Next Article in Journal
Challenges of Diagnosing Antibody-Mediated Rejection: The Role of Invasive and Non-Invasive Biomarkers
Previous Article in Journal
Intraocular Pressure Reduction after Femtolaser Assisted Cataract Surgery and Its Association with the Use of Ultrasound
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Medicina
Volume 57
Issue 5
10.3390/medicina57050438
medicina-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Recombinant Human Adenovirus-p53 Therapy for the Treatment of Oral Leukoplakia and Oral Squamous Cell Carcinoma: A Systematic Review

by
Jagadish Hosmani
1,
Shazia Mushtaq
2,
Shahabe Saquib Abullais
3,
Hussain Mohammed Almubarak
1,
Khalil Assiri
1,
Luca Testarelli
4,
Alessandro Mazzoni
4 and
Shankargouda Patil
5,*
1
Department of Diagnostic Dental Sciences, College of Dentistry, King Khalid University, Abha 62529, Saudi Arabia
2
Dental Health Department, College of Applied Medical Sciences, King Saud University, Riyadh 11451, Saudi Arabia
3
Periodontics and Community Dental Sciences, College of Dentistry, King Khalid University, Abha 62529, Saudi Arabia
4
Department of Oral and Maxillo Facial Sciences, Sapienza University of Rome, 00185 Rome, Italy
5
Department of Maxillofacial Surgery and Diagnostic Sciences, Division of oral Pathology, College of Dentistry, Jazan University, Jazan 45142, Saudi Arabia
*
Author to whom correspondence should be addressed.
Medicina 2021, 57(5), 438; https://doi.org/10.3390/medicina57050438
Submission received: 13 March 2021 / Revised: 19 April 2021 / Accepted: 21 April 2021 / Published: 1 May 2021
(This article belongs to the Section Dentistry and Oral Health)
Browse Figures
Versions Notes

Abstract

:
Background and Objectives: Oral cancer is the 6th most common cancer in the world and oral leukoplakia is an oral potentially malignant disorder that could develop into oral cancer. This systematic review focusses on randomized clinical trials for recombinant adenovirus p-53 (rAD-p53) therapy for the treatment of oral leukoplakia and cancer. Materials and Methods: We searched for research articles on various databases such as Pubmed/Medline, Embase, CNKI (China National Knowledge Infra-structure), Springerlink, cochrane and Web of sciences from 2003 to 2020. MeSH (Medical Subject Headings) terms were used for the search. Inclusion criteria included original research, randomized clinical trials and articles only in English language. Exclusion criteria were any articles that were not research articles, not randomized trials, non-human studies, etc. The articles were further graded on the Jadad scale. Results: 578 articles were assessed from various databases; only 3 articles were found to be appropriate for this review. Thus, meta-analysis was not performed because of heterogeneity and lack of data. In the three studies, whether rAD-p53 was used as a standalone therapy or with other therapies, there was a beneficial effect of the therapy. Furthermore, there were no serious adverse events and the only adverse events reported were fever, pain at the local injection site, flu-like symptoms and lowered WBC count. Conclusions: Thus, we can conclude that this therapy has a potential for beneficial therapeutic effects and further clinical trials with more patients need to be performed to get better understanding of the effect of rAD-p53 therapy, which probably will pave the way to its approval in other parts of the world.

1. Introduction

Oral cancer is one the most prevalent cancers around the world (6th) and shows a much higher occurrence in Asia [1]. Oral leukoplakia (OLP), a white plaque formed on the oral mucosa, is considered an oral potentially malignant disorder (OPMD) [2,3,4]. The presence and grade of dysplasia are predictors of the risk of transformation of OLP to oral squamous cell carcinoma (OSCC) [4]. The number of cases where malignant transformation occurs varies in different parts of the world and is also dependent on tobacco consumption, some viral infections, and other exogenous factors [5].Anywhere between 1.5% to 34% of OLP transforms to OSCC, which is one the significant subset of head and neck squamous cell carcinomas (HNSCC) and accounts for almost 90% of all the oral cancers [6]. The primary aim of treatment for OLP is to prevent the progression to OSCC. The treatment for OSCC aims to eliminate cancer and avoid recurrence. If in later stages, I ensure the best quality of life possible without affecting the function of the organs [7]. The treatment that a patient receives for OLP depends on the spread of the lesion, type of OLP (classified after biopsy), and patient health [6]. The standard treatment includes surgery and topical/systemic medicines such as beta carotene, lycopene, vitamin A, bleomycin, etc. [8]. For OSCC, the treatment depends on the stage, primary site, location, proximity to lymph nodes and patient health [9]. The first line of treatment for early stage cancer has been surgery and sometimes, neck resections to prevent metastasis [9].
In the last 20 years or so, gene therapy has emerged as a treatment option for various diseases, including sarcomas and carcinomas [10]. Gene therapy involves manipulation of target DNA/RNA for the treatment of diseases, and various methods have been used, for example, viral-based delivery systems, cultured patient cells, etc. [10]. With the recent advances in the clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR associated protein 9 (Cas9) tehnology, gene therapy is once more at the forefront of efforts to fight diseases [11].
Mutations in P53, a tumor suppressor gene, is a hallmark of human cancers and they have been observed in most cases of OLP and OSCC as well [12]. The inactivation of p53 not only plays an important role in early tumor development, but also in proliferation of the tumor [13]. The mutant p53 may function through various molecular mechanisms- it can bind to the DNA to alter gene expression. It can bind to transcription factors to improve or impede their functions or interact with proteins to change their function [14]. The restoration of p53 function using the wild type p53 with adenovirus as a delivery system, resulted in complete tumor regression in murine models and cell lines [15,16]. There have been clinical trials of potential Adenovirus-based therapy since 1990s [17,18]. Gendicine became the first gene therapy to be approved anywhere in the world in 2003, when China’s State Food and Drug Administration, approved the therapy developed by Shenzhen SiBiono GenTech. The recombinant Adenovirus p53 gene (rAD-p53) therapy was approved for HNSCC [19]. Since then, 22 gene therapies have been approved till the end of 2019 [20]. Although there have been research on the efficacy of rAD-p53 therapy for the treatment of HNSCC [21,22,23], the emphasis of this systematic review is on assessing the clinical benefits of using rAD-p53 gene therapy for oral leukoplakia and OSCC as a stand-alone or in combination with other treatments. We examine the effectiveness of the drugs and speculate on their potential for OLP and OSCC.

2. Materials and Methods

The systematic review was registered with The International Prospective register for Systematic Reviews (PROSPERO) with ID number: CRD42020192065. The PICO framework was adhered to for this review: P- Population (Patients with oral leukoplakia or OSCC); I- Intervention (Adenovirus p53 therapy + chemotherapy); C- Comparison between adenovirus p53 therapy vs. traditional treatments; O- Outcomes (response rate, disease control rate, symptom improvement and adverse effects).

2.1. Search Method

A literature search was performed using Pubmed, Medline, Embase, SpringerLink, Ovid, Cochrane Library, Web of Science and CNKI (China National Knowledge Infrastructure). The MeSH terms used for the search were: “recombinant human adenovirus p53 injection”, “rAD-p53”, “ADp53 gene therapy”, “Gendicine”, “oral pre-malignant lesions”, “oral potentially malignant disorders”, and “oral leukoplakia”, “oral squamous cell carcinoma”, and/or “oral cancer”.

2.2. Inclusion and Exclusion Criteria

Inclusion criteria: (1) patients included in selected studies must have been diagnosed with OLP & OSCC clinically and histology; (2) study design must be clinical randomized controlled trial (RCT); (3) studies must have reported the outcome measures, which include response, (RR), disease control rate (DCR), symptom improvement (SI) and adverse effects (AEs); (4) Only English language studies. Exclusion criteria: (1) non-original articles, such as abstract, meeting record, editorial, review, book chapters and correspondence; (2) non-human studies; (3) in-vitro studies. The PRISMA flowchart is given in Figure 1.

2.3. Jadad Scoring

Jadad scoring system [24] was used to assess the methodological quality of the randomized clinical trials. The scoring questionnaire is presented in Figure 2.

Literature Search Summary

The search on various databases like pubmed/medline, CNKI, cochrane, embase with the MeSH terms resulted in a total of 578 articles. After all the inclusion and exclusion criteria were met, our list was reduced to 4 research articles. It was further reduced to 3 because one of the articles [25] was a report of the same subset of patients summarized in another article [26] (Table 1). We further used the JADAD scoring system to evaluate the methodological quality of the RCTs. The results are summarized in Table 2.

2.4. Outcome Measures

In the RCTs, the patients were followed up for 24–86 months after the treatment with rAD-53 and outcome measures such as response rate (RR), recurrence rate, symptom improvement (SI) were recorded. Any adverse events (AEs) associated with the treatment were also recorded, for example, fever, pain at injection site or any serious AEs (SAEs).

3. Results

3.1. Literature Search Summary

The search on various databases like pubmed/medline, CNKI, cochrane, embase with the MeSH terms resulted in a total of 578 articles. After all the inclusion and exclusion criteria were met, our list was reduced to 4 research articles. It was further reduced to 3 because one of the articles [25] was a report of the same subset of patients summarized in another article [26] (Table 1). We further used the JADAD scoring system to evaluate the methodological quality of the RCTs. The results are summarized in Table 2.

3.2. Synthesis of Evidence: Treatment, Follow-Up and the Outcome

The treatment and outcome measures for the 3 RCTs are summarized in Table 3. Li et al., 2009 [26] used rAD-p53 therapy alone as a treatment option for 22 patients who had varying degrees of OLP in this phase I study. Gendicine was injected locally into the lesions. Out of the 22, 18 showed mucous membrane necrosis in the regions with lesions after treatment. 22.7% showed complete regression and showed no recurrence even after 24 months of treatment. 11/22 showed reduction in the size of the lesion area; 4 did not have any effect and 2 went on to develop cancer and had resection surgery. AEs reported were fever, pain in the injection area, flu-like symptoms after first injection and an increase in WBC count after therapy. Furthermore, immunohistochemical staining of biopsied tissues before and after treatment, saw differential and increased staining for p53 (however p > 0.05) and p21CIP/WAF (p < 0.01). The results are summarized in Table 3 rAD-p53 clearly showed positive beneficial effects in the treatment of OLP.
Liu et al., 2013 [27] recruited a total of 107 patients with oral cancer (51 patients with tongue cancer and 56 with gingival cancer) primarily of stages II and III, and randomized them to either the experiment group (EG, 57 patients) or the control group (CG, 50 patients). The experimental group was injected with rAD-p53 on the wound surface, after being treated with surgical resection and radiotherapy. The CG group only received the radiotherapy doses similar to EG group after the surgery, but no rAD-p53 injection. The patients were all followed up for 36 months. In the EG group recurrence rate was 4/57, whereas in the CG group was 16/50, and this was statistically significant. The time of disease-free survival (DFS) was significantly higher for the EG group. The overall survival (OS) rate was 100% for EG group and 94% for CG group. There were no SAEs and the only AEs reported were fever and flu-like systems (Table 3). This Phase II clinical trial showed positive effects of rAD-p53 therapy when combined with radiotherapy.
Li et al., 2014 [28] performed a phase III RCT (double-blinded and placebo-controlled) with 99 patients of oral carcinoma and used rAD-p53 gene therapy in conjunction witFh chemotherapy. None of the patient had undergone any cancer treatment. The patients were diagnosed with either stage III or stage IV oral carcinoma and were randomly divided into three treatment groups: 35 patients in group I received intra-arterial infusion of rAD-p53 and chemotherapy, 33 in group II received intra-arterial infusion of rAD-p53 and placebo chemotherapy and 31 in group III received intra-arterial infusion of placebo rAD-p53 and chemotherapy. There was a large variation in the follow up length from 3 months to 86 months because of advanced stages of carcinoma. Fifty-eight patients (16 in group I, 20 in Group II and 22 in group III) died during the follow up period. The primary lesions in 58 out of 92 patients showed response to therapy. The complete response plus the partial response rates were highest for group I (82%). Group II and Group III response rates were 53% and 54%, respectively. Group I showed the highest response rate for patients with stage IV carcinoma (Table 3). The rate of non-responders was also the lowest among the stage IV patients in group I. Patients with stage III carcinoma had higher survival rate in group I as compared to group III. Most common adverse events were flu-like symptoms and bone marrow suppression. However, gene therapy alone did not induce bone marrow suppression (group II), thus, it might have been a side-effect of chemotherapy. Immunohistochemistry was performed on the biopsy samples before and after treatment for p53, bcl-2 (a protein downregulated by p-53) and Bax (a protein upregulated by p-53). The levels of these three proteins were same among the three groups. However, after treatment, the levels of p53 expression was higher in group I. Higher Bax levels were observed in 85% of group I patients and 90% of group II patients, whereas in group III (no rAD-p53 treatment), only 1 patient showed higher levels. Conversely, bcl-2 expression was lower in 90% of patients in group I and 80% in group II. All the results and p-values are summarized in Table 3.
Thus, treatment with rAD-p53 and chemotherapy together had better clinical outcomes as compared to either of them alone.

4. Discussion

4.1. Oral Cancer, Oral Leukoplakia and rAD-p53 Therapy: Summary of the Studies

Gene therapy for the treatment of various diseases, especially rare genetic disorders and solid carcinomas, is slowly gaining grounds as advances in genetic technology, such as, next-generation sequencing, better delivery vector designs, new gene editing technology such as CRISPR-CAS9, use of immune responses, make it safer and reliable [11,29,30,31]. Gendicine (commercial name for the rAD-p53 therapy) became the first gene therapy across the world when it was approved by Chinese Food and Drug Administration [19]. rAD-p53 gene therapy is either given as intra-arterial infusion or local wound injection and consists of introduction of an unmutated copy of p53, a known tumor suppressor gene, which induces apoptosis, necrosis and autophagy under cellular stress, thus leading to the death of tumor/cancer cells [13]. Since its approval, rAD-p53 has been used as a therapy for other carcinomas such as nasopharyngeal cancer, non-small cell lung cancer, prostate cancer as well [18,22,32].
Oral cancer, a subtype of HNSCC, is one the most common cancers in the world and has been shown to be linked to lifestyle factors such as tobacco use, alcohol consumption and betelnut use [33]. The incidence of oral cancer across the world is highly dependent on these lifestyle factors. OSCC is the most common type of oral cancer and can affect the tongue, floor of the mouth, buccal cavity, etc. [7]. Oral leukoplakia, the potential pre-malignant lesions, lead to the development of OSCC in 1.5–34% of cases [6]. The traditional treatment methods of surgical resections, chemotherapy and radiotherapy have been successful, but in a limited way as the prognosis for survival at 5 years after diagnosis is still around only 50% [5]. Thus, the approval of Gendicine for the treatment of oral cancer and oral leukoplakia was a great news. However, since its approval, though it has been used for various types of cancer, their use for oral cancers and leukoplakia have been limited. We could only find three RCTs for rAD-p53 use as a therapy for oral cancer or OLP. All the three studies showed clear beneficial effects of rAD-p53 in the treatment of OLP or oral cancer when used alone or in combination with other traditional treatments. Li et al., used rAD-p53 alone as a therapy in phase I study in 22 patients and saw complete regression in 22.7% and partial regression in 50% of the patients.
When rAD-p53 was used along with surgery and radiotherapy, the survival was 100% till the follow up was done (36 months) [27]. Along with chemotherapy, it had significant beneficial effects for patients with stage III oral cancer [28]. Moreover, this therapy showed very few adverse events like flu-like symptoms, increase in WBC count and pain at injection site. There were no SAEs. The three studies were part of the clinical trials of the therapy. However, direct comparisons among the three studies is difficult to make on account of different study design, different phases of trial, and therapy was either given alone or in conjunction with other therapies, but no two studies had similar designs.

4.2. Mode of Action and Outcome of rAD-p53 Treatment

A conspicuous feature of rAD-p53 is that it facilitates for seamless gene transfer as well as overt expression of p53 protein in the nucleus of transfected cells. Regulating cell cycle progression, inducing programmed cell death, control on senescence of cells and autophagy are the important direct effects of p53 protein [34].
Stalling cellular growth: p53 protein regulates the checkpoints of different stages of cell cycle. P53 enhances the manifestation of CDK inhibitor p21. This inhibitor attaches itself to cyclin E/cdk2 and cyclin A/cdk2 complexes and arrests the progression of cell cycle and replication of DNA. This step of inhibition permits for fixing damaged DNA. Management of S-phase checkpoints is attributed to p53-p21 signaling axix. p53 transcriptionally modulates manifestation of Cdc25C, 14-3-3σ, p21 and GADD45 which has significant functional bearing on G2/M checkpoints [35].
Inciting programmed cell death: p53 spells its cast vis-à-vis death receptor and mitochondrial pathways. Caspase cascade stimulation is ignited through the extrinsic, death receptor pathway. Apotosome formation takes place through the mitochondrial/intrinsic pathway, which leads to alteration in Bcl-2 family proteins, leaning towards the proapoptotic members [36,37,38,39].
Controlling autophagy: This is an existence tactic and depends on the presence of p53 at subcellular locations. Nuclear p53 primarily impedes autophagy via transcription dependent mechanisms. Also, the p53 invoked regulator of autophagy, DRAM, is crucial for programmed cell death. rAD-p53 augments overexpression of p53 thereby controlling the autophagy [40,41,42].
Instilling cell senescence: p53 activated cellular senescence by transcriptional activation of target genes like p21, PAI1, and PML in riposte to oxidative stress or damage to DNA. rAD-p53 enhances the expression of p21 which induce cell senescence in malignancies [43].
p53 executes through signalling and epigenetic tessellations. rAD-p53 intratumor injections enable the transduced tumor cells to exhibit exalted levels of exogenetic wt-p53. The molecular mechanisms of rAD-p53 are accredited primarily to binding of p53 to the accompaniment/synergist elements of target genes and igniting cellular events that are related to tumor suppression. p53 also regulates epigenetic changes occurring in cells [44]. Methylation, demethylation and post transcriptional modification are mediated by p53 which lead to prevention of tumor formation [45].

4.3. rAD-p53 Gene Therapy in US

However, in spite of the success of this gene therapy in patients with HNSCC and also, for other solid tumors and carcinomas, the therapy has not been fully utilized because it has not been approved in other parts of the world for treatment. A therapy similar to Gendicine, Advexin, developed by Introgen was turned down by the FDA in September 2008. In fact, the first gene therapy to be approved in US was Kymriah in August 2017 for acute lymphoblastic leukemia (ALL).
Till now, there are more than 30 clinical trials using Gendicine as a therapy for various cancers only in China, where the therapy is approved [46]. It has mostly been used in conjunction with other standard intervention regimes. In fact, it was initially approved for use with chemotherapy or radiotherapy [46]. Since its approval, the mechanism of its action has been elucidated and the molecular pathways involved are much clear now [47,48,49]. Though it has been shown to be safe and had only minor adverse events, adenovirus as a vector can elicit host’s innate as well as adaptive immune responses. There have been development of safer adenovirus and other vectors to be used as a delivery system [50]. Furthermore, the therapy is not very expensive and pegged at around 390$ for one dose and a patient requires 5 doses [46,51]. Since it is not yet approved in most countries, we do not know how the health insurance might cover the costs. Further clinical studies determining the safety of the therapy are needed before it could be approved by the FDA which has stringent guidelines.

4.4. p53 as Biosignature for Gene Therapy

Tumor p53 biosignature analysis may prognosticate p53 gene therapy effectuality. Presence of normal p53 gene sequences was indicator for favorable response to gene therapy in 116 recurrent HNSCC patients. In phase I and II trials, a statistically significant increase in tumor response was evident for patients with favorable p53 efficacy profiles. In phase III trials too, statistically significant increases in time to progression and survival was noted in patients with favorable p53 profiles [52]. p53 mutation status can be utilized to predict the outcomes of radiotherapy and chemotherapy in HNSCC patients as per the observations chronicled by The Cancer Genome Atlas-based analysis of HNSCC patients [53].

5. Conclusions

rAD-p53 gene therapy, approved by China in 2003, for HNSCC has been shown to be effective alone and in conjunction with standard regimes for oral cancer and OLP. However, lack of studies in populations other than Chinese, restricts its potential. More clinical studies, focusing on the safety of the therapy needs to be performed and as the mechanisms of its actions get elucidated further, we can hope that the therapy will be approved for treatment in other countries around the globe.

Author Contributions

Conceptualization, J.H. and S.P.; methodology, J.H., H.M.A. and K.A.; software, S.M.; validation, S.P., L.T. and A.M.; formal analysis, J.H.; investigation, J.H. and S.M.; resources, K.A.; data curation, S.S.A.; writing—J.H., S.M., S.S.A.; original draft preparation, J.H.; writing—review and editing, J.H., S.S.A., S.P.; visualization, H.M.A. and S.M.; supervision, J.H. and S.P.; project administration, L.T. and A.M. funding acquisition, S.S.A. All authors have read and agreed to the published version of the manuscript. Please turn to the CRediT taxonomy for the term explanation. Authorship must be limited to those who have contributed substantially to the work reported.

Funding

The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University, Abha, Saudi Arabia for funding this work through the Small Research Group Project under grant number (RGP-1/247/1442).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable

Data Availability Statement

Not applicable.

Acknowledgments

The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University, Abha, Saudi Arabia for funding this work through the Small Research Group Project under grant number (RGP-1/247/1442).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Warnakulasuriya, S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 2009, 45, 309–316. [Google Scholar] [CrossRef]
  2. Van der Waal, I. Oral leukoplakia, the ongoing discussion on definition and terminology. Med. Oral Patol. Oral Cir. Bucal 2015, 20, e685–e692. [Google Scholar] [CrossRef]
  3. Van der Waal, I.; Schepman, K.P.; van der Meij, E.H.; Smeele, L.E. Oral leukoplakia: A Clinicopathological review. Oral Oncol. 1997, 33, 291–301. [Google Scholar] [CrossRef]
  4. Warnakulasuriya, S.; Johnson, N.W.; Van der Waal, I. Nomenclature and classification of potentially malignant disorders of the oral mucosa. J. Oral Pathol. Med. 2007, 36, 575–580. [Google Scholar] [CrossRef] [PubMed]
  5. Scully, C. Oral cancer aetiopathogenesis; past, present and future aspects. Med. Oral Patol. Oral Cir. Bucal 2011, 16, 306–311. [Google Scholar] [CrossRef]
  6. Speight, P.M.; Khurram, S.A.; Kujan, O. Oral potentially malignant disorders: Risk of progression to malignancy. Oral Surg. Oral Med. Oral Patol. Oral Radiol. 2018, 125, 612–627. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Feller, L.; Lemmer, J. Oral Squamous Cell Carcinoma: Epidemiology, Clinical Presentation and Treatment. J. Cancer Ther. 2012, 3, 263–268. [Google Scholar] [CrossRef] [Green Version]
  8. Lodi, G.; Franchini, R.; Warnakulasuriya, S.; Varoni, E.M.; Sardella, A.; Kerr, A.R.; Carrassi, A.; MacDonald, L.C.; Worthington, H.V. Interventions for treating oral leukoplakia to prevent oral cancer. Cochrane Database Syst. Rev. 2016, 7, CD001829. [Google Scholar] [CrossRef]
  9. Noguti, J.; De Moura, C.F.G.; De Jesus, G.P.P.; Da Silva, V.H.P.; Hossaka, T.A.; Oshima, C.T.F.; Ribeiro, D.A. Metastasis from Oral Cancer: An Overview. Cancer Genom. Proteom. 2012, 9, 329–335. [Google Scholar]
  10. Anguela, X.M.; High, K.A. Entering the Modern Era of Gene Therapy. Annu. Rev. Med. 2019, 70, 273–288. [Google Scholar] [CrossRef] [Green Version]
  11. Mollanoori, H.; Teimourian, S. Therapeutic applications of CRISPR/Cas9 system in gene therapy. Biotechnol. Lett. 2018, 40, 907–914. [Google Scholar] [CrossRef] [PubMed]
  12. Ries, J.C.; Schreiner, D.; Steininger, H.; Girod, S.C. p53 mutation and detection of p53 protein expression in oral leukoplakia and oral squamous cell carcinoma. Anticancer Res. 1998, 18, 2031–2036. [Google Scholar] [PubMed]
  13. Goh, A.M.; Coffill, C.R.; Lane, D.P. The role of mutant p53 in human cancer. J. Pathol. 2011, 223, 116–126. [Google Scholar] [CrossRef] [PubMed]
  14. Muller, P.A.; Vousden, K.H. p53 mutations in cancer. Nat. Cell Biol. 2013, 15, 2–8. [Google Scholar] [CrossRef] [PubMed]
  15. Ventura, A.; Kirsch, D.G.; McLaughlin, M.E.; Tuveson, D.A.; Grimm, J.; Lintault, L. Restoration of p53 function leads to tumour regression in vivo. Nature 2007, 445, 661–665. [Google Scholar] [CrossRef]
  16. Xue, W.; Zender, L.; Miething, C.; Dickins, R.A.; Hernando, E.; Krizhanovsky, V.; Cordon-Cardo, C.; Lowe, S.W. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 2007, 445, 656–660. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Boulay, J.-L.; Perruchoud, A.P.; Reuter, J.; Bolliger, C.; Herrmann, R.; Rochlitz, C. P21 gene expression as an indicator for the activity of adenovirus-p53 gene therapy in non-small cell lung cancer patients. Cancer Gene Ther. 2000, 7, 1215–1219. [Google Scholar] [CrossRef] [Green Version]
  18. Eastham, J.A.; Hall, S.J.; Sehgal, I.; Wang, J.; Timme, T.L.; Yang, G.; Connell-Crowley, L.; Elledge, S.J.; Zhang, W.W.; Harper, J.W. In vivo gene therapy with p53 or p21 adenovirus for prostate cancer. Cancer Res. 1995, 55, 5151–5155. [Google Scholar] [PubMed]
  19. Pearson, S.; Jia, H.; Kandachi, K. China approves first gene therapy. Nat. Biotechnol. 2004, 22, 3–4. [Google Scholar] [CrossRef]
  20. Ma, C.-C.; Wang, Z.-L.; Xu, T.; He, Z.-Y.; Wei, Y.-Q. The approved gene therapy drugs worldwide: From 1998 to 2019. Biotechnol. Adv. 2020, 40, 107502. [Google Scholar] [CrossRef]
  21. Pan, J.-J.; Zhang, S.-W.; Chen, C.-B.; Xiao, S.-W.; Sun, Y.; Liu, C.-Q.; Su, X.; Li, D.M.; Xu, G.; Xu, B.; et al. Effect of recombinant adenovirus-p53 combined with radiotherapy on long-term prognosis of advanced nasopharyngeal carcinoma. J. Clin. Oncol. 2009, 27, 799–804. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. He, X.; Xu, J.; Guo, W.; Kong, C. Therapeutic p53 gene agent in the treatment of NPC cases: Preliminary results. J. Clin. Oncol. 2015, 33, 15. [Google Scholar] [CrossRef]
  23. Li, L.; Huang, Y.; Wang, L.; Li, Y.; Wen, Y.; Han, B. A Combination Therapy of Selective Intraarterial Gendicine Infusion with Chemotherapy for Locally Advanced Head and Neck Carcinoma. Mol. Ther. 2006, 13, S20. [Google Scholar] [CrossRef]
  24. Jadad, A.R.; Moore, R.A.; Carroll, D.; Jenkinson, C.; Reynolds, D.J.; Gavaghan, D.J.; McQuay, H.J. Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Control Clin. Trials 1996, 17, 1–12. [Google Scholar] [CrossRef]
  25. Zhang, S.; Li, Y.; Li, L.; Zhang, Y.; Gao, N.; Zhang, Z.; Zhao, H. Phase I study of repeated intraepithelial delivery of adenoviral p53 in patients with dysplastic oral leukoplakia. J. Oral Maxillofac. Surg. 2009, 7, 1074–1082. [Google Scholar] [CrossRef]
  26. Li, Y.; Li, L.-J.; Zhang, S.-T.; Wang, L.-J.; Zhang, Z.; Gao, N.; Zhang, Y.Y.; Chen, Q.M. In vitro and Clinical Studies of Gene Therapy with Recombinant Human Adenovirus-p53 Injection for Oral Leukoplakia. Clin. Cancer Res. 2009, 15, 6724–6731. [Google Scholar] [CrossRef] [Green Version]
  27. Liu, S.; Chen, P.; Hu, M.; Tao, Y.; Chen, L.; Liu, H.; Wang, J.; Luo, J.; Gao, G. Randomized, controlled phase II study of post-surgery radiotherapy combined with recombinant adenoviral human p53 gene therapy in treatment of oral cancer. Cancer Gene Ther. 2013, 20, 375–378. [Google Scholar] [CrossRef]
  28. Li, Y.; Li, L.-J.; Wang, L.-J.; Zhang, Z.; Gao, N.; Liang, C.-Y.; Huang, Y.D.; Han, B. Selective intra-arterial infusion of rAd-p53 with chemotherapy for advanced oral cancer: A randomized clinical trial. BMC Med. 2014, 12, 16. [Google Scholar] [CrossRef] [Green Version]
  29. Naldini, L. Gene therapy returns to centre stage. Nature 2015, 526, 351–360. [Google Scholar] [CrossRef] [PubMed]
  30. Boycott, K.M.; Vanstone, M.R.; Bulman, D.E.; MacKenzie, A.E. Rare-disease genetics in the era of next-generation sequencing: Discovery to translation. Nat. Rev. Genet. 2013, 14, 681–691. [Google Scholar] [CrossRef] [PubMed]
  31. Farkona, S.; Diamandis, E.P.; Blasutig, I.M. Cancer immunotherapy: The beginning of the end of cancer? BMC Med. 2016, 14, 73. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Biaoxue, R.; Hui, P.; Wenlong, G.; Shuanying, Y. Evaluation of efficacy and safety for recombinant human adenovirus-p53 in the control of the malignant pleural effusions via thoracic perfusion. Sci. Rep. 2016, 6, 39355. [Google Scholar] [CrossRef]
  33. Petti, S. Lifestyle risk factors for oral cancer. Oral Oncol. 2009, 45, 340–350. [Google Scholar] [CrossRef]
  34. Bieging, K.T.; Mello, S.S.; Attardi, L.D. Unravelling mechanisms of p53-mediated tumour suppression. Nat. Rev. Cancer 2014, 14, 359–370. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Giono, L.E.; Manfredi, J.J. The p53 tumor suppressor participates in multiple cell cycle checkpoints. J. Cell Physiol. 2006, 209, 13–20. [Google Scholar] [CrossRef]
  36. Haupt, S.; Berger, M.; Goldberg, Z.; Haupt, Y. Apoptosis—The p53 network. J. Cell Sci. 2003, 116, 4077–4085. [Google Scholar] [CrossRef] [Green Version]
  37. Stegh, A.H. Targeting the p53 signaling pathway in cancer therapy—the promises, challenges and perils. Expert Opin. Ther. Targets 2012, 16, 67–83. [Google Scholar] [CrossRef]
  38. Tang, J.; Di, J.; Cao, H.; Bai, J.; Zheng, J. p53-mediated autophagic regulation: A prospective strategy for cancer therapy. Cancer Lett. 2015, 363, 101–107. [Google Scholar] [CrossRef]
  39. Zhang, W.W.; Alemany, R.; Wang, J.; Koch, P.E.; Ordonez, N.G.; Roth, J.A. Safety evaluation of Ad5CMV-p53 in vitro and in vivo. Hum. Gene Ther. 1995, 6, 155–164. [Google Scholar] [CrossRef]
  40. Crighton, D.; Wilkinson, S.; O’Prey, J.; Syed, N.; Smith, P.; Harrison, P.R.; Gasco, M.; Garrone, O.; Crook, T.; Ryan, K.M. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 2006, 126, 121–134. [Google Scholar] [CrossRef] [Green Version]
  41. Brady, C.A.; Attardi, L.D. p53 at a glance. J. Cell Sci. 2010, 123, 2527–2532. [Google Scholar] [CrossRef] [Green Version]
  42. Kaiser, A.M.; Attardi, L.D. Deconstructing networks of p53-mediated tumor suppression in vivo. Cell Death Differ. 2018, 25, 93–103. [Google Scholar] [CrossRef] [Green Version]
  43. Wu, M.; Ye, H.; Tang, Z.; Shao, C.; Lu, G.; Chen, B.; Yang, Y.; Wang, G.; Hao, H. p53 dynamics orchestrates with binding affinity to target genes for cell fate decision. Cell Death Dis. 2017, 8, e3130. [Google Scholar] [CrossRef] [Green Version]
  44. Levine, A.J.; Berger, S.L. The interplay between epigenetic changes and the p53 protein in stem cells. Genes Dev. 2017, 31, 1195–1201. [Google Scholar] [CrossRef] [Green Version]
  45. Scoumanne, A.; Chen, X. Protein methylation: A new mechanism of p53 tumor suppressor regulation. Histol. Histopathol. 2008, 23, 1143–1149. [Google Scholar] [CrossRef]
  46. Zhang, W.W.; Li, L.; Li, D.; Liu, J.; Li, X.; Li, W.; Xu, X.; Zhang, M.J.; Chandler, L.A.; Lin, H.; et al. The First Approved Gene Therapy Product for Cancer Ad-p53 (Gendicine): 12 Years in the Clinic. Hum. Gene Ther. 2018, 29, 160–179. [Google Scholar] [CrossRef] [Green Version]
  47. Jin, S.; Levine, A.J. The p53 functional circuit. J. Cell Sci. 2001, 114, 4139–4140. [Google Scholar]
  48. Liu, Y.; Zheng, X.; Liu, F. The mechanism and inhibitory effect of recombinant human P53 adenovirus injection combined with paclitaxel on human cervical cancer cell HeLa. Eur. Rev. Med. Pharmacol. Sci. 2015, 19, 1037–1042. [Google Scholar]
  49. Tu, K.; Zheng, X.; Zhou, Z.; Li, C.; Zhang, J.; Gao, J.; Yao, Y.; Liu, Q. Recombinant human adenovirus-p53 injection induced apoptosis in hepatocellular carcinoma cell lines mediated by p53-Fbxw7 pathway, which controls c-Myc and cyclin E. PLoS ONE 2013, 8, e68574. [Google Scholar]
  50. Chen, G.-X.; Zhang, S.; He, X.-H.; Liu, S.-Y.; Ma, C.; Zou, X.-P. Clinical utility of recombinant adenoviral human p53 gene therapy: Current perspectives. Onco Targets Ther. 2014, 7, 1901–1909. [Google Scholar] [CrossRef] [Green Version]
  51. Shahryari, A.; Saghaeian Jazi, M.; Mohammadi, S.; Razavi Nikoo, H.; Nazari, Z.; Hosseini, E.S.; Burtscher, I.; Mowla, S.J.; Lickert, H. Development and Clinical Translation of Approved Gene Therapy Products for Genetic Disorders. Front Genet. 2019, 10, 868. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Nemunaitis, J.; Clayman, G.; Agarwala, S.S.; Hrushesky, W.; Wells, J.R.; Moore, C.; Hamm, J.; Yoo, G.; Baselga, J.; Murphy, B.A.; et al. Biomarkers Predict p53 Gene Therapy Efficacy in Recurrent Squamous Cell Carcinoma of the Head and Neck. Clin. Cancer Res. 2009, 15, 7719–7725. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Zhou, G.; Liu, Z.; Myers, J.N. TP53 Mutations in Head and Neck Squamous Cell Carcinoma and Their Impact on Disease Progression and Treatment Response. J. Cell Biochem. 2016, 117, 2682–2692. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Medicina 57 00438 g001 550
Figure 1. The flowchart showing database literature search and the method of shortlisting articles for review.
Figure 1. The flowchart showing database literature search and the method of shortlisting articles for review.
Medicina 57 00438 g001
Medicina 57 00438 g002 550
Figure 2. Modified Jadad questionnaire.
Figure 2. Modified Jadad questionnaire.
Medicina 57 00438 g002
Table
Table 1. List of articles reviewed in this study and the study characteristics.
Table 1. List of articles reviewed in this study and the study characteristics.
Author and YearStudy Type and DesignSample Population; Age RangerAD-p53 Alone or with Other
Li et al., 2009 [24]Oral lichen planus (OLP), RCT, Phase I, Blinding not defined22; 35–74; Male (M) and Female (F)rAD-p53 alone
Liu et al., 2013 [25]Oral cancer, RCT, Phase II107; 27–80; M and Fradical resection followed by radiotherapy and rAD-p53
Li et al., 2014 [26]Oral cancer; RCT, double-blinded, Phase III99; mean age around 57; M and FrAD-p53 and chemotherapy
Table
Table 2. The Jadad scores of the three articles used for this systematic review.
Table 2. The Jadad scores of the three articles used for this systematic review.
Article and Year PublishedJadad Score
1. Li et al., 2009 [24]2/5 (no blinding)
2. Liu et al., 2013 [25]4/5 (unmasked)
3. Li et al., 2014 [26]5/5 (double-blind)
Table
Table 3. Summary of results from the three RCTs.
Table 3. Summary of results from the three RCTs.
Article and YearPrimary Outcomes (%)p-ValueAdverse Eventsp-ValueIHC
Pre- vs. Post Treatment (%)
Li et al., 2009 [24]Complete regression 22.7
Partial regression 50
No effect 18.2
Progress to cancer 9		NATransient fever 31.8
Injection site pain 22.7
Flu-like symptoms 9.1
Increase in WBC 18.2		NAp-53 low or negative vs. high in all samples
p-21CIP/WAF 22.7 vs. 86.4
Bcl-2 54.5 vs. 18.2
Liu et al., 2013 [25]TC recurrence: EG 7.4 CG 33.3
GC recurrence: EG 6.7 CG 30.8
3-year OS: EG 100 CG 94
3-year DFS EG 93 CG 68		0.0326
0.0332
0.0586
0.0002		Transient Fever: EG 84 CG 12
Flu-like symtomps EG 64 CG 4
Oral Membrane EG 24.6
Burn and pain CG 30		<0.0001
<0.0001
0.6634		NA
Li et al., 2014 [26]CR:
G I 48.5
GII 16.7
GIII 17.2
PR:
GI 33.3
GII 36.7
G III 34.5
SD or PD:
GI 18.2
GII 46.7
GIII 48.3
Recurrence:
GI 9.1
GII 20.0
GIII 24.1		0.006
0.961
0.020
0.267		Flu-like symptoms
GI 81.8
GII 76.7
GIII 55.2
Bone Marrow
Suppression
GI 36.4
GII 0.0
GIII 37.89		0.051Bax Increase
GI 84.8
GII 90.0
GIII 3.4
Bcl-2 decrease
GI 90.0
GII 80.0
GIII 27.6
NA, Not Applicable; IHC, Immunohistochemistry.TC, Tongue Cancer; GC, Gingival Cancer; OS, Overall Survival; DFS, Disease Free Survival; EG, Experimental Group receiving rAD-p53+ radiotherapy; CG, Control Group receiving only radiotherapy. G I, Group I, rAD-p53 + chemotherapy; G II, Group II, rAD-p53 + placebo chemotherapy; G III, placebo rAD-p53 + chemotherapyCR, Complete Response; PR, Partial Response; PD, Progressive Disease; SD, Stagnant Disease.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Hosmani, J.; Mushtaq, S.; Abullais, S.S.; Almubarak, H.M.; Assiri, K.; Testarelli, L.; Mazzoni, A.; Patil, S. Recombinant Human Adenovirus-p53 Therapy for the Treatment of Oral Leukoplakia and Oral Squamous Cell Carcinoma: A Systematic Review. Medicina 2021, 57, 438. https://doi.org/10.3390/medicina57050438

AMA Style

Hosmani J, Mushtaq S, Abullais SS, Almubarak HM, Assiri K, Testarelli L, Mazzoni A, Patil S. Recombinant Human Adenovirus-p53 Therapy for the Treatment of Oral Leukoplakia and Oral Squamous Cell Carcinoma: A Systematic Review. Medicina. 2021; 57(5):438. https://doi.org/10.3390/medicina57050438

Chicago/Turabian Style

Hosmani, Jagadish, Shazia Mushtaq, Shahabe Saquib Abullais, Hussain Mohammed Almubarak, Khalil Assiri, Luca Testarelli, Alessandro Mazzoni, and Shankargouda Patil. 2021. "Recombinant Human Adenovirus-p53 Therapy for the Treatment of Oral Leukoplakia and Oral Squamous Cell Carcinoma: A Systematic Review" Medicina 57, no. 5: 438. https://doi.org/10.3390/medicina57050438

APA Style

Hosmani, J., Mushtaq, S., Abullais, S. S., Almubarak, H. M., Assiri, K., Testarelli, L., Mazzoni, A., & Patil, S. (2021). Recombinant Human Adenovirus-p53 Therapy for the Treatment of Oral Leukoplakia and Oral Squamous Cell Carcinoma: A Systematic Review. Medicina, 57(5), 438. https://doi.org/10.3390/medicina57050438

Article Metrics

Back to TopTop