differently administered BMSCs in thin-endometrium rat models

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Q Guo ◽  
Y Chang
Keyword(s):  
Therapeutic Efficacy ◽  
Bioluminescence Imaging ◽  
Basal Layer ◽  
Post Treatment ◽  
Clinical Settings ◽  
Positive Staining ◽  
Therapeutic Effects ◽  
Thin Endometrium ◽  
Therapeutic Efficiency ◽  
Sd Rats

Abstract Study question This study aims to compare the engraftment, retaining time and therapeutic efficiency of differently administered BMSCs and help to select an optimal therapeutic route in clinical settings. Summary answer Compared with intrauterine infusion, BMSCs could better promote angiogenesis by upregulating related cytokines, such as VEGF, when administered through the ipsilateral iliac artery. What is known already MSC-based therapy has become a promising method for endometrial disease(thin endomtrium or Ashernmen’s syndrowe). Therapeutic effects could always be observed even though different MSC administration routes or MSCs of different tissue sources were used in these studies. Only a few studies compared efficacy of different transplantation routes. However, the results seem to be controversial. Comparable therapeutic effects were reported in some studies, while others stated that systematic administration gave a better outcome than local administration. Study design, size, duration Experimental animal study. Forty-eight female Sprague-Dawley (SD) rats were used in this study. They were randomly assigned to 4 groups: normal, injured, intra-arterial and intra-uterine group. For all rats except for normal group, the thin endometrium models were established by infusing 95% ethanol into the uterine horns and BMSCs were transplanted either locally or intra-arterially after modeling. The therapeutic efficacy were evaluated in the following month. Participants/materials, setting, methods The thin endometrium models induced by ethanol in SD rats, GFP/Luciferin labeled BMSCs were injected either locally or intra-arterially. The retaining time and quantitative distribution were assessed by in vivo bioluminescence imaging and immune-histological analysis. The precise location and differentiation of differently administered BMSCs were determined by immunofluorescence methods. The endometrial fibrosis, angiogenesis were detected by immunohistochemistry and western blotting at a consecutive time after treatment to compare the therapeutic efficiency of two administration methods. Main results and the role of chance The engraftment and differentiation abiility were comparable in 2 groups. The luminescent signal both remained distinct and strong in the abdomen in the first 4 days post-treatment(7.98 × 105 and 6.02 × 105p/s for IU and IA group), indicating the precise and concentrated distribution of BMSCs administered both locally or intra-arterially. The luminescent signals disappeared under bioluminescence imaging over time. We further evaluated the precise distribution, differentiation ability and retaining time of the BMSCs delivered in two strategies by immunofluorescence analysis. All the GFP positive cell localized in stroma, but not in the epithelium or myometrium. Furthermore, there are significantly more positive staining in basal layer of the endometrium close to the glands and vessels than the outer layer of the endometrium in the intra-arterial group. At the 28th days post treatment, we could capture a few GFP staining in the basalis layel of endometrium in intra-arterial group and there were no GFP fluorescence signals detected in intra-uterine group(P &lt; 0.05), suggesting a better survival of BMSCs administered intra-arterially. Differentiation ability of differently administered BMSCs were similar. A few BMSCs began to differentiate into stromal cell 12 days after therapy. Limitations, reasons for caution No pregnancy tests were carried out in these rats to further confirm the regeneration of thin endometrium and compare the therapeutic efficacy. Wider implications of the findings: Our study unveiled that the location of MSCs might determined their regenerarive ability and retaining time, and provided an optimal therapeutic route in clinical settings. Trial registration number Not applicable

scholarly journals Improvement of Outcomes in Patients with Lupus Nephritis: Management Evolution in Chinese Patients from 1994 to 2010

2019 ◽  
Vol 46 (8) ◽  
pp. 912-919 ◽  
Author(s):  
Si-Jia Shao ◽  
Jin-Hua Hou ◽  
Guo-Tong Xie ◽  
Wen Sun ◽  
Dan-Dan Liang ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Activity Index ◽  
Survival Rates ◽  
Standard Of Care ◽  
Chinese Patients ◽  
Renal Outcome ◽  
Therapeutic Effects ◽  
Endstage Renal Disease ◽  
Renal Relapse ◽  
Chronicity Index

Objective.To assess how the longterm outcomes have changed over the past decades in Chinese patients with lupus nephritis (LN). The trends in patient manifestation at presentation, treatment pattern, and therapeutic effects were evaluated.Methods.A cohort of biopsy-proven patients with LN (n = 1945) from January 1994 to December 2010 was analyzed. Treatment regimens, treatment response, renal relapse, and renal outcome were compared at different time periods (1994–1998, 1999–2004, and 2005–2010).Results.Patients in the later periods had shorter duration of disease, lower serum creatinine value and chronicity at biopsy, and more frequent followup. They were more likely to receive standard-of-care therapies, which included cyclophosphamide, mycophenolate mofetil, and combination therapy. Patients in the later periods had higher probabilities of achieving remission (p < 0.001) and lower probabilities of experiencing renal flare (p = 0.007). The 5-year renal survival rates were 92.6%, 90.6%, and 94.3% in 1994–1998, 1999–2004, and 2005–2010, respectively. The 5-year risk of endstage renal disease (ESRD) did not differ between 1994–1998 and 1999–2004, but was significantly lower in 2005–2010 (HR 0.40, 95% CI 0.19–0.85 vs 1999–2004). In multivariable Cox analysis, standard therapy was independently associated with lower risk of ESRD (adjusted HR 0.72, 95% CI 0.52–0.98, p = 0.04). Variables of renal damage at biopsy (renal function, activity index, and chronicity index) were independently associated with poor outcome.Conclusion.The outcomes of Chinese patients with LN have improved from 1994 to 2010. With the increased use of standard therapies, the remission rates have increased and renal relapse has decreased.

Targeting the PI3K Pathway in Head and Neck Squamous Cell Carcinoma

2015 ◽  
pp. 123-128 ◽  
Author(s):  
Pedro Henrique Isaacsson Velho ◽  
Gilberto Castro ◽  
Christine H. Chung
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Anticancer Agents ◽  
Neck Region ◽  
Hpv Infection ◽  
Pi3k Pathway ◽  
Neck Squamous Cell Carcinoma ◽  
Preclinical Data

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease arising from the mucosal epithelia in the head and neck region. The most common risk factors are tobacco use, alcohol consumption, and HPV infection, particularly in the oropharynx. The HPV-positive HNSCC is biologically and clinically distinct from the HPV-negative HNSCC; however, deregulations within the phosphatidylinositol 3-kinase (PI3K) pathway are frequent in both HPV-positive and HPV-negative HNSCC as it is the most frequently altered oncogenic pathway with a gain-of-function in HNSCC. This article reviews the basic biology and clinical data from the trials involving anticancer agents targeting the PI3K pathway in HNSCC. It also discusses the difficulties of translating the preclinical data to tangible clinical efficacy of these agents in patients with HNSCC even when there is significant preclinical data suggesting the PI3K pathway is a promising therapeutic target in HNSCC. We conclude that additional studies to determine appropriate patient selection for the activation of PI3K pathway and to develop targeted agents either as a monotherapy or combination therapy with favorable toxicity profiles are required before a broader clinical application.

20. Utility of human papillomavirus (HPV) 16 E6 and L1 DNA levels for anal cancer screening in HIV-infected individuals

Sexual Health ◽  
2013 ◽  
Vol 10 (6) ◽  
pp. 580 ◽  
Author(s):  
Doreen Lee ◽  
Mark H. Einstein ◽  
Rebecca A. Levine ◽  
Mark J. Suhrland ◽  
Samer Khader ◽  
...  
Keyword(s):  
Cancer Screening ◽  
Anal Cancer ◽  
Pap Smear ◽  
Standard Of Care ◽  
Molecular Testing ◽  
Hpv Testing ◽  
Hpv16 E6 ◽  
Screening Programs ◽  
Anal Cancer Screening ◽  
Better Than

Background In this prospective study we evaluate the sampling performance of HPV16 DNA E6 and L1 levels in detecting anal intraepithelial neoplasm using either a moistened Dacron swab (DS) or cytobrush (CB). Methods: We recruited HIV-infected (n = 57) and organ-transplanted subjects (n = 3) with an abnormal anal Pap smear who presented for high-resolution anoscopy (HRA). Prior to HRA, the first 30 subjects underwent sampling with a moistened DS, and the next 30 with a CB. HRA was then performed in the usual fashion. Samples were tested for HPV16 DNA E6 and L1 DNA using a validated qPCR technique. Anal biopsies were taken as per standard-of-care and categorised as negative, AIN 1/warts, or AIN 2 or 3. Results: 59 of 60 samples had adequate DNA and were evaluated for the comparison of HPV16 E6 and L1 DNA levels. A CB performed better than the DS in detecting low positive and positive levels of HPV16 E6 DNA (P = 0.01). We then further evaluated the correlation of HRA-directed biopsies and HPV16 DNA E6 levels. There was a positive correlation of HRA-directed biopsy results stratified by increasing histological levels with HPV16 E6 DNA (P = 0.018, Kruskal–Wallis test). Conclusions: A CB performed better than DS for molecular HPV testing. If molecular testing is included in anal cancer screening, consideration should be made for co-sampling with both a DS for cytology and CB for HPV testing. Further studies evaluating the sample yields should be performed to assist in implementation of anal cancer screening programs in defined populations of at-risk individuals.

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