Journal Articles

Experimental Immunotherapy

Preclinical and clinical cancer immunotherapy approaches

Reprogramming the murine colon cancer microenvironment using lentivectors encoding shRNA against IL-10 as a component of a potent DC-based chemoimmunotherapy

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BACKGROUND: The excessive amounts of immunosuppressive factors present in a tumor microenvironment (TME) reduce the effectiveness of cancer vaccines. The main objective of our research was to improve the effectiveness of dendritic cell (DC)-based immunotherapy or chemoimmunotherapy composed of cyclophosphamide (CY) and DCs by application of lentivectors encoding shRNA specific to IL-10 (shIL10 LVs) in murine colon carcinoma MC38 model. METHODS: The efficacy of shIL10 LVs in silencing of IL-10 expression was measured both in vitro and in vivo using Real-Time PCR and ELISA assays. In addition, the influence of intratumorally inoculated lentivectors on MC38 tumor microenvironment was examined using flow cytometry method. The effect of applied therapeutic schemes was determined by measurement of tumor growth inhibition and activation state of local and systemic immune response. RESULTS: We observed that intratumorally inoculated shIL10 LVs transduced tumor and TME-infiltrating cells and reduced the secretion of IL-10. Application of shIL10 LVs for three consecutive weeks initiated tumor growth inhibition, whereas treatment with shIL10 LVs and BMDC/TAg did not enhance the antitumor effect. However, when pretreatment with CY was introduced to the proposed scheme, we noticed high MC38 tumor growth inhibition accompanied by reduction of MDSCs and Tregs in TME, as well as activation of potent local and systemic Th1-type antitumor response. CONCLUSIONS: The obtained data shows that remodeling of TME by shIL10 LVs and CY enhances DC activity and supports them during regeneration and actuation of a potent antitumor response. Therefore, therapeutic strategies aimed at local IL-10 elimination using lentiviral vectors should be further investigated in context of combined chemoimmunotherapies.

Author Info: (1) Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, ul. R. Weigla 12, 53-114, Wroclaw, Poland. joanna@iitd.pan.wroc.pl. (2) Hirszfeld Institute of Immunology

Author Info: (1) Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, ul. R. Weigla 12, 53-114, Wroclaw, Poland. joanna@iitd.pan.wroc.pl. (2) Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, ul. R. Weigla 12, 53-114, Wroclaw, Poland. (3) Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, ul. R. Weigla 12, 53-114, Wroclaw, Poland. (4) Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, ul. R. Weigla 12, 53-114, Wroclaw, Poland. (5) Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, ul. R. Weigla 12, 53-114, Wroclaw, Poland.

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Indoleamine 2,3-dioxygenase provides adaptive resistance to immune checkpoint inhibitors in hepatocellular carcinoma

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Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Immune checkpoint blockade with anti-CTLA-4 and anti-PD-1 antibodies has shown promising results in the treatment of patients with advanced HCC. The anti-PD-1 antibody, nivolumab, is now approved for patients who have had progressive disease on the current standard of care. However, a subset of patients with advanced HCC treated with immune checkpoint inhibitors failed to respond to therapy. Here, we provide evidence of adaptive resistance to immune checkpoint inhibitors through upregulation of indoleamine 2,3-dioxygenase (IDO) in HCC. Anti-CTLA-4 treatment promoted an induction of IDO1 in resistant HCC tumors but not in tumors sensitive to immune checkpoint blockade. Using both subcutaneous and hepatic orthotopic models, we found that the addition of an IDO inhibitor increases the efficacy of treatment in HCC resistant tumors with high IDO induction. Furthermore, in vivo neutralizing studies demonstrated that the IDO induction by immune checkpoint blockade was dependent on IFN-gamma. Similar findings were observed with anti-PD-1 therapy. These results provide evidence that IDO may play a role in adaptive resistance to immune checkpoint inhibitors in patients with HCC. Therefore, inhibiting IDO in combination with immune checkpoint inhibitors may add therapeutic benefit in tumors which overexpress IDO and should be considered for clinical evaluation in HCC.

Author Info: (1) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA

Author Info: (1) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. (2) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea. (3) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. (4) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. (5) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. (6) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. (7) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. (8) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. (9) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. (10) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. tim.greten@nih.gov. National Cancer Institute, Center for Cancer Research, Liver Cancer Program, Bethesda, USA. tim.greten@nih.gov.

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An Anti-CLL-1 Antibody-Drug Conjugate for the Treatment of Acute Myeloid Leukemia

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PURPOSE: The treatment of acute myeloid leukemia (AML) has not significantly changed in 40 years. Cytarabine and anthracyclinebased chemotherapy induction regimens (7 + 3) remain the standard of care, and most patients have poor long-term survival. The re-approval of Mylotarg, an anti-CD33-calicheamicin antibody-drug conjugate (ADC), has demonstrated ADCs as a clinically validated option to enhance the effectiveness of induction therapy. We are interested in developing a next generation ADC for AML to improve upon the initial success of Mylotarg. EXPERIMENTAL DESIGN: The expression pattern of CLL-1 and its hematopoietic potential were investigated. A novel anti-CLL-1-ADC, with a highly potent pyrrolobenzodiazepine (PBD) dimer conjugated through a self-immolative disulfide linker, was developed. The efficacy and safety profiles of this ADC were evaluated in mouse xenograft models and in cynomolgus monkeys. RESULTS: We demonstrate that CLL-1 shares similar prevalence and trafficking properties that make CD33 an excellent ADC target for AML, but lacks expression on hematopoietic stem cells that hampers current CD33 targeted ADCs. Our anti-CLL-1-ADC is highly effective at depleting tumor cells in AML xenograft models and lacks target independent toxicities at doses that depleted target monocytes and neutrophils in cynomolgus monkeys. CONCLUSIONS: Collectively, our data suggest that an anti-CLL-1-ADC has the potential to become an effective and safer treatment for AML in humans, by reducing and allowing for faster recovery from initial cytopenias than the current generation of ADCs for AML.

Author Info: (1) Translational Oncology & Cancer Signaling, Genentech Inc. (2) Translational Oncology, Genentech, Inc. (3) In Vivo Pharmacology, Genentech. (4) Research and Early Development, Genentech, Inc

Author Info: (1) Translational Oncology & Cancer Signaling, Genentech Inc. (2) Translational Oncology, Genentech, Inc. (3) In Vivo Pharmacology, Genentech. (4) Research and Early Development, Genentech, Inc. (5) Translational Oncology, Genentech, Inc. (6) Research and Early Development, Genentech, Inc. (7) Research and Early Development, Genentech, Inc. (8) Antibody Engineering, Genentech, Inc. (9) Antibody Engineering, Genentech, Inc. (10) Pathology, Genentech. (11) Genentech, Inc. (12) Safety Assessment, Genentech, Inc. (13) Research and Early Development, Genentech, Inc. (14) Safety Assessment, Amgen, Inc. (15) Oncology Clinical Science, Genentech Inc. (16) Genentech, Inc. (17) Safety Assessment, Genentech. (18) Genentech, Inc. (19) Research and Early Development, Genentech, Inc. polson@gene.com.

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Glycogen Synthase Kinase 3 Inhibition Lowers PD-1 Expression, Promotes Long-term Survival and Memory Generation in Antigen-specific CAR-T cells

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Successful remission in hematological cancers by CAR-T cell immunotherapy has yet to be replicated in solid tumors like GBM. A significant impediment of CAR-T immunotherapy in solid tumors is poor exposure of T cells to tumor antigens resulting in suboptimal CAR-T cell activation, which ultimately fails to induce a robust anti-tumor immune response. Costimulatory moieties in advanced-generation CARs, along with additional IL2 therapy has been shown to be insufficient to overcome this hurdle and have its cytotoxic limitations. GSK3 is constitutively active in naive T cells and is transiently inactivated during T cell activation resulting in rapid T cell proliferation. Pharmacologic inhibition of GSK3 in GBM-specific CAR-T cells reduced FasL expression, increased T cell proliferation and reduced exhaustion by lowering PD-1 levels resulting in the development of CAR-T effector memory phenotype. Treatment with GSK3-inhibited CAR-T cells resulted in 100% tumor elimination during the tumor-rechallenge experiment in GBM-bearing animals and increased accumulation of memory CAR-T cells in secondary lymphoid organs. These adjuvant-like effects of GSK3 inhibition on activated CAR-T cells may be a valuable adjunct to a successful implementation of CAR-T immunotherapy against GBM and other solid tumors.

Author Info: (1) Brain Tumor Laboratory, Roger Williams Medical Center, Providence, RI, USA; Department of Neurosurgery, Alpert School of Medicine, Brown University, Providence, RI, USA. Electronic address

Author Info: (1) Brain Tumor Laboratory, Roger Williams Medical Center, Providence, RI, USA; Department of Neurosurgery, Alpert School of Medicine, Brown University, Providence, RI, USA. Electronic address: sadhak_sengupta@brown.edu. (2) Department of Surgery, Roger Williams Medical Center, Providence, RI, USA; Department of Surgery, Boston University School of Medicine, Boston, MA, USA. (3) Brain Tumor Laboratory, Roger Williams Medical Center, Providence, RI, USA. (4) Brain Tumor Laboratory, Roger Williams Medical Center, Providence, RI, USA; Department of Neurosurgery, Alpert School of Medicine, Brown University, Providence, RI, USA.

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Combination therapy improves immune response and prognosis in patients with advanced oral mucosal melanoma: A clinical treatment success

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OBJECTIVE: This study was undertaken to analyze disease response and immune response to assess treatment effectiveness and success in patients with advanced oral mucosal melanoma treated with cytokines injection, cryosurgery, and adoptive cell transfer therapy. STUDY DESIGN: Ten patients were enrolled in the study, and the relevant characteristics and immunologic differences were evaluated. RESULTS: All patients achieved an objective clinical response according to the Response Evaluation Criteria in Solid Tumors, including 7 cases of continuing complete remission (55, 27, 87 + , 58(+), 58 + , 45 + , and 37 + months) and 3 cases of partial remission (30, 12, and 9 months). Five responders are currently alive. After combination therapy, we observed that the proportion of CD3+ lymphocytes and the secretion of interferon-gamma increased, whereas interleukin-10 decreased. In the assay of improved cytokine-induced killer cells, CD4+CD25+ regulatory T cells declined, and natural killer cells upregulated. Meanwhile, the proliferation rate of in vitro cultured improved cytokine-induced killer cells improved after courses of therapy. CONCLUSIONS: Combination therapy of cytokine injection, cryosurgery, and transfer of improved cytokine-induced killer cells may be a promising approach for patients with oral mucosal melanoma.

Author Info: (1) Department of Oral and Maxillofacial Surgery, Clinical Laboratory, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology

Author Info: (1) Department of Oral and Maxillofacial Surgery, Clinical Laboratory, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China. (2) Department of Oral and Maxillofacial Surgery, Clinical Laboratory, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China. (3) Department of Oral and Maxillofacial Surgery, Clinical Laboratory, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China. (4) Department of Oral and Maxillofacial Surgery, Clinical Laboratory, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China. (5) Department of Oral and Maxillofacial Surgery, Clinical Laboratory, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China. Electronic address: Wanghua9@mail.sysu.edu.cn.

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TLS11a Aptamer/CD3 Antibody Anti-Tumor System for Liver Cancer

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New therapeutic approaches are needed for hepatocellular carcinoma (HCC), which is the most common primary malignancy of the liver. Bispecific T-cell engagers (BiTE) can effectively redirect T cells against tumors and show a strong anti-tumor effect. However, the potential immunogenicity, complexity, and high cost significantly limit their clinical application. In this paper, we used the hepatoma cells-specific aptamer TLS11a and anti-CD3 for to establish an aptamer/antibody bispecific system (AAbs), TLS11a/CD3, which showed advantages over BiTE and can specifically redirect T cells to lyse tumor cells. TLS11a-SH and anti-CD3-NH2 were crosslinked with sulfosuccinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (sulfo-SMCC). T cell activation, proliferation, and cytotoxicity of TLS11a/CD3 were analyzed by flow cytometry. Cytokine array was used to detect cytokine released from activated T cells. Hepatoma xenograft model was used to monitor the tumor volume and survival. TLS11a/CD3 could specifically bind hepatoma cells (H22) and T cells, activated T cells to mediate antigen-specific lysis of H22 cells in vitro, and effectively inhibited the growth of implanted H22 tumors as well as prolonged mice survival. TLS11a/CD3 could simultaneously target hepatoma cells and T cells, specifically guide T cells to kill tumor cells, and enhance the anti-tumor effect of T cells both in vitro and in vivo.

Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13)

Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13)

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Stereotactic radiosurgery and immunotherapy in melanoma brain metastases: Patterns of care and treatment outcomes

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PURPOSE: Preclinical studies have suggested that radiation therapy (RT) enhances antitumor immune response and can act synergistically when administered with immunotherapy. However, this effect in melanoma brain metastasis is not well studied. We aim to explore the clinical effect of combining RT and immunotherapy in patients with melanoma brain metastasis (MBM). MATERIALS AND METHODS: Patients with MBM between 2011 and 2013 were obtained from the National Cancer Database. Patients who did not have identifiable sites of metastasis and who did not receive RT for the treatment of their MBM were excluded. Patients were separated into cohorts that received immunotherapy versus patients who did not. Univariable and multivariable analyses were performed using Cox model to determine predictors of OS. Kaplan-Meier method was used to compare OS. Univariable and multivariable analyses using logistic regression model were used to determine the factors predictive for the use of immunotherapy. Propensity score analysis was used to account for differences in baseline patient characteristics between the RT and RT+immunotherapy groups. Significance was defined as a P value

Author Info: (1) Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, United States. (2) Department of Radiation Oncology, Washington University School of Medicine, Saint

Author Info: (1) Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, United States. (2) Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, United States. (3) Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, United States. (4) Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, United States. (5) Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, United States. (6) Department of Neurosurgery, Washington University School of Medicine, Saint Louis, United States. (7) Department of Neurosurgery, Washington University School of Medicine, Saint Louis, United States. (8) Department of Neurosurgery, Washington University School of Medicine, Saint Louis, United States. (9) Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, United States. (10) Department of Neurosurgery, Washington University School of Medicine, Saint Louis, United States. (11) Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, United States. (12) Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, United States. Electronic address: cabraham@wustl.edu.

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Fusogenic Viruses in Oncolytic Immunotherapy

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Oncolytic viruses are under intense development and have earned their place among the novel class of cancer immunotherapeutics that are changing the face of cancer therapy. Their ability to specifically infect and efficiently kill tumor cells, while breaking immune tolerance and mediating immune responses directed against the tumor, make oncolytic viruses highly attractive candidates for immunotherapy. Increasing evidence indicates that a subclass of oncolytic viruses, which encodes for fusion proteins, could outperform non-fusogenic viruses, both in their direct oncolytic potential, as well as their immune-stimulatory properties. Tumor cell infection with these viruses leads to characteristic syncytia formation and cell death due to fusion, as infected cells become fused with neighboring cells, which promotes intratumoral spread of the infection and releases additional immunogenic signals. In this review, we discuss the potential of fusogenic oncolytic viruses as optimal candidates to enhance immunotherapy and initiate broad antitumor responses. We provide an overview of the cytopathic mechanism of syncytia formation through viral-mediated expression of fusion proteins, either endogenous or engineered, and their benefits for cancer therapy. Growing evidence indicates that fusogenicity could be an important feature to consider in the design of optimal oncolytic virus platforms for combinatorial oncolytic immunotherapy.

Author Info: (1) 2nd Department of Internal Medicine, Klinikum rechts der Isar, Technical University of Munich, 81675 Munchen, Germany. teresa.krabbe@tum.de. (2) 2nd Department of Internal Medicine, Klinikum

Author Info: (1) 2nd Department of Internal Medicine, Klinikum rechts der Isar, Technical University of Munich, 81675 Munchen, Germany. teresa.krabbe@tum.de. (2) 2nd Department of Internal Medicine, Klinikum rechts der Isar, Technical University of Munich, 81675 Munchen, Germany. jennifer.altomonte@tum.de.

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Size-Dependent Segregation Controls Macrophage Phagocytosis of Antibody-Opsonized Targets

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Macrophages protect the body from damage and disease by targeting antibody-opsonized cells for phagocytosis. Though antibodies can be raised against antigens with diverse structures, shapes, and sizes, it is unclear why some are more effective at triggering immune responses than others. Here, we define an antigen height threshold that regulates phagocytosis of both engineered and cancer-specific antigens by macrophages. Using a reconstituted model of antibody-opsonized target cells, we find that phagocytosis is dramatically impaired for antigens that position antibodies >10 nm from the target surface. Decreasing antigen height drives segregation of antibody-bound Fc receptors from the inhibitory phosphatase CD45 in an integrin-independent manner, triggering Fc receptor phosphorylation and promoting phagocytosis. Our work shows that close contact between macrophage and target is a requirement for efficient phagocytosis, suggesting that therapeutic antibodies should target short antigens in order to trigger Fc receptor activation through size-dependent physical segregation.

Author Info: (1) Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA; UC Berkeley/UC San Francisco Graduate Group in Bioengineering, Berkeley, CA 94720, USA. (2)

Author Info: (1) Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA; UC Berkeley/UC San Francisco Graduate Group in Bioengineering, Berkeley, CA 94720, USA. (2) Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA; UC Berkeley/UC San Francisco Graduate Group in Bioengineering, Berkeley, CA 94720, USA. (3) Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA. (4) Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA. (5) Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA. (6) Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA; UC Berkeley/UC San Francisco Graduate Group in Bioengineering, Berkeley, CA 94720, USA; Division of Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. Electronic address: fletch@berkeley.edu.

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It is finally time for adjuvant therapy in melanoma

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Although melanoma is amenable to early detection, there has been no decline in the mortality rate of this disease and the prognosis of patients with high-risk primary melanoma or with macroscopic nodal involvement remains poor. The best option for patients with higher-risk melanoma is to receive effective adjuvant therapy in order to reduce their chances of recurrence. Multiple systemic therapeutic agents have been tested as adjuvant therapy for melanoma with durable benefits seen only with interferon- to date. More recently ipilimumab at the high dose of 10mg/kg has shown a significant improvement in terms of Relapse free survival and Overall survival for stage III melanoma patients but at a significant cost in terms of immune-related toxicities. More recently, novel treatment options have emerged. The results from the latest trials with immunotherapy (PD-1 inhibitors) and molecular targeted therapy (BRAF inhibitor+MEK inhibitor) have revolutionized the management of adjuvant treatment for melanoma. As the results from these trials will mature in the next years, a change in the landscape of adjuvant treatment for melanoma is expected, resulting in new challenges in treatment decisions such as optimizing patients' selection through predictive and prognostic biomarkers, and management of treatment related adverse events, in particular immune related toxicities.

Author Info: (1) Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F. Magrassi", Universita degli Studi della Campania "Luigi Vanvitelli", Via S. Pansini 5, Napoli 80131, Italy

Author Info: (1) Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F. Magrassi", Universita degli Studi della Campania "Luigi Vanvitelli", Via S. Pansini 5, Napoli 80131, Italy. (2) Dermatologia e Venerologia, Dipartimento di salute mentale e fisica e medicina riabilitativa, Universita degli Studi della Campania "Luigi Vanvitelli", Via S. Pansini 5, Napoli 80131, Italy. (3) Dermatologia e Venerologia, Dipartimento di salute mentale e fisica e medicina riabilitativa, Universita degli Studi della Campania "Luigi Vanvitelli", Via S. Pansini 5, Napoli 80131, Italy. (4) Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F. Magrassi", Universita degli Studi della Campania "Luigi Vanvitelli", Via S. Pansini 5, Napoli 80131, Italy. (5) Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F. Magrassi", Universita degli Studi della Campania "Luigi Vanvitelli", Via S. Pansini 5, Napoli 80131, Italy. (6) Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F. Magrassi", Universita degli Studi della Campania "Luigi Vanvitelli", Via S. Pansini 5, Napoli 80131, Italy. (7) Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F. Magrassi", Universita degli Studi della Campania "Luigi Vanvitelli", Via S. Pansini 5, Napoli 80131, Italy. Electronic address: teresa.troiani@unicampania.it.

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