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Oncolytic virotherapy, alone or in combination with immune checkpoint inhibitors, for advanced melanoma: A systematic review and meta-analysis
International Immunopharmacology 78 (2020) 106050
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Oncolytic virotherapy, alone or in combination with immune checkpoint inhibitors, for advanced melanoma: A systematic review and meta-analysis Puyu Zoua, Rui Tangb, Mei Luoc,
T
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a
Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China Department of Rheumatology and Immunology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China c Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China b
A B S T R A C T
Background: Advanced melanoma, one of the most lethal forms of skin cancer, remains a difficult condition to treat, despite the substantial scientific progression in cancer treatment. Oncolytic virotherapy (OV), either alone or combined with immune checkpoint inhibitors (ICIs), has often been administrated in an attempt to cure this malignancy. However, the clinical outcomes dramatically vary among different reports. Methods: In this study, we performed a meta-analysis to evaluate the clinical efficacy and safety profile of OV, combined with ICIs in some cases, in advanced melanoma patients. The original clinical studies were identified based on the online query in PubMed, Cochrane, and Web of Science before December 30, 2018. Results: A total of 18 publications involving 1472 patients were included for the final meta-analysis. The data concerning objective response rate (ORR) and incidence rate of severe immune-related adverse events (irAEs) were extracted accordingly from the text or supplementary materials. The results illustrated that a single treatment of OV could generate a 25% ORR for advanced melanoma, and the ORR could be improved to 45% if combined with ICIs. Further analysis demonstrated that the introduction of ICIs in OV could increase the incidence rate of severe irAEs (AE ≥ 3) from 12% to 39%. However, the rate attributed to OV remains at 12% in the combination group. Conclusion: The clinical efficacy of OV can be significantly improved by ICIs even though more onerous burden will be exerted simultaneously on the safety profile.
1. Introduction Advanced melanoma contributes to the majority of skin cancer-related deaths and presents an accelerative incidence during last years. Despite pleasing survival outcome for melanoma in a benign stage, prognosis remains poor for malignant stage with a median of overall survival (OS) of 8–10 months [1]. Recently, USA Food and Drug Administration (FDA) approved a variety of treatments designed for advanced melanoma [2]. One compelling treatment is oncolytic virotherapy (OV) [3]. OV involves a virus which is genetically engineered to selectively propagate and damage cancerous tissues without harmful effects on normal tissues. Several properties are needed for implementing OV [4]. The first property is the attenuation or deletion of the virulence factor. This action will induce OV’s disability to generate severe infectious symptoms [5]. Second, the preferential infection and precise propagation in tumor cells are conferred by tumor-specific disruption in the signaling pathway, which can terminate the protein translation and block infection in normal cells. For example, PKR, TP53, WNT, and PTEN signaling pathways have been well affirmed to make cancer cells vulnerable to viral infection [6]. Third, specific cytotoxicity to tumor cells of OV can be induced in various means, such as direct
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viral cytotoxicity or the stimulation of innate and adaptive immunity [7]. Last, it is essential to note OV is a replicating biotherapy which spreads locoregionally or systematically to react to both primary and metastatic tumor sites [8]. The clinical safety and feasibility of OV for melanoma, especially the metastasis, has been well confirmed by several groups [9]. Lately, a wide variety of OV-targeting strategies have been evolving across the spectrum of basic, preclinical, and clinical investigation. Each study has its unique individual characteristic. For example, Talimogene Laherparepvec (T-VEC), the first FDA approved OV, is elicited from herpes simplex virus type 1 (HSV-1) [10]. In spite of clinical certificate to HSV [11–15], a mass of viruses can be engineered to function as oncolytic viruses: OreienX010 engrafted with GM-CSF [16]; HF10 generated from a naturally mutated virus statin HF [17]; CVA21 (CAVATAK) rendered from Coxsackievirus [18]; Reolysin engendered from oncolytic reovirus [19,20], and other OVs established from adenovirus or poxvirus [21–23]. Another substantiated regimen for advanced melanoma extends to inhibition of immune checkpoint molecules, which serve as pivotal regulators for immune system [24]. These immune checkpoint pathways are essential for self-tolerance due to their inhibitory effect on
Corresponding author at: No. 87 Xiangya Road, Kaifu District, Changsha 410008, China. E-mail address: [email protected] (M. Luo).
https://doi.org/10.1016/j.intimp.2019.106050 Received 10 August 2019; Received in revised form 29 October 2019; Accepted 11 November 2019 1567-5769/ © 2019 Elsevier B.V. All rights reserved.
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Rui Tang) from eligible studies. The following parameters were extracted from each manuscript and supplementary material: first author’s name, year of publication, WHO tumor stage, therapeutic regimen, and clinical endpoints. The objective response rate (ORR) and the incidence rate of severe irAEs were applied for final evaluation. Newcastle-Ottawa Scale was used to assess the quality of the included studies. Each study was scored according to selection, comparability, and outcome. Any discrepancies were solved by mutual discussion.
immune cells. In fact, the antitumor immune response could be stopped if those immunosuppressive regulators were in action. In other words, immune checkpoint blockade will augment the antitumor reaction [25]. Currently, various immune checkpoint molecules (e.g., CTLA-4, PD-1, Tim-3, LAG-3) have been defined as the target for immune checkpoint inhibitors (ICIs). It is well established that clinical administration of the ICIs against CTLA-4 (ipilimumab) and PD-1 (pembrolizumab and nivolumab) can substantially boost the function of the immune system [26]. Current clinical outcome of ICIs has revealed their favorable roles for melanoma’s prognosis [27]. Herein, both treatments via OV and ICIs in advanced melanoma result in long-lasting antitumor responses in patients. However, each of them holds some fatal disadvantages [9]. In terms of OV, the activation and recruitment of immune cells during OV-mediated oncolysis ultimately activate the immune checkpoints for limiting antitumor reaction and inflammation. This inactivation of T cells will subsequently devalue clinical efficacy of OV. In regards to ICIs, clinical evidence has reported some patients not responding to ICIs, and the de novo and acquired resistance to ICIs have been proposed [28]. One major factor is the deficiency of effector T cells inside tumor lesions during ICIs, which may be complemented by the advantage of OV. Rationally, it seems that the scarcity of both OV and ICIs might be diminished or eradicated if they could be combined [29]. Under this background, investigations about the combination therapy of OV with ICIs is arising [17,30–34]. However, whether the combined treatment furthering improves the clinical outcome and how to appraise immune-related adverse events (irAEs) after combined therapy remain controversial [35]. In this systematic review, we firstly focus on the illustration of objective response rate (ORR) of OV, alone or combined with ICIs, for advanced melanoma. And we secondly try to exemplify and further discuss the manifestation of severe irAEs (AE ≥ 3) during those immunotherapeutic processes.
2.4. Statistical analysis Stata version14 (Stata Corporation; college station, Tx, USA) was applied to perform statistical analysis. Pooled ORR and incidence rate of severe irAEs were presented to evaluate the clinical outcome. Heterogenicity among studies was assessed by the Chi-squared test and I2. A fixed-effects model was applied when there was no significant heterogenicity (I2 < 50% or p-value > 0.05). Otherwise, the randomeffects model was in use. We used Begg’s test and Egger’s test to precisely estimate the publication bias of eligible studies. 3. Results 3.1. Literature search and study selection The initial search strategy identified 1472 records after systematic literature retrieval. After removing 864 duplicates and excluding 539 irrelevant records, we included 69 articles after review of the title and abstract. The full text of remaining 69 articles were carefully screened and assessed. 51 pieces of literature were excluded due to following reasons: reviews, case reports, articles without ORR or incidence rate of irAEs. Eventually, 18 studies were selected according to the inclusion and exclusion criteria. Details for searching strategies were presented in Fig. 1.
2. Materials and methods 3.2. Characteristics of included studies 2.1. Literature search strategy The main characteristics of the included studies were summarized in Table 1. 18 studies and 1472 patients were included for final analysis. All included studies were published before December 31, 2018. The WHO tumor grade of melanoma was either equal to or higher than stage III, which was defined as advanced melanoma. The formulas of oncolytic virus were indicated, especially for application of ICIs. 12 studies were sorted as single OV treatment without ICIs, and 6 studies were categorized as combined therapy group of OV with ICIs. 17 studies reported ORR and 10 studies presented the incidence rate of severe irAE after treatment of OV, with or without ICIs. In our assessment of study quality, 4 studies have the quality scores of 7 or higher, while others were less than 7.
This meta-analysis was conducted according to Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) statement. A systematic literature retrieval was executed in PubMed, Cochrane, and Web of Science. The time endpoint of online search was December 31, 2018. Privately and publicly funded clinical studies posted on ClinicalTrials.gov were also screened. Following terms were applied to comprehensively seize the articles: 1) (Oncolytic Virus) or (Virus, Oncolytic) or (Viruses, Oncolytic) and 2) (Melanomas) or (Malignant Melanoma) or (Malignant Melanomas) or (Melanoma, Malignant) or (Melanomas, Malignant). References of included studies were conditionally screened, and on-topic articles were reviewed while off-topic items were excluded.
3.3. Overall response rate 2.2. Inclusion criteria Eligible studies were: (1) The stage of melanoma was either equal to or higher than stage III; (2) Patients in experimental arms were treated with single OV or combined therapy of OV with ICIs; (3) The primary or secondary outcome should contain objective response rate (ORR) and/ or the incidence rate of severe irAEs. Studies were excluded if they were: (1) Case report, review, letter, or conference abstract; (2) Articles published without English version; (3) Duplicated or overlapping data. If several publications from the same project were identified simultaneously, the newest version and most comprehensive data would be included.
A total of 17 studies consisting of 793 patients reported ORR after treatment. There were 11 studies in the group treated with a single OV and 6 studies in the group treated with combined therapy of OV with ICIs. The ORR for advanced melanoma patients after single OV was 25% (95% CI = 0.21–0.28) (Fig. 2A), while the pooled ORR after combined therapy of OV with ICIs was 45% (95% CI = 0.38–0.52) (Fig. 2B). Both single OV treatment group and combined therapy groups were of low heterogenicity in ORR (single OV: I2 = 46.2%, p = 0.046; OV + ICIs: I2 = 44.9%, p = 0.106). The data indicated that the ORR of combined therapy was significantly improved compared with single OV therapy.
2.3. Data extraction and quality assessment
3.4. Immune-related adverse events
Data were extracted by two independent reviewers (Puyu Zou and
Next, we analyzed 10 studies and 402 patients that provided data of 2
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Fig. 1. Flow diagram of online literature retrieval.
3.5. Publication bias
incidence rate of severe irAEs. The pooled incidence rate of severe irAEs caused by OV in single OV treatment group was 12% (95% CI = 0.08–0.16) without heterogenicity (I2 = 0%, p = 0.626) (Fig. 3A). And the pooled incidence rate of severe irAEs in the combined therapy group was 39% (95% CI = 0.32–0.46) without heterogenicity (I2 = 13.3%, p = 0.326) (Fig. 3B), which means the incidence rate of severe irAEs was dramatically increased after involvement of ICIs. However, further analysis of severe irAEs in the combined therapy group confirmed that only 12% (95% CI = 0.07–0.16) of them were attributed to OV (Fig. 3C).
We combined Begg’s test and Egger’s test to evaluate whether a publication bias existed. In terms of ORR, both tests did not indicate any publication bias in a single OV treatment group (Begg’s test, Pr > |z| = 0.697, Egger’s test, p > |t| = 0.514) and the combined therapy group (Begg’s test, Pr > |z| = 0.188, Egger’s test, p > |t| = 0.162). As for severe irAEs, no significant publication bias was observed in single OV treatment group (Begg’s test, Pr > |z| = 0.851, Egger’s test, p > |t| = 0.516) and the combined therapy group (Begg’s test, Pr > |z| = 1.000, Egger’s test,
Table 1 Main characteristics of included studies. Study and years
WHO tumor grade
Therapeutic regimen
Endpoints
Score
Perez MC 2018 [11] Chesney J 2018 [12] Senzer NN 2009 [13] Andtbacka RHI 2018 [14] Kaufman HL 2005 [21] Kaufman HL 2006 [22] Hwang TH 2011 [23] Andtbacka RHI 2015 [18] Mahalingam D 2017 [19] Cui C 2016 [16] Andtbacka RH 2015 [15] Galanis E 2012 [20] Ribas A 2017 [30] Chesney J 2018 [31] Puzanov I 2016 [32] Andtbacka RHI 2017 [17] Curti BD 2017 [33] Silk AW 2017 [34]
Unresectable stage IIIB - IV melanoma Unresectable stage IIIB-IVM1c melanoma Unresectable metastatic melanoma Resectable stage IIIB/C-IVM1a melanoma Metastatic melanoma Metastatic melanoma Metastatic melanoma Stage IIIc-IV melanoma. Advanced melanoma Unresectable stage IIIC-IV acral melanoma Stages IIIB-IV melanoma Metastatic melanoma Advanced melanoma Unresectable stages IIIB-IV melanoma Unresectable stage IIIB-IV melanoma Unresectable stage IIIB-IV melanoma Advanced melanoma Advanced melanoma
T-VEC T-VEC T-VEC T-VEC Vaccinia virus expressing B7.1 Vaccinia virus rV-TRICOM Pexastimogene devacirepvec CVA21 Reolysin OrienX010 T-VEC Reolysin T-VEC with perbrolizumab T-VEC with ipilimumab T-VEC with ipilimumab HF10 with ipilimumab CVA21 with ipilimumab CVA21 with pembrolizumab
ORR ORR ORR ORR ORR ORR ORR ORR ORR ORR ORR AE ORR ORR ORR ORR ORR ORR
5 7 6 7 5 5 5 6 6 5 9 6 7 6 6 6 6 6
and and and and
irAEs irAEs irAEs irAEs
and irAEs
and and and and
irAEs irAEs irAEs irAEs
T-VEC, Talimogene Laherparepvec; TRICOM, triad of costimulatory molecules; CVA21, Coxsackievirus A21; ORR; objective response rate; irAEs, immune-related adverse events. 3
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Fig. 2. Forest plot (left) and Begg’s funnel plot (right) of pooled ORR. (A) ORR after oncolytic virotherapy alone. (B) ORR after combined treatment of oncolytic virotherapy with immune checkpoint inhibitors.
adding ICIs will not induce additional toxicity for OV treatment. The notion of oncolytic virotherapy, which is based on principle of a viral agent selectively infecting and destroying cancer cells, originated almost a century ago [5]. Since the first FDA approval of oncolytic virotherapy (T-VEC) for advanced melanoma in 2015, the clinical administration of OV to melanoma patients has expanded drastically [38]. However, which oncolytic virus is the best one keeps controversial. Current clinical response rate did not reveal a dramatic discrepancy among different oncolytic viruses. Thus, more clinical trial data may help us in selecting the best platform from the current available oncolytic viruses. As a single regimen for melanoma, the clinical efficacy of OV can be interfered with many factors. The immunosuppressive factors, particularly immune checkpoint pathways, have the most destructive effect on the progress of immunotherapy. Those suppressive effects will be harmful to the proliferation, differentiation, trafficking, and survival of immune cells [29]. Since the aforementioned ICIs became a standard of care for melanoma, a combination of OV with ICIs is evolving. Advantage of promoting immune response by ICIs should be excellent facilitation for OV development. According to our meta-analysis data of current clinical trials, it is obvious that clinical response rate can be improved dramatically via combination of OV with ICIs. However, whether the tremendous clinical response rate can be translated into survival benefit remains unclarified [39]. Thus, further investigation of single administration and combined therapy of OV with ICIs are essential.
p > |t| = 0.0.459). Severe irAEs attributed to OV in the combined therapy also didn’t show any publication bias (Begg’s test, Pr > |z| = 0.174, Egger’s test, p > |t| = 0.0.05). And each funnel plot of Begg’s test was attached to the forest plot in Figs. 2 and 3. 4. Discussion Although a growing number of advances have been made in the management of melanoma, it remains one of the most lethal cutaneous malignancies. The exploitation of novel therapeutic options is imperative for improving life expectancy and overall quality of life for advanced melanoma patients [36]. Recently, more and more trials of OV, alone or in combination with ICIs, have been launched. The clinical outcome has suggested that these methods can have a dramatic clinical benefit in advanced melanoma patients [37]. However, the clinical response rate and severe irAEs caused by single OV treatment and combined therapy of OV with ICIs have not been systematically reviewed. Based on those therapies, we conducted a comprehensive analysis of single OV treatment and combined therapy of OV with ICIs for advanced melanoma. According to our results, the single OV treatment can generate 25% ORR, and 12% of patients suffer severe irAEs. The combination of OV with ICIs can accelerate ORR to 48%, which means the combined therapy was a more feasible and efficient strategy for management of advanced melanoma. Although the severe irAEs of combined therapy arise from 12% to 39%, the severe irAEs attributed to OV was still restricted to 12%. This process indicates 4
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Fig. 3. Forest plot (left) and Begg’s funnel plot (right) of pooled incidence rate of severe irAEs (AE ≥ 3). (A) Severe irAEs after oncolytic virotherapy alone. (B) Severe irAEs after combined treatment of oncolytic virotherapy with immune checkpoint inhibitors. (C) Severe irAEs attributed to oncolytic virotherapy in combined treatment group.
ligand (PD-L1) expression level, germline genetics, tumor mutation burden (TMB), tumor microsatellite instability, other features of the tumor microenvironment, and the microbiome [42]. Undoubtedly, one way to accelerate the development of combined therapy is to understand OV and ICIs better, while another attractive niche of combined therapy is to genetically engineer OVs with ICIs[43]. This process may reduce the need for single administration of OV and ICIs separately. Selective replication of OV in tumor sites will induce localized expression of ICIs, which in turn could provide a superior safety profile comparing with systematic administration. Although this attractive approach is still futuristic, several groups have demonstrated the markedly better therapeutic efficacy of OV-encoding PD-1antibody
Concerning OV exploration, one major obstacle is that the host innate and adaptive immune system could recognize OV as exogenous antigens. This falsehood recognition reduces the amplification and the migration in local and remote lesions. Accordingly, we can reform oncolytic virus with less immunogenic viral antigens, or conceal them with polymer or carrier cells to circumvent the antiviral immune responses [40,41]. As for ICIs, different ICIs applied with OV probably differ from each other. In our subgroup analysis, the application of Pembrolizumab shows a significantly better ORR comparing with Ipilimumab (data not shown). Thus, exploration of the best ICI is vital for the combination of OV with ICIs. Furthermore, better understanding of biomarkers' evolving landscape predicts beneficial effects, such as PD1 5
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than every singular application [44]. Interestingly, triple combination therapy of OV, immune checkpoint inhibitor, and MEK inhibitor can further augment the clinical response [45]. Better understanding of the alteration of biological markers during the therapeutic process may provide more information for future OV design. Besides, we can’t neglect that a significant number of patients develop severe irAEs in the combined therapy group. Current methods to monitor those severe irAEs including the administration of immunosuppressive agents, mostly glucocorticoids [46]. However, lots of investigators presented that application of those agents may decrease clinical efficacy. A consensus has not been reached on how to balance the beneficial and harmful effects of immunosuppressive agents during immunotherapy; whether irAEs are distinct from conventional autoimmune disease; how manifestation of irAEs is associated with clinical efficacy. With limited knowledge about pathophysiology of irAEs during OV and ICIs, future understanding of mechanistic factors will help clinicians to manage irAEs better [47]. Furthermore, customized immunotherapy strategies are the next trend for both OV and ICIs. Our study has several limitations that should be concerned before a definite conclusion. Firstly, most of included studies in our analysis are phase I or phase II clinical trials. Currently, there are lacking phase III randomized clinical trials in oncolytic virotherapy area. More convincible results and reliable clinical trials are still essential for oncologists to draw a solid conclusion about clinical efficacy and safety for advanced melanoma. Secondly, we choose the ORR to evaluate the final clinical efficacy of OV in advanced melanoma. Whether the improvement of ORR in OV can be transferred to be better survival outcome are still controversial. Finally, we combine all OV without consideration of different virus component and variable OV regimen [48]. In the future, more insight should be applied to discuss those factors separately.
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5. Conclusion ORR for advanced melanoma can be improved from 25% to 45% after collaboration with ICIs. The increased clinical response may benefit patients’ survival outcomes and future OV investigation in combination with ICIs is warranted. Noteworthy, the incidence rate of severe irAEs can also be extended from 12% to 39%, which means the manifestation of irAES during combined therapy is more intricate and essential than a single administration of OV. These findings are suggestive for requiring additional clinical trials to obtain more precise understanding of OV’s clinical efficacy, OV’s safety profile, and its combination with ICIs. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or non-for-profit sectors. Declaration of Competing Interest The authors declared that there is no Conflict of Interest. References [1] D. Schadendorf, A.C.J. van Akkooi, C. Berking, K.G. Griewank, R. Gutzmer, A. Hauschild, A. Stang, A. Roesch, S. Ugurel, Melanoma, Lancet 392 (10151) (2018) 971–984. [2] C. Franklin, E. Livingstone, A. Roesch, B. Schilling, D. Schadendorf, Immunotherapy in melanoma: recent advances and future directions, Eur. J. Surg. Oncol. 43 (3) (2017) 604–611. [3] S.E. Lawler, M.C. Speranza, C.F. Cho, E.A. Chiocca, Oncolytic viruses in cancer treatment: a review, JAMA Oncol. 3 (6) (2017) 841–849. [4] K. Twumasi-Boateng, J.L. Pettigrew, Y.Y.E. Kwok, J.C. Bell, B.H. Nelson, Oncolytic viruses as engineering platforms for combination immunotherapy, Nat. Rev. Cancer 18 (7) (2018) 419–432. [5] S.J. Russell, K.W. Peng, J.C. Bell, Oncolytic virotherapy, Nat. Biotechnol. 30 (7) (2012) 658–670. [6] L.A. Pikor, J.C. Bell, J.S. Diallo, Oncolytic viruses: exploiting cancer's deal with the
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[31]
[32]
[33]
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Oncolytic virotherapy, alone or in combination with immune checkpoint inhibitors, for advanced melanoma: A systematic review and meta-analysis Puyu Zoua, Rui Tangb, Mei Luoc,
T
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a
Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China Department of Rheumatology and Immunology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China c Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China b
A B S T R A C T
Background: Advanced melanoma, one of the most lethal forms of skin cancer, remains a difficult condition to treat, despite the substantial scientific progression in cancer treatment. Oncolytic virotherapy (OV), either alone or combined with immune checkpoint inhibitors (ICIs), has often been administrated in an attempt to cure this malignancy. However, the clinical outcomes dramatically vary among different reports. Methods: In this study, we performed a meta-analysis to evaluate the clinical efficacy and safety profile of OV, combined with ICIs in some cases, in advanced melanoma patients. The original clinical studies were identified based on the online query in PubMed, Cochrane, and Web of Science before December 30, 2018. Results: A total of 18 publications involving 1472 patients were included for the final meta-analysis. The data concerning objective response rate (ORR) and incidence rate of severe immune-related adverse events (irAEs) were extracted accordingly from the text or supplementary materials. The results illustrated that a single treatment of OV could generate a 25% ORR for advanced melanoma, and the ORR could be improved to 45% if combined with ICIs. Further analysis demonstrated that the introduction of ICIs in OV could increase the incidence rate of severe irAEs (AE ≥ 3) from 12% to 39%. However, the rate attributed to OV remains at 12% in the combination group. Conclusion: The clinical efficacy of OV can be significantly improved by ICIs even though more onerous burden will be exerted simultaneously on the safety profile.
1. Introduction Advanced melanoma contributes to the majority of skin cancer-related deaths and presents an accelerative incidence during last years. Despite pleasing survival outcome for melanoma in a benign stage, prognosis remains poor for malignant stage with a median of overall survival (OS) of 8–10 months [1]. Recently, USA Food and Drug Administration (FDA) approved a variety of treatments designed for advanced melanoma [2]. One compelling treatment is oncolytic virotherapy (OV) [3]. OV involves a virus which is genetically engineered to selectively propagate and damage cancerous tissues without harmful effects on normal tissues. Several properties are needed for implementing OV [4]. The first property is the attenuation or deletion of the virulence factor. This action will induce OV’s disability to generate severe infectious symptoms [5]. Second, the preferential infection and precise propagation in tumor cells are conferred by tumor-specific disruption in the signaling pathway, which can terminate the protein translation and block infection in normal cells. For example, PKR, TP53, WNT, and PTEN signaling pathways have been well affirmed to make cancer cells vulnerable to viral infection [6]. Third, specific cytotoxicity to tumor cells of OV can be induced in various means, such as direct
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viral cytotoxicity or the stimulation of innate and adaptive immunity [7]. Last, it is essential to note OV is a replicating biotherapy which spreads locoregionally or systematically to react to both primary and metastatic tumor sites [8]. The clinical safety and feasibility of OV for melanoma, especially the metastasis, has been well confirmed by several groups [9]. Lately, a wide variety of OV-targeting strategies have been evolving across the spectrum of basic, preclinical, and clinical investigation. Each study has its unique individual characteristic. For example, Talimogene Laherparepvec (T-VEC), the first FDA approved OV, is elicited from herpes simplex virus type 1 (HSV-1) [10]. In spite of clinical certificate to HSV [11–15], a mass of viruses can be engineered to function as oncolytic viruses: OreienX010 engrafted with GM-CSF [16]; HF10 generated from a naturally mutated virus statin HF [17]; CVA21 (CAVATAK) rendered from Coxsackievirus [18]; Reolysin engendered from oncolytic reovirus [19,20], and other OVs established from adenovirus or poxvirus [21–23]. Another substantiated regimen for advanced melanoma extends to inhibition of immune checkpoint molecules, which serve as pivotal regulators for immune system [24]. These immune checkpoint pathways are essential for self-tolerance due to their inhibitory effect on
Corresponding author at: No. 87 Xiangya Road, Kaifu District, Changsha 410008, China. E-mail address: [email protected] (M. Luo).
https://doi.org/10.1016/j.intimp.2019.106050 Received 10 August 2019; Received in revised form 29 October 2019; Accepted 11 November 2019 1567-5769/ © 2019 Elsevier B.V. All rights reserved.
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Rui Tang) from eligible studies. The following parameters were extracted from each manuscript and supplementary material: first author’s name, year of publication, WHO tumor stage, therapeutic regimen, and clinical endpoints. The objective response rate (ORR) and the incidence rate of severe irAEs were applied for final evaluation. Newcastle-Ottawa Scale was used to assess the quality of the included studies. Each study was scored according to selection, comparability, and outcome. Any discrepancies were solved by mutual discussion.
immune cells. In fact, the antitumor immune response could be stopped if those immunosuppressive regulators were in action. In other words, immune checkpoint blockade will augment the antitumor reaction [25]. Currently, various immune checkpoint molecules (e.g., CTLA-4, PD-1, Tim-3, LAG-3) have been defined as the target for immune checkpoint inhibitors (ICIs). It is well established that clinical administration of the ICIs against CTLA-4 (ipilimumab) and PD-1 (pembrolizumab and nivolumab) can substantially boost the function of the immune system [26]. Current clinical outcome of ICIs has revealed their favorable roles for melanoma’s prognosis [27]. Herein, both treatments via OV and ICIs in advanced melanoma result in long-lasting antitumor responses in patients. However, each of them holds some fatal disadvantages [9]. In terms of OV, the activation and recruitment of immune cells during OV-mediated oncolysis ultimately activate the immune checkpoints for limiting antitumor reaction and inflammation. This inactivation of T cells will subsequently devalue clinical efficacy of OV. In regards to ICIs, clinical evidence has reported some patients not responding to ICIs, and the de novo and acquired resistance to ICIs have been proposed [28]. One major factor is the deficiency of effector T cells inside tumor lesions during ICIs, which may be complemented by the advantage of OV. Rationally, it seems that the scarcity of both OV and ICIs might be diminished or eradicated if they could be combined [29]. Under this background, investigations about the combination therapy of OV with ICIs is arising [17,30–34]. However, whether the combined treatment furthering improves the clinical outcome and how to appraise immune-related adverse events (irAEs) after combined therapy remain controversial [35]. In this systematic review, we firstly focus on the illustration of objective response rate (ORR) of OV, alone or combined with ICIs, for advanced melanoma. And we secondly try to exemplify and further discuss the manifestation of severe irAEs (AE ≥ 3) during those immunotherapeutic processes.
2.4. Statistical analysis Stata version14 (Stata Corporation; college station, Tx, USA) was applied to perform statistical analysis. Pooled ORR and incidence rate of severe irAEs were presented to evaluate the clinical outcome. Heterogenicity among studies was assessed by the Chi-squared test and I2. A fixed-effects model was applied when there was no significant heterogenicity (I2 < 50% or p-value > 0.05). Otherwise, the randomeffects model was in use. We used Begg’s test and Egger’s test to precisely estimate the publication bias of eligible studies. 3. Results 3.1. Literature search and study selection The initial search strategy identified 1472 records after systematic literature retrieval. After removing 864 duplicates and excluding 539 irrelevant records, we included 69 articles after review of the title and abstract. The full text of remaining 69 articles were carefully screened and assessed. 51 pieces of literature were excluded due to following reasons: reviews, case reports, articles without ORR or incidence rate of irAEs. Eventually, 18 studies were selected according to the inclusion and exclusion criteria. Details for searching strategies were presented in Fig. 1.
2. Materials and methods 3.2. Characteristics of included studies 2.1. Literature search strategy The main characteristics of the included studies were summarized in Table 1. 18 studies and 1472 patients were included for final analysis. All included studies were published before December 31, 2018. The WHO tumor grade of melanoma was either equal to or higher than stage III, which was defined as advanced melanoma. The formulas of oncolytic virus were indicated, especially for application of ICIs. 12 studies were sorted as single OV treatment without ICIs, and 6 studies were categorized as combined therapy group of OV with ICIs. 17 studies reported ORR and 10 studies presented the incidence rate of severe irAE after treatment of OV, with or without ICIs. In our assessment of study quality, 4 studies have the quality scores of 7 or higher, while others were less than 7.
This meta-analysis was conducted according to Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) statement. A systematic literature retrieval was executed in PubMed, Cochrane, and Web of Science. The time endpoint of online search was December 31, 2018. Privately and publicly funded clinical studies posted on ClinicalTrials.gov were also screened. Following terms were applied to comprehensively seize the articles: 1) (Oncolytic Virus) or (Virus, Oncolytic) or (Viruses, Oncolytic) and 2) (Melanomas) or (Malignant Melanoma) or (Malignant Melanomas) or (Melanoma, Malignant) or (Melanomas, Malignant). References of included studies were conditionally screened, and on-topic articles were reviewed while off-topic items were excluded.
3.3. Overall response rate 2.2. Inclusion criteria Eligible studies were: (1) The stage of melanoma was either equal to or higher than stage III; (2) Patients in experimental arms were treated with single OV or combined therapy of OV with ICIs; (3) The primary or secondary outcome should contain objective response rate (ORR) and/ or the incidence rate of severe irAEs. Studies were excluded if they were: (1) Case report, review, letter, or conference abstract; (2) Articles published without English version; (3) Duplicated or overlapping data. If several publications from the same project were identified simultaneously, the newest version and most comprehensive data would be included.
A total of 17 studies consisting of 793 patients reported ORR after treatment. There were 11 studies in the group treated with a single OV and 6 studies in the group treated with combined therapy of OV with ICIs. The ORR for advanced melanoma patients after single OV was 25% (95% CI = 0.21–0.28) (Fig. 2A), while the pooled ORR after combined therapy of OV with ICIs was 45% (95% CI = 0.38–0.52) (Fig. 2B). Both single OV treatment group and combined therapy groups were of low heterogenicity in ORR (single OV: I2 = 46.2%, p = 0.046; OV + ICIs: I2 = 44.9%, p = 0.106). The data indicated that the ORR of combined therapy was significantly improved compared with single OV therapy.
2.3. Data extraction and quality assessment
3.4. Immune-related adverse events
Data were extracted by two independent reviewers (Puyu Zou and
Next, we analyzed 10 studies and 402 patients that provided data of 2
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Fig. 1. Flow diagram of online literature retrieval.
3.5. Publication bias
incidence rate of severe irAEs. The pooled incidence rate of severe irAEs caused by OV in single OV treatment group was 12% (95% CI = 0.08–0.16) without heterogenicity (I2 = 0%, p = 0.626) (Fig. 3A). And the pooled incidence rate of severe irAEs in the combined therapy group was 39% (95% CI = 0.32–0.46) without heterogenicity (I2 = 13.3%, p = 0.326) (Fig. 3B), which means the incidence rate of severe irAEs was dramatically increased after involvement of ICIs. However, further analysis of severe irAEs in the combined therapy group confirmed that only 12% (95% CI = 0.07–0.16) of them were attributed to OV (Fig. 3C).
We combined Begg’s test and Egger’s test to evaluate whether a publication bias existed. In terms of ORR, both tests did not indicate any publication bias in a single OV treatment group (Begg’s test, Pr > |z| = 0.697, Egger’s test, p > |t| = 0.514) and the combined therapy group (Begg’s test, Pr > |z| = 0.188, Egger’s test, p > |t| = 0.162). As for severe irAEs, no significant publication bias was observed in single OV treatment group (Begg’s test, Pr > |z| = 0.851, Egger’s test, p > |t| = 0.516) and the combined therapy group (Begg’s test, Pr > |z| = 1.000, Egger’s test,
Table 1 Main characteristics of included studies. Study and years
WHO tumor grade
Therapeutic regimen
Endpoints
Score
Perez MC 2018 [11] Chesney J 2018 [12] Senzer NN 2009 [13] Andtbacka RHI 2018 [14] Kaufman HL 2005 [21] Kaufman HL 2006 [22] Hwang TH 2011 [23] Andtbacka RHI 2015 [18] Mahalingam D 2017 [19] Cui C 2016 [16] Andtbacka RH 2015 [15] Galanis E 2012 [20] Ribas A 2017 [30] Chesney J 2018 [31] Puzanov I 2016 [32] Andtbacka RHI 2017 [17] Curti BD 2017 [33] Silk AW 2017 [34]
Unresectable stage IIIB - IV melanoma Unresectable stage IIIB-IVM1c melanoma Unresectable metastatic melanoma Resectable stage IIIB/C-IVM1a melanoma Metastatic melanoma Metastatic melanoma Metastatic melanoma Stage IIIc-IV melanoma. Advanced melanoma Unresectable stage IIIC-IV acral melanoma Stages IIIB-IV melanoma Metastatic melanoma Advanced melanoma Unresectable stages IIIB-IV melanoma Unresectable stage IIIB-IV melanoma Unresectable stage IIIB-IV melanoma Advanced melanoma Advanced melanoma
T-VEC T-VEC T-VEC T-VEC Vaccinia virus expressing B7.1 Vaccinia virus rV-TRICOM Pexastimogene devacirepvec CVA21 Reolysin OrienX010 T-VEC Reolysin T-VEC with perbrolizumab T-VEC with ipilimumab T-VEC with ipilimumab HF10 with ipilimumab CVA21 with ipilimumab CVA21 with pembrolizumab
ORR ORR ORR ORR ORR ORR ORR ORR ORR ORR ORR AE ORR ORR ORR ORR ORR ORR
5 7 6 7 5 5 5 6 6 5 9 6 7 6 6 6 6 6
and and and and
irAEs irAEs irAEs irAEs
and irAEs
and and and and
irAEs irAEs irAEs irAEs
T-VEC, Talimogene Laherparepvec; TRICOM, triad of costimulatory molecules; CVA21, Coxsackievirus A21; ORR; objective response rate; irAEs, immune-related adverse events. 3
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Fig. 2. Forest plot (left) and Begg’s funnel plot (right) of pooled ORR. (A) ORR after oncolytic virotherapy alone. (B) ORR after combined treatment of oncolytic virotherapy with immune checkpoint inhibitors.
adding ICIs will not induce additional toxicity for OV treatment. The notion of oncolytic virotherapy, which is based on principle of a viral agent selectively infecting and destroying cancer cells, originated almost a century ago [5]. Since the first FDA approval of oncolytic virotherapy (T-VEC) for advanced melanoma in 2015, the clinical administration of OV to melanoma patients has expanded drastically [38]. However, which oncolytic virus is the best one keeps controversial. Current clinical response rate did not reveal a dramatic discrepancy among different oncolytic viruses. Thus, more clinical trial data may help us in selecting the best platform from the current available oncolytic viruses. As a single regimen for melanoma, the clinical efficacy of OV can be interfered with many factors. The immunosuppressive factors, particularly immune checkpoint pathways, have the most destructive effect on the progress of immunotherapy. Those suppressive effects will be harmful to the proliferation, differentiation, trafficking, and survival of immune cells [29]. Since the aforementioned ICIs became a standard of care for melanoma, a combination of OV with ICIs is evolving. Advantage of promoting immune response by ICIs should be excellent facilitation for OV development. According to our meta-analysis data of current clinical trials, it is obvious that clinical response rate can be improved dramatically via combination of OV with ICIs. However, whether the tremendous clinical response rate can be translated into survival benefit remains unclarified [39]. Thus, further investigation of single administration and combined therapy of OV with ICIs are essential.
p > |t| = 0.0.459). Severe irAEs attributed to OV in the combined therapy also didn’t show any publication bias (Begg’s test, Pr > |z| = 0.174, Egger’s test, p > |t| = 0.0.05). And each funnel plot of Begg’s test was attached to the forest plot in Figs. 2 and 3. 4. Discussion Although a growing number of advances have been made in the management of melanoma, it remains one of the most lethal cutaneous malignancies. The exploitation of novel therapeutic options is imperative for improving life expectancy and overall quality of life for advanced melanoma patients [36]. Recently, more and more trials of OV, alone or in combination with ICIs, have been launched. The clinical outcome has suggested that these methods can have a dramatic clinical benefit in advanced melanoma patients [37]. However, the clinical response rate and severe irAEs caused by single OV treatment and combined therapy of OV with ICIs have not been systematically reviewed. Based on those therapies, we conducted a comprehensive analysis of single OV treatment and combined therapy of OV with ICIs for advanced melanoma. According to our results, the single OV treatment can generate 25% ORR, and 12% of patients suffer severe irAEs. The combination of OV with ICIs can accelerate ORR to 48%, which means the combined therapy was a more feasible and efficient strategy for management of advanced melanoma. Although the severe irAEs of combined therapy arise from 12% to 39%, the severe irAEs attributed to OV was still restricted to 12%. This process indicates 4
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Fig. 3. Forest plot (left) and Begg’s funnel plot (right) of pooled incidence rate of severe irAEs (AE ≥ 3). (A) Severe irAEs after oncolytic virotherapy alone. (B) Severe irAEs after combined treatment of oncolytic virotherapy with immune checkpoint inhibitors. (C) Severe irAEs attributed to oncolytic virotherapy in combined treatment group.
ligand (PD-L1) expression level, germline genetics, tumor mutation burden (TMB), tumor microsatellite instability, other features of the tumor microenvironment, and the microbiome [42]. Undoubtedly, one way to accelerate the development of combined therapy is to understand OV and ICIs better, while another attractive niche of combined therapy is to genetically engineer OVs with ICIs[43]. This process may reduce the need for single administration of OV and ICIs separately. Selective replication of OV in tumor sites will induce localized expression of ICIs, which in turn could provide a superior safety profile comparing with systematic administration. Although this attractive approach is still futuristic, several groups have demonstrated the markedly better therapeutic efficacy of OV-encoding PD-1antibody
Concerning OV exploration, one major obstacle is that the host innate and adaptive immune system could recognize OV as exogenous antigens. This falsehood recognition reduces the amplification and the migration in local and remote lesions. Accordingly, we can reform oncolytic virus with less immunogenic viral antigens, or conceal them with polymer or carrier cells to circumvent the antiviral immune responses [40,41]. As for ICIs, different ICIs applied with OV probably differ from each other. In our subgroup analysis, the application of Pembrolizumab shows a significantly better ORR comparing with Ipilimumab (data not shown). Thus, exploration of the best ICI is vital for the combination of OV with ICIs. Furthermore, better understanding of biomarkers' evolving landscape predicts beneficial effects, such as PD1 5
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than every singular application [44]. Interestingly, triple combination therapy of OV, immune checkpoint inhibitor, and MEK inhibitor can further augment the clinical response [45]. Better understanding of the alteration of biological markers during the therapeutic process may provide more information for future OV design. Besides, we can’t neglect that a significant number of patients develop severe irAEs in the combined therapy group. Current methods to monitor those severe irAEs including the administration of immunosuppressive agents, mostly glucocorticoids [46]. However, lots of investigators presented that application of those agents may decrease clinical efficacy. A consensus has not been reached on how to balance the beneficial and harmful effects of immunosuppressive agents during immunotherapy; whether irAEs are distinct from conventional autoimmune disease; how manifestation of irAEs is associated with clinical efficacy. With limited knowledge about pathophysiology of irAEs during OV and ICIs, future understanding of mechanistic factors will help clinicians to manage irAEs better [47]. Furthermore, customized immunotherapy strategies are the next trend for both OV and ICIs. Our study has several limitations that should be concerned before a definite conclusion. Firstly, most of included studies in our analysis are phase I or phase II clinical trials. Currently, there are lacking phase III randomized clinical trials in oncolytic virotherapy area. More convincible results and reliable clinical trials are still essential for oncologists to draw a solid conclusion about clinical efficacy and safety for advanced melanoma. Secondly, we choose the ORR to evaluate the final clinical efficacy of OV in advanced melanoma. Whether the improvement of ORR in OV can be transferred to be better survival outcome are still controversial. Finally, we combine all OV without consideration of different virus component and variable OV regimen [48]. In the future, more insight should be applied to discuss those factors separately.
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