Treatment Of Unresectable Melanoma Research Articles

Beyond Immunotherapy: Seizing the Momentum of Oncolytic Viruses in the Ideal Platform of Skin Cancers.

Simple SummaryOncolytic viruses (OVs) are the most innovative and promising class of intratumoral immunotherapies. The broad immunogenic landscape of skin cancer, accessible to intralesional infusion and available for direct response assessment, seems to be an ideal platform to expand the role of OVs. The established efficacy of immune checkpoint inhibitors (ICIs) in this field and their hypothetical synergy with OVs have generated expectations for their combined use beyond the current immunotherapy achievements. Despite the recent negative phase III results of the MASTERKEY-265 trial for the combination of T-VEC plus pembrolizumab, such projects, including different ICIs and various natural or genetically modified OVs, continue to attract considerable interest, with numerous clinical trials underway for all the subtypes of skin cancer. To date, the majority of studies confirm the safety of tested OVs in patients with advanced skin cancers but cannot clearly prove whether these viral agents add any therapeutic benefit in the standard ICI-based approach. The aim of this overview is to present the main findings related to the examined OV-containing regimens at pre-clinical and clinical levels, and to discuss the previous failures as well as the future perspectives of oncolytic virotherapy.Despite the durable remissions induced by ICIs and targeted therapies in advanced melanoma and non-melanoma skin cancers, both subtypes usually relapse. Many systematic therapies have been tested to increase efficacy and delay relapse in ICIs, but their success has been limited. Due the feasibility of this approach, skin cancers have become the ideal platform for intralesional infusions of many novel agents, including oncolytic viruses (OVs). Talimogene laherparepvec (T-VEC) was the first FDA-approved OV for the treatment of unresectable melanoma and this virus opened up further potential for the use of this class of agents, especially in combination with ICIs, in order to achieve deeper and longer immune-mediated responses. However, the recently announced phase III MASTERKEY-265 trial was not able to confirm that the addition of T-VEC to pembrolizumab treatment improves progression-free or overall survival over the use of pembrolizumab alone. Despite these results, numerous studies are currently active, evaluating T-VEC and several other OVs as monotherapies or in regimens with ICIs in different subtypes of skin cancer. This overview provides a comprehensive update on the evolution status of all available OVs in melanoma and non-melanoma skin cancers and summarizes the more interesting preclinical findings, the latest clinical evidence, and the future insights in relation to the expected selective incorporation of some of these OVs into oncological practice.

Novel regional therapies in the treatment of unresectable melanoma

Novel regional therapies in the treatment of unresectable melanoma

Abstract A068: Determinants of efficacy in cancer immunovirotherapy

Abstract Replicating oncolytic viruses (OVs) are emerging as a promising therapeutic approach for different tumor entities. Positive data from numerous clinical studies are accumulating and as a first-in-class oncolytic herpes virus encoding GM-CSF, Talimogene Laherparepvec (T-VEC), has been approved for treatment of unresectable melanoma by the U.S. Food and Drug Administration at the end of 2015. Although it has been recognized that combinations of OVs with different immunomodulators can significantly improve therapeutic outcome, understanding of immune effector mechanisms determining success of a particular approach remains limited, restricting the development of rational combination strategies. In this study we aimed to determine the most beneficial immunomodulation strategies for combination with oncolytic measles virus (MeV). Furthermore, we performed a comprehensive analysis of anti-tumor immune effector mechanisms associated with response to pinpoint mechanisms crucial for therapeutic efficacy. We developed MeV Schwarz vaccine strain vectors (MeVac) encoding different immunomodulators to target the main phases in establishment of an anti-tumor immune response: GM-CSF - to enhance maturation of antigen-presenting cells, an IL-12 fusion protein (FmIL-12) and IP-10 - to enhance immune effector cell responses, antibodies against CTLA-4 and PD-L1 and a soluble form of CD80 - to counteract immunosuppression in the tumor microenvironment. Therapeutic efficacy of the novel vectors was evaluated in the fully immunocompetent murine colon adenocarcinoma model MC38cea. MeVac encoding anti-PD-L1 and FmIL-12, respectively, were identified as the most effective therapeutics. Notably, MeVac encoding FmIL-12 showed a superior therapeutic efficacy, achieving 90% complete remissions of established tumors. Animals treated with the immunomodulatory MeVac vectors rejected secondary tumor engraftments, indicating establishment of protective anti-tumor immunity. Higher IFN-γ production upon restimulation of splenocytes with tumor cells in vitro was observed for animals treated with MeVac FmIL-12 in comparison to treatment with MeVac anti-PD-L1 and a control vector encoding constant region of antibody (MeVac IgG1-Fc), indicating establishment of a more potent memory response. Intratumoral cytokine profiling with cytokine bead arrays revealed upregulation of the effector cytokines IFN-γ and TNF-α after treatment with MeVac FmIL-12. A massive decrease in intratumoral natural killer (NK) cell counts and an increase of activation marker CD69 expression on NK cells as well as an increase in T cell amount was observed in flow cytometry analysis one day after treatment with MeVac FmIL-12. This indicates early direct activation of these lymphocyte subsets through direct IL-12 signaling. An increase in intratumoral T cells and a decrease in NK cells and activated cytotoxic T cells (CD8+CD69+) was observed four days after the last treatment with both MeVac anti-PD-L1 and MeVac IgG1-Fc, with slightly more pronounced effects in the MeVac anti-PD-L1 group. This suggests that MeVac vectors per se activate T and NK cell responses, which can further be supported with PD-L1 blockade. This study establishes MeVac encoding FmIL-12 as a potent immunomodulatory oncolytic vector and provides insights into its mechanisms of action, thereby creating a basis for further rational vector modifications to translate immunomodulatory MeV into clinical application. Citation Format: Rūta Veinalde, Christian Grossardt, Marie-Claude Bourgeois-Daigneault, Christof von Kalle, Dirk Jaeger, Guy Ungerechts, Christine E. Engeland. Determinants of efficacy in cancer immunovirotherapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A068.

Metastatic Melanoma: Insights Into the Evolution of the Treatments and Future Challenges.

Melanoma is the deadliest form of skin cancer. While associated survival prognosis is good when diagnosed early, it dramatically drops when melanoma progresses into its metastatic form. Prior to 2011, the favored therapies include interleukin-2 and chemotherapies, regardless of their low efficiency and their toxicity. Following key biological findings, two new types of therapy have been approved. First, there are the targeted therapies, which rely on small molecule B-Raf and MEK inhibitors and allow the treatment of patients with B-Raf mutated melanoma. Second, there are the immunotherapies, with anti-CTLA-4 and anti-PD-1 antibodies that are used for patients harboring a B-Raf wild-type status. Both approaches have significantly improved patient survival, compared with alkylating agents, in the treatment of unresectable melanoma. Herein, we review the evolution of the treatment of melanoma starting from early discoveries to current therapies. A focus will be provided on drug discovery, synthesis, and mode of action of relevant drugs and the future directions of the domain to overcome the emergence of the resistance events.

A rational approach to dose optimisation of pembrolizumab using cost analysis and pharmacokinetic modelling and simulation.

9547Background: Pembrolizumab is a PDL1 inhibitor licensed for the treatment of unresectable melanoma at a dose of 2mg/kg every three weeks. A population pharmacokinetic model based on two compartm...

Interferon-α Combined with Radiotherapy in the Treatment of Unresectable Melanoma

A case of recurrent and twice resected sinonasal melanoma is presented. The large recurrent tumor was found to regress by a concurrent combination of 6660 cGy photon radiation and subcutaneous interferon-α injections given for a period of 8 weeks. Possible mechanisms of potentiation between interferon and radiation are discussed. The unexpected result in this case report raises interesting questions about this treatment combination.