In-transit metastatic cutaneous melanoma: current management and future directions

Management of in-transit melanoma encompasses a variety of possible treatment pathways and modalities. Depending on the location of disease, number of lesions, burden of disease and patient preference and characteristics, some treatments may be more beneficial than others. After full body radiographic staging is performed to rule out metastatic disease, curative therapy may be performed through surgical excision, intraarterial regional perfusion and infusion therapies, intralesional injections, systemic therapies or various combinations of any of these. While wide excision is limited in indication to superficial lesions that are few in number, the other listed therapies may be effective in treating unresectable disease. Where intraarterial perfusion based therapies have been shown to successfully treat extremity disease, injectable therapies can be used in lesions of the head and neck. Although systemic therapies for in-transit melanoma have limited specific data to support their primary use for in-transit disease, there are patients who may not be eligible for any of the other options, and current clinical trials are exploring the use of concurrent and sequential use of regional and systemic therapies with early results suggesting a synergistic benefit for oncologic response and outcomes.

     

Effective treatment of multiple unresectable skin melanoma metastases by electrochemotherapy

Multiple unresectable melanoma skin metastases pose a treatment problem, especially in centers where isolated limb perfusion is not available. We report the case of a 59-year-old woman who developed multiple small unresectable cutaneous melanoma metastases on the thigh after her lower limb was amputated. Electrochemotherapy with bleomycin resulted in good local control of the disease, with a complete response of the treated melanoma nodules (224 tumor nodules) after 4 treatment sessions. Comparison between electrochemotherapy using repetition frequency of the applied electric pulses of 1 Hz and 5 kHz demonstrated equal antitumor effectiveness. Electrochemotherapy with intravenous bleomycin can also be used as a treatment of choice for local control of multiple unresectable cutaneous melanoma skin metastases.     

The use of Fas Ligand,TRAIL and Bax in gene therapy of prostate cancer

Prostate cancer is the second leading cause of cancer death in the United States. Treatment options for confined disease are generally successful in prolonging life but long-term cures (10-15 years) are elusive for the majority of patients. The prognosis for advanced extra-capsular prostate cancer is grim. However, we are now entering the era of gene therapy options for treatment of prostate cancer. The human genome project coupled with genomics and protemics are providing information that will lead to selection of genes for treatment of prostate cancer. The problem is the science of delivery lags behind knowledge of gene function. Thus, it is important to develop therapies that do not require delivery to 100% of tumor cells but which nevertheless kills the entire cancer by virtue of the bystander effect or other means. This review covers the use, in gene therapy, of apoptotic inducing molecules such as Fas Ligand, and TRAIL which are believed to induce bystander killing activity and Bax which also may function in a similar way.     

Harnessing the immune system for the treatment of melanoma: current status and future prospects

When malignant melanoma is diagnosed early, surgical resection is the intervention of choice and is often curative, but many patients present with unresectable disease at later stages. Due to its complex etiology paired with well-documented chemoresistance and high metastatic potential, patients with advanced melanoma had a poor prognosis, and the treatment of this disease remained unsatisfactory for many years. Recently, targeted therapy, immune checkpoint inhibition, or combinatory approaches have revolutionized the therapeutic options of melanoma allowing considerable improvement in disease control and survival. In this review we will summarize these novel therapeutic strategies with particular focus on combinatory immunotherapies and further discuss recent data derived from immunogenomic studies and potential options to improve the therapeutic efficacy of immune modulatory approaches.     

Electrochemotherapy of skin metastases from malignant melanoma: a PRISMA-compliant systematic review

Clinical & Experimental Metastasis - The main treatment of MM metastases are systemic therapies, surgery, limb perfusion, and intralesional talimogene laherparepvec. Electrochemotherapy (ECT)...     

中性粒细胞/淋巴细胞比值对晚期肝细胞癌FOLFOX肝动脉灌注化疗近期疗效的影响

目的:探讨中性粒细胞/淋巴细胞比值（NLR）对晚期肝细胞癌（HCC）动脉灌注化疗近期疗效的影响。方法:回顾性收集分析2017年5月~2019年3月使用FOLFOX肝动脉灌注化疗的晚期HCC患者共92例。通过CT或MR比较患者每个治疗周期后肿瘤局部反应,通过相关检查结果及临床症状观察患者疗效及肝动脉灌注安全性等。结果:根据mRECIST标准对肝内病灶进行评价,NLR＜4.0组患者的客观缓解率显著高于NLR≥4.0组患者（41.5% vs 17.9%, P=0.016）。NLR＜4.0组患者的疾病控制率显著优于NLR≥4.0组（52.8% vs 28.2%;P=0.018）。对于肝内病灶,NLR＜4.0组的中位PFS（月）较NLR≥4.0组更长（6.1 vs 4.1, P=0.013）。针对全身肿瘤病灶进行疗效评估,NLR＜4.0组和NLR≥4.0组之间的中位PFS（月）也有显著差异（4.3 vs 3.1, P=0.022）。结论:使用FOLFOX肝动脉灌注治疗HCC安全性及有效性均较好,且NLR是预测HCC灌注化疗术后疗效的指标,术前高NLR的HCC患者治疗后PFS较短。     

Mitf-Mdel,a novel melanocyte/melanoma-specific isoform of microphthalmia-associated transcription factor-M,as a candidate biomarker for melanoma

Background  

Melanoma incidence is on the rise and advanced melanoma carries an extremely poor prognosis. Treatment options, including chemotherapy and immunotherapy, are limited and offer low response rates and transient efficacy. Thus, identification of new melanocyte/melanoma antigens that serve as potential novel candidate biomarkers in melanoma is an important area for investigation.     

Talimogene Laherparepvec: A Review in Unresectable Metastatic Melanoma

Talimogene laherparepvec (Imlygic?) is a first-in-class oncolytic viral immunotherapy derived from herpes simplex virus type 1, which has been genetically modified to increase tumour selectivity and stimulate antitumour immune response. This article reviews the pharmacological properties of intralesional talimogene laherparepvec and its clinical efficacy and tolerability in patients with unresectable metastatic melanoma. In the phase III OPTiM trial, talimogene laherparepvec was more effective than subcutaneous human granulocyte-macrophage colony-stimulating factor (GM-CSF), both in patients with stage IIIB–IV melanoma [intention-to-treat (ITT) population] and in those with stage IIIB–IVM1a disease (in an exploratory subgroup analysis). Durable response rate (DRR) was significantly higher with talimogene laherparepvec in the ITT population; beneficial results in DRR were also observed in talimogene laherparepvec recipients in patients with stage IIIB–IVM1a disease. Talimogene laherparepvec was generally well tolerated in clinical trials. In conclusion, talimogene laherparepvec is a novel, effective and well tolerated option for the treatment of patients with unresectable metastatic melanoma.     

Release of Biologically Functional Interferon-Alpha from a Nanochannel Delivery System

Metastatic melanoma lesions often are unresectable due to their size and/or location near critical structures. These lesions represent a significant challenge for the oncologist, because radiation therapy and chemotherapy are infrequently successful in halting tumor growth. Of primary concern is the fact that these lesions are usually painful and present a cosmetic dilemma. We hypothesized that the development of a silicon-based nano-device capable of delivering antitumor compounds (e.g. immune modulators), locally, at a constant rate, to the tumor microenvironment could avoid the toxicity of systemic administration and the inconvenience of frequent clinic visits for local injections. Because of its diminutive size, such a device could be implanted using a minimally invasive procedure in close proximity to unresectable melanoma lesions. The current report uses interferon alpha-2b (IFN-) as a model antitumor agent, since it is commonly used in the treatment of malignant melanoma and metastatic renal cell carcinoma. In this system, IFN- is delivered directly to the tumor microenvironment by a novel nanochannel delivery system (nDS) that is capable of zero order release of small molecules. We have demonstrated that the IFN- released from the nDS is functionally active on both host immune cells and a human melanoma cell line in vitro. This drug delivery platform could be used to develop alternative strategies for the treatment of unresectable tumors.These authors contributed equally to this work.     

Recent discoveries in the genetics of melanoma and their therapeutic implications

The incidence of cutaneous malignant melanoma, tumors arising from melanocytes, has increased markedly over the past few years in many countries. Although early melanoma is curable through surgical excision, the prognosis of advanced melanoma is very poor, this tumor being resistant to current therapies. Thus there is a need for new therapies to improve the treatment of advanced melanoma. This review provides an overview of recent discoveries in the genetics of melanoma which could offer new therapeutic opportunities.     

Vandetanib: A Guide to Its Use in Advanced Medullary Thyroid Cancer

Vandetanib (Caprelsa?) provides an acceptable treatment option in patients with advanced medullary thyroid cancer for whom, historically, there have been no effective therapies. Vandetanib, an orally active, multitargeted tyrosine kinase inhibitor, improves progression-free survival and tumor response in patients with unresectable, locally advanced or metastatic medullary thyroid cancer. It has an acceptable tolerability profile in this patient population, although it does have the potential to prolong the corrected QT interval.     

T-cell-based immunotherapy of melanoma: what have we learned and how can we improve?

The lack of effective treatment for advanced stage melanoma by conventional therapies, such as radiation and chemotherapy, has highlighted the need to develop alternative therapeutic strategies. Among them, immunotherapy has attracted much attention because of the potential role played by immunological events in the clinical course of melanoma and the availability of well-characterized melanoma antigens to target melanoma lesions with immunological effector mechanisms. In recent years, T-cell-based immunotherapy has been emphasized, in part because of the disappointing results of the antibody-based trials conducted in the early 1980s, and in part because of the postulated major role played by T-cells in tumor growth control. In this review, the characteristics of antibody and T-cell-defined melanoma antigens will first be described, with emphasis on those used in clinical trials. Following a review of the current immunization and immunomonitoring strategies, the results from the T-cell-based immunotherapy clinical trials conducted to date will be reviewed.     

T cell receptor therapy against melanoma—Immunotherapy for the future?

Malignant melanoma has seen monumental changes in treatment options the last decade from the very poor results of dacarbazine treatment to the modern-day use of targeted therapies and immune checkpoint inhibitors. Melanoma has a high mutational burden making it more capable of evoking immune responses than many other tumours. Even when considering double immune checkpoint blockade with anti-CTLA-4 and anti-PD-1, we still have far to go in melanoma treatment as 50% of patients with metastatic disease do not respond to current treatment. Alternative immunotherapy should therefore be considered. Since melanoma has a high mutational burden, it is considered more immunogenic than many other tumours. T cell receptor (TCR) therapy could be a possible way forward, either alone or in combination, to improve the response rates of this deadly disease. Melanoma is one of the cancers where TCR therapy has been frequently applied. However, the number of antigens targeted remains fairly limited, although advanced personalized therapies aim at also targeting private mutations. In this review, we look at possible aspects of targeting TCR therapy towards melanoma and provide an implication of its use in the future.     

Gene therapy in in vivo isolated perfusion models

Locoregional administration of a genetic construct by means of in vivo, in situ isolated perfusion (IP) of a target organ or extremity is a method that may increase in vivo efficacy. Vascular isolation and perfusion minimizes systemic exposure and thereby reduces unwanted side effects. Isolated hepatic perfusion (IHP) is the most extensively studied IP model, especially in gene therapy protocols for inborn errors of metabolism. To achieve stable transduction most frequently retroviruses are used in IHP. IHP is combined with hepatectomy or vascular ligation of liver lobes to induce liver regeneration increasing transduction efficacy. When adenoviruses are used in IHP high transduction percentages of hepatocytes can be achieved without significant toxicity. In tumor models adenoviral IHP has been performed, but has not been very successful up till now. Isolated limb perfusion (ILP) is a promising treatment modality in pre-clinical cancer gene therapy studies. After ILP a homogeneous distribution of transduced cells was demonstrated especially at the viable rim of the tumor and around tumor associated vessels. Moreover complete tumor responses have been observed. Isolated pulmonary perfusion (IPP) results in selective expression in the perfused lung and the duration of expression is longer than after systemic administration. In rats a significant decrease of tumor nodules upon IPP can be achieved. Furthermore other less studied perfusion models are discussed: isolated kidney perfusion (IKP), isolated spleen perfusion (ISP) and isolated cardiac perfusion (ICP). IP is a methodology that delivers vectors highly selectively, with a long exposure time and high concentrations at the target side. This results in higher transduction rates and thereby may improve therapeutic effects.     

Melanoma therapeutics: a literature review

Melanoma is a relentless type of skin cancer which involves myriad signaling pathways which regulate many cellular processes. This makes melanoma difficult to treat, especially when identified late. At present, therapeutics include chemotherapy, surgical resection, biochemotherapy, immunotherapy, photodynamic and targeted approaches. These interventions are usually administered as either a single-drug or in combination, based on tumor location, stage, and patients’ overall health condition. Howe...     

Current immunotherapy of melanoma

The immunotherapy of patients with metastatic melanoma is currently at a crossroads. Indeed, recent results from vaccine strategies worldwide have revealed a strikingly low overall response rate in patients with stage IV melanoma. Although disappointing, we have gained valuable insight and knowledge about how vaccines interact with the host immune response and to melanoma. However, although an immunological response to therapy is often reported from various clinical trials, it does not contribute to a patient's long term survival. It has been proven time and again that an immunological response to therapy does not necessarily translate into a meaningful clinical response. This frustrating dichotomy of response continues to vex investigators, providing a glaring example of our poor understanding of the immunologic response to cancer. Thus, we remain at the crossroads of understanding and treatment. On the one hand, we have dramatically advanced the field of tumor immunology/immunotherapy over the last 20 years. On the other hand, we have made little headway in truly developing effective treatment options for patients with stage IV disease. We must realize our previous shortcomings and failures in order to learn from them and develop improved therapies. The future of immunotherapy remains a bright ray of hope for everyone, with the road to success paved with the previous hard work of thousands of clinicians and researchers everywhere. Towards this end, this review hopes to provide the reader with the current state of affairs for the immunotherapy of melanoma as well as a primer of where we might be heading in the future.     

Regulation of local host-mediated anti-tumor mechanisms by cytokines: direct and indirect effects on leukocyte recruitment and angiogenesis.

The regulation of tumor growth by cytokine-induced alterations in host effector cell recruitment and activation is intimately associated with leukocyte adhesion and angiogenic modulation. In the present study, we have developed a novel tumor model to investigate this complex series of events in response to cytokine administration. Gelatin sponges containing recombinant human basic fibroblast growth factor (rhFGFb) and B16F10 melanoma cells were implanted onto the serosal surface of the left lateral hepatic lobe in syngeneic C57BL/6 mice. The tumor model was characterized by progressive tumor growth initially localized within the sponge and the subsequent development of peritoneal carcinomatosis. Microscopic examination of the sponge matrix revealed well developed tumor-associated vascular structures and areas of endothelial cell activation as evidenced by leukocyte margination. Treatment of mice 3 days after sponge implantation with a therapeutic regimen consisting of pulse recombinant human interleukin-2 (rhIL-2) combined with recombinant murine interleukin-12 (rmIL-12) resulted in a marked hepatic mononuclear infiltrate and inhibition of tumor growth. In contrast to the control group, sponges from mice treated with rhIL-2/rmIL-12 demonstrated an overall lack of cellularity and vascular structure. The regimen of rhIL-2 in combination with rmIL-12 was equally effective against gelatin sponge implants of rhFGFb/B16F10 melanoma in SCID mice treated with anti-asialo-GM1 in the absence of a mononuclear infiltration, suggesting that T, B, and/or NK cells were not the principal mediators of the anti-tumor response in this tumor model. The absence of vascularity within the sponge after treatment suggests that a potential mechanism of rhIL-2/rmIL-12 anti-tumor activity is the inhibition of neovascular growth associated with the establishment of tumor lesions. This potential mechanism could be dissociated from the known activities of these two cytokines to induce the recruitment and activation of host effector cells. Moreover, this model provides a unique opportunity to study the cellular and molecular mechanism(s) underlying both tumor angiogenesis and leukocyte recruitment to metastatic lesions.     

The highly attenuated vaccinia virus strain modified virus Ankara induces apoptosis in melanoma cells and allows bystander dendritic cells to generate a potent anti-tumoral immunity

Vaccinia virus (VV) has been tested as oncolytic virus against malignant melanoma in clinical trials for more than 40 years. Until now, mainly strains comparable to viral strains used for smallpox vaccination have been probed for anti-tumoral therapy. We have shown recently that the wild-type strain Western Reserve (WR) can interfere with crucial functions of monocyte-derived dendritic cells (DCs). Our aim was to examine whether viral immune evasion mechanisms might be responsible for the ineffectiveness of WR-based vaccination strategies and whether the highly attenuated strain modified virus Ankara (MVA) differs from WR with respect to its possible immunostimulatory capacity after intratumoral injection. Using in vitro experiments, we compared the effect of both strains on melanoma cells and on local bystander DCs. We found that both VV-strains infected melanoma cells efficiently and caused disintegration of the actin cytoskeleton, as shown by fluorescence microscopy. In addition, both VV-strains caused apoptotic cell death in melanoma cells after infection. In contrast to MVA, WR underwent a complete viral replication cycle in melanoma cells. Bystander DCs were consecutively infected by newly generated WR virions and lost their capacity to induce allogeneic T cell proliferation. DCs in contact with MVA-infected melanoma cells retained their capacity to induce T cell proliferation. Immature DCs were capable of phagocytosing MVA-infected melanoma cells. Priming of autologous CD8(+) T cells by DCs that had phagocytosed MVA-infected, MelanA positive melanoma cells resulted in the induction of T cell clones specifically reactive against the model antigen MelanA as shown by enzyme-linked immunospot (ELISPOT) analysis. We conclude that the clinical trials with oncolytic wild-type VV failed probably because of suppression of bystander DCs and consecutive suppression of T cell-mediated anti-melanoma immunity. The attenuated VV-strain MVA facilitates the generation of tumour associated antigen (TAA)-specific T cell response as it is oncolytic for melanoma cells, but non-toxic for DC, and should be a promising candidate for intralesional metastatic melanoma therapy.     

Update on systemic therapy for advanced cutaneous melanoma and recent development of novel drugs

Malignant melanoma is generally chemo- and radio-resistant, and patients with advanced melanoma have a poor prognosis. However, with our increased understanding of the checkpoint immune molecules and genetic alterations of melanoma cells, more effective immunotherapy, such as anti CTLA4 antibody and anti PD-1 antibodies, and targeted drug therapy, such as BRAF inhibitors and MEK inhibitors, have been developed, resulting in improved overall survival and quality of life of patients with advanced melanoma. In addition, emerging technologies to develop prognostic and predictive biomarkers for response to systemic therapy could help clinicians make more accurate assessments of the disease and formulate more effective treatment plans. In this review, current standard systemic therapy options and recently developed novel drugs for advanced melanoma are discussed.     

Regorafenib: A Guide to Its Use in Advanced Gastrointestinal Stromal Tumor (GIST) After Failure of Imatinib and Sunitinib

Regorafenib (Stivarga^®), a new inhibitor of multiple kinases, is indicated as third-line treatment in patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib and sunitinib in the USA. In a phase III trial in patients with progressive GIST after failure of standard therapies, regorafenib plus best supportive care increased median progression-free survival by >5-fold relative to best supportive care alone. Although regorafenib is associated with several specific drug-related adverse events, it is reasonably well tolerated if recommendations for dose modifications (i.e. treatment interruption, dose reductions and/or permanent treatment discontinuation based on tolerability) and other precautions are followed.