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      Beyond PD-1 Immunotherapy in Malignant Melanoma

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          Abstract

          For many years, the standard therapy for malignant melanoma was based mainly on surgical resection. Unfortunately, this treatment is curative only in the early localized stage of this malignancy. The metastatic stage of malignant melanoma still remains a huge therapeutic challenge. Despite the many new therapeutic options that have become available over the last years, there is a constant need for safer and more effective treatment modalities. There has been a dynamic development of various anti-cancer immunotherapies directed against new molecular targets. A number of clinical trials are currently being conducted to confirm their effectiveness and safety. In this review of the literature, we summarize the contemporary knowledge on promising new immunotherapies beyond the currently available treatment options for malignant melanoma, including oncolytic immunotherapy, selective inhibitors of indoleamine 2,3-dioxygenease, anti-PD-(L)1 (programmed death ligand 1) drugs, immune checkpoint protein LAG-3 antibodies, inhibitors of histone deacetylase (HDAC) and inhibitors of B7-H3.

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          ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties.

          B. L. Liu, M. Robinson, Z-Q Han … (2003)
          Herpes simplex virus type-1 (HSV1) in which the neurovirulence factor ICP34.5 is inactivated has been shown to direct tumour-specific cell lysis in several tumour models. Such viruses have also been shown to be safe in Phase I clinical trials by intra-tumoral injection in glioma and melanoma patients. Previous work has used serially passaged laboratory isolates of HSV1 which we hypothesized may be attenuated in their lytic capability in human tumour cells as compared to more recent clinical isolates. To produce ICP34.5 deleted HSV with enhanced oncolytic potential, we tested two clinical isolates. Both showed improved cell killing in all human tumour cell lines tested compared to a laboratory strain (strain 17+). ICP34.5 was then deleted from one of the clinical isolate strains (strain JS1). Enhanced tumour cell killing with ICP34.5 deleted HSV has also been reported by the deletion of ICP47 by the up-regulation of US11 which occurs following this mutation. Thus to further improve oncolytic properties, ICP47 was removed from JS1/ICP34.5-. As ICP47 also functions to block antigen processing in HSV infected cells, this mutation was also anticipated to improve the immune stimulating properties of the virus. Finally, to provide viruses with maximum oncolytic and immune stimulating properties, the gene for human or mouse GM-CSF was inserted into the JS1/34.5-/47- vector backbone. GM-CSF is a potent immune stimulator promoting the differentiation of progenitor cells into dendritic cells and has shown promise in clinical trials when delivered by a number of means. Combination of GM-CSF with oncolytic therapy may be particularly effective as the necrotic cell death accompanying virus replication should serve to effectively release tumour antigens to then induce a GM-CSF-enhanced immune response. This would, in effect, provide an in situ, patient-specific, anti-tumour vaccine. The viruses constructed were tested in vitro in human tumour cell lines and in vivo in mice demonstrating significant anti-tumour effects. These were greatly improved compared to viruses not containing each of the modifications described. In vivo, both injected and non-injected tumours showed significant shrinkage or clearance and mice were protected against re-challenge with tumour cells. The data presented indicate that JS1/ICP34.5-/ICP47-/GM-CSF acts as a powerful oncolytic agent which may be appropriate for the treatment of a number of solid tumour types in man.
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            Randomized, Open-Label Phase II Study Evaluating the Efficacy and Safety of Talimogene Laherparepvec in Combination With Ipilimumab Versus Ipilimumab Alone in Patients With Advanced, Unresectable Melanoma

            Jason Chesney, Igor Puzanov, Frances A Collichio … (2017)
            Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, ≤ 4 mL × 10 6 plaque-forming units/mL; after 3 weeks, ≤ 4 mL × 10 8 plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. Results One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone (n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response (odds ratio, 2.9; 95% CI, 1.5 to 5.5; P = .002). Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade ≥ 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. Conclusion The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.
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              Local and distant immunity induced by intralesional vaccination with an oncolytic herpes virus encoding GM-CSF in patients with stage IIIc and IV melanoma.

              Howard L. Kaufman, Dae Kim, Gail DeRaffele … (2010)
              An oncolytic herpes simplex virus engineered to replicate selectively in tumor cells and to express granulocyte-macrophage colony-stimulating factor (GMCSF) was tested as a direct intralesional vaccination in melanoma patients. The work reported herein was performed to better characterize the effect of vaccination on local and distant antitumor immunity. Metastatic melanoma patients with accessible lesions were enrolled in a multicenter 50-patient phase II clinical trial of an oncolytic herpesvirus encoding GM-CSF (Oncovex(GM-CSF)). An initial priming dose of 10(6) pfu vaccine was given by intratumoral injection, followed by 10(8) pfu every 2 weeks to 24 total doses. Peripheral blood and tumor tissue were collected for analysis of effector T cells, CD4(+)FoxP3(+) regulatory T cells (Treg), CD8(+)FoxP3(+) suppressor T cells (Ts), and myeloid-derived suppressive cells (MDSC). Phenotypic analysis of T cells derived from tumor samples suggested distinct differences from peripheral blood T cells. There was an increase in melanomaassociated antigen recognized by T cells (MART-1)-specific T cells in tumors undergoing regression after vaccination compared with T cells derived from melanoma patients not treated with vaccine. There was also a significant decrease in Treg and Ts cells in injected lesions compared with noninjected lesions in the same and different melanoma patients. Similarly MDSC were increased in melanoma lesions but underwent a significant decrease only in vaccinated lesions. Melanoma patients present with elevated levels of Tregs, Ts, and MDSC within established tumors. Direct injection of Oncovex(GM-CSF) induces local and systemic antigen-specific T cell responses and decreases Treg, Ts, and MDSC in patients exhibiting therapeutic responses.
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                Author and article information

                Contributors
                Adam Reich:
                ORCID: http://orcid.org/0000-0002-5573-1754
                adi_medicalis@go2.pl
                Journal
                Journal ID (nlm-ta): Dermatol Ther (Heidelb)
                Journal ID (iso-abbrev): Dermatol Ther (Heidelb)
                Title: Dermatology and Therapy
                Publisher: Springer Healthcare (Cheshire )
                ISSN (Print): 2193-8210
                ISSN (Electronic): 2190-9172
                Publication date (Electronic): 29 March 2019
                Publication date PMC-release: 29 March 2019
                Publication date Collection: June 2019
                Volume: 9
                Issue: 2
                Pages: 243-257
                Affiliations
                [1 ]ISNI 0000 0001 2154 3176, GRID grid.13856.39, Department of Dermatology, , University of Rzeszow, ; Rzeszów, Poland
                [2 ]ISNI 0000 0000 9805 3178, GRID grid.7005.2, Wroclaw University of Science and Technology, ; Wrocław, Poland
                Author information
                http://orcid.org/0000-0002-5573-1754
                Article
                Publisher ID: 292
                DOI: 10.1007/s13555-019-0292-3
                PMC ID: 6522569
                PubMed ID: 30927248
                SO-VID: 4f30f953-5747-4d56-bb6d-45a03d5909ac
                Copyright © © The Author(s) 2019
                History
                Date received : 26 January 2019
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © The Author(s) 2019

                ScienceOpen disciplines: Dermatology
                Keywords: atezolizumab,epacadostat,immunotherapy,indoximod,lag3 inhibitors,malignant melanoma,oncolytic immunotherapy,talimogene laherparepvec
                Data availability:
                ScienceOpen disciplines: Dermatology
                Keywords: atezolizumab, epacadostat, immunotherapy, indoximod, lag3 inhibitors, malignant melanoma, oncolytic immunotherapy, talimogene laherparepvec

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