Advances in melanoma immunotherapy (original) (raw)

Immunotherapy of melanoma: efficacy and mode of action

Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG, 2016

Forty years of research have brought about the development of antibodies that induce effective antitumor immune responses through sustained activation of the immune system. These "immune checkpoint inhibitors" are directed against immune inhibitory molecules, such as cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1). Disruption of the PD-1/PD-L1 interaction improves the intermediate-term prognosis even in patients with advanced stage IV melanoma. One and a halfyears after treatment initiation, 30-60 % of these patients are still alive. While cancer immunotherapies usually do not eradicate metastases completely, they do cause a regression by 20-80 %. It is well established that the immune system is able to kill tumor cells, and this has also been demonstrated for immunotherapies. Preclinical data, however, has shown that anti-cancer immunity is not limited to killing cancer cells. Thus, through interferon gamma and tum...

Immune based therapy for melanoma

Indian Journal of Medical Research, 2016

A few years ago therapeutic options in advanced melanoma were very limited and the prognosis was somber. Although recent progresses are far from providing a cure for advanced melanoma, yet these have kindled new hopes and searching for a cure does not seem unreasonable. Seven new medicines have been authorized in various regions of the world in the recent past in the therapy of advanced melanoma, over half of them acting by mechanisms involving the immune system of the host. The anti-CTLA-4 (cytotoxic T lymphocyte associated protein-4) ipilimumab has been followed by anti-PD1 (programmed death1) inhibitors, more effective and safer. Very recently, the first oncolytic immunotherapy, talimogene laherparepvec (T-VEC) has been authorized for placing on the market and a variety of combinations of the new therapies are currently being evaluated or considered. Besides, a plethora of other molecules and approaches, especially monoclonal antibodies, are in the preliminary phases of clinical investigation and are likely to bring new benefits for the treatment of this potentially fatal form of cancer.

Current immunotherapy of melanoma

Clinical and Applied Immunology Reviews, 2005

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. ą

PD-1 pathway inhibitors: The next generation of immunotherapy for advanced melanoma

Oncotarget, 2015

Checkpoint inhibitors are revolutionizing treatment options and expectations for patients with melanoma. Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), was the first approved checkpoint inhibitor. Emerging long-term data indicate that approximately 20% of ipilimumab-treated patients achieve long-term survival. The first programmed death 1 (PD-1) inhibitor, pembrolizumab, was recently approved by the United States Food and Drug Administration for the treatment of melanoma; nivolumab was previously approved in Japan. PD-1 inhibitors are also poised to become standard of care treatment for other cancers, including non-small cell lung cancer, renal cell carcinoma and Hodgkin's lymphoma. Immunotherapy using checkpoint inhibition is a different treatment approach to chemotherapy and targeted agents: instead of directly acting on the tumor to induce tumor cell death, checkpoint inhibitors enhance or de novo stimulate antitumor immune res...

Molecular Fundamentals and Rationale for Immunotherapy in Metastatic Melanoma Treatment

Clinical application of immune checkpoint blockades has dramatically changed the landscape of cancer immunotherapy, especially in the field of metastatic melanoma. For the first time in the history of treatment of melanoma, immunotherapies using immune checkpoint blockades such as anti-Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) and Program Death-1 (PD-1) antibodies have consistently shown regression of metastatic tumors with survival benefit. However, the treatment of metastatic melanoma with immune checkpoint blockades has also brought new scientific and clinical challenges to treating physicians and clinical investigators. Such new challenges include: (1) how should we manage/ minimize serious immune-related adverse events without sacrificing anti-cancer effects?, (2) how should we choose one immune checkpoint blockade over others and in what sequence?, (3) how should we combine the immune checkpoint blockade with other cancer treatments such as chemotherapy, radiotherapy and signal blockades?, and (4) how can we predict clinical response with new immunological agents? In this review, we provide an overview of the molecular basis of new immunotherapies for metastatic melanoma and discussed potential strategies to improve the treatment outcomes using immune checkpoint blockades alone or in combination with various therapeutic modalities.

A New Era of Immunotherapy in Malignant Melanoma

2017

Even though melanoma skin cancer is less common than non-melanoma skin cancers (squamous cell carcinoma and basal cell carcinoma), still its mortality rate is relatively higher. Early diagnosis is the mainstay option to improve the disease outcome as early-stage melanoma made a favorable prognosis with surgical intervention. In contrast, advanced stage melanoma which is disseminated to distant sites through the lymphatics is associated with poor prognosis. Earlier traditional treatment modalities like interleukin 2 and non-specific anti-neoplastic agents are ineffective in improving the survival outcome and also the side-effects of these drugs have always been a treatment burden. However, recent understanding of immunotherapeutic approach against melanoma cancer has revolutionized the whole treatment scenario. Various adaptations of immunotherapies like targeted therapy, monoclonal antibodies, Toll-like receptors, T-cell therapy and oncolytic viral therapy has shown significant impr...

Targeted therapy and immunotherapy in advanced melanoma: an evolving paradigm

Therapeutic advances in medical oncology, 2013

Metastatic melanoma is one of the most challenging malignancies to treat and often has a poor outcome. Until recently, systemic treatment options were limited, with poor response rates and no survival advantage. However, the treatment of metastatic melanoma has been revolutionized by developments in targeted therapy and immunotherapy; the BRAF inhibitor, vemurafenib, and anticytotoxic T-lymphocyte antigen 4 antibody, ipilimumab, are the first agents to demonstrate a survival benefit. Despite the success of these treatments, most patients eventually progress, and research into response and resistance mechanisms, rationally designed combination therapies and evaluation of the role of these agents in the adjuvant setting is critically important.

Cancer immunology and melanoma immunotherapy

Anais brasileiros de dermatologia

The stimulation of the immune system, in order to generate an attack against cancer cells, similarly to that which occurs in infectious disease, has long been matter of interest in oncology; however, only limited success has been achieved, with different treatment strategies tested in recent years. The development of new immune checkpoint inhibitors is currently changing this scenario, and immunotherapy is becoming a real choice among traditional cytotoxic treatments to fight cancer. Recent reports have shown efficacy and safety with the use of pembrolizumab, nivolumab, and ipilimumab for the treatment of different neoplasms, especially melanoma. In this article, we propose a review of the mechanisms of action involved in cancer immunology, the response evaluation of immunotherapies, and its toxicity profile, as well as a summary of the main clinical trials that led to the adoption of these new drugs for melanoma treatment.

Modern Aspects of Immunotherapy with Checkpoint Inhibitors in Melanoma

International Journal of Molecular Sciences

Although melanoma is one of the most immunogenic tumors, it has an ability to evade anti-tumor immune responses by exploiting tolerance mechanisms, including negative immune checkpoint molecules. The most extensively studied checkpoints represent cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein 1 (PD-1). Immune checkpoint inhibitors (ICI), which were broadly applied for melanoma treatment in the past decade, can unleash anti-tumor immune responses and result in melanoma regression. Patients responding to the ICI treatment showed long-lasting remission or disease control status. However, a large group of patients failed to respond to this therapy, indicating the development of resistance mechanisms. Among them are intrinsic tumor properties, the dysfunction of effector cells, and the generation of immunosuppressive tumor microenvironment (TME). This review discusses achievements of ICI treatment in melanoma, reasons for its failure, and promising...