Current clinical trials for melanoma vaccines: where do we stand? (original) (raw)
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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
Melanoma immunology: past, present and future
Current Opinion in Oncology, 2007
Metastatic melanoma is a disease for which no effective therapeutic options have been developed during the last 30 years with the possible exception of high dose interferon-a in the adjuvant setting of stage III patients. The immunotherapy approach was initiated decades ago using cell-based vaccines and adoptive immunotherapy with functionally illdefined lymphocytes. This paper aims to evaluate the last three decades of research in melanoma immunotherapy and to provide insights in the future of this strategy.
Expert Review of Dermatology, 2012
Background: Immunotherapy for cancers is based on the principle that the host's immune system is capable of generating immune responses against tumor cells. Currently available treatments for melanoma patients are limited by poor response rates. Interferon-α has been approved for adjuvant treatment of stage III melanoma with improved survival. New and more innovative approaches with improved efficacy are needed. Methods: We reviewed the various new approaches and strategies for immunotherapy for the treatment of melanoma. Results: Immunotherapy for melanoma includes a number of different strategies with vaccines utilizing whole cell tumors, peptides, cytokine-mediated dendritic cells, DNA and RNA, and antibodies. Conclusions: A variety of approaches can be used to enhance immune reactivity in patients with melanoma. Preclinical studies and initial clinical trials have shown promising results. Additional clinical trials are currently ongoing to evaluate the clinical efficacy and the associated toxicities of these novel treatment strategies. Immunotherapy holds promise as an innovative and more effective approach for treatment of melanoma.
Strategies to overcome obstacles to successful immunotherapy of melanoma
International journal of immunopathology and pharmacology
The immunogenicity of malignant melanomas has been recognized by the observed recruitment of tumor-specific cytotoxic T-cells (CTL), leading to the identification of several melanoma associated antigen (MAA). However, numerous strategies to treat melanoma with immunotherapy have resulted in only partial success. In this editorial, we discuss recent data related to the ability of tumors to elude immune responses. We therefore discuss different strategies to induce a clinically effective immune response. These approaches include 1) immunostimulation: including peptide/protein based vaccines, dendritic cell vaccines, and adoptive cell transfer; and 2) overcoming immunosuppression, including targeting of checkpoint molecules such as CTLA-4, circumventing the activity of Tregs, and assuring antigen expression by tumor cells (thwarting antigen silencing). Finally, we discuss recent advances in gene therapy, including adoptive therapy with engineered T cell receptors (TCRs). These issues l...
Melanoma vaccines: The problems of local immunosuppression
Human Immunology, 2009
The incidence of cutaneous melanoma in Europe is rising, and the disease is incurable once metastases occur. Because melanoma expresses antigens that can be specifically recognized by the immune system, and because this disease occasionally undergoes spontaneous regression mediated by anti-tumor immunity, a number of different melanoma vaccines have been developed and tested clinically. Although most such vaccines show efficacy in vitro and an ability to stimulate anti-melanoma immune responses in blood, they have proved disappointing in clinical practice. It has become increasingly clear that the interaction between melanoma and the immune system is determined locally, within the tumor or draining lymph nodes. It is now clear that melanoma cells have the ability to anergize the immune system by inducing an immunosuppressive microenvironment that may explain the inability of systemic vaccines to alter patient outcomes. This subversion of the immune system involves alteration of dendritic cell (DC) function by tumor-derived cytokines, leading to the generation of suppressive and regulatory T lymphocytes. Successful melanoma vaccination probably requires therapeutic neutralization of the immunosuppressive microenvironment, which will require greater understanding of the molecular mechanisms used by the tumor to promote immunosuppression. Nevertheless, if these problems can be overcome, it seems likely that the efficacy of melanoma vaccines could be greatly enhanced. ᭧ Cutaneous melanoma affects approximately 60,000 patients each year in Europe, resulting in approximately 14,400 deaths, and the incidence is still rising. The prognosis for the patient with a melanoma depends upon its extent: although the 5-year survival is close to 90% for localized malignancies, it is less than 20% once the patient has distant metastases [1].
Immunotherapy of melanoma: a critical review of current concepts and future strategies
Expert Opinion on Biological Therapy, 2007
Advanced melanoma is a devastating disease with a very poor overall prognosis. There are only two agents that are approved by the FDA for use in patients with metastatic melanoma: dacarbazine and IL-2. Both agents have an overall response rate well below 20%, with only rare long-term responders noted. Metastatic melanoma is known to be one of the most resistant cancers to a plethora of treatment modalities, such as single-agent and combination chemotherapy, chemoimmunotherapy and immunotherapy with a host of immune stimulators. Indeed, researchers worldwide have recognized the lack of effective therapies and have refocused their efforts on developing novel and cutting-edge strategies of treatment. This is based on an improved understanding of the complex interactions that occur within the tumor microenvironment, and the central role that the host immune system plays in the surveillance of cancer. This review summarizes the recent results of novel immunotherapeutic regimens and focuses on cutting-edge modalities of treatment that encompass new lines of thinking in the war against cancer and, in particular, melanoma. GORE M, EGGERMONT A, SUCIU S: Does adjuvant interferon-α for high-risk melanoma provide a worthwhile benefit? A meta-analysis of the randomised trials. Cancer Treat. Rev. (2003) 29:241-252. •• This is one of the most thorough meta-analyses to date discussing the statistical outcomes of patients treated with all forms of IFN-α (high, intermediate and low).
Melanoma Immunomodulation: A War of Attrition
Treatment of Metastatic Melanoma, 2011
At the cellular level, melanoma tumors differentially express cytokines, chemokines, and soluble molecules responsible for immunosuppression and tumor proliferation which will be discussed further in this chapter, particularly those with potential for targeting or with therapeutic benefits (Lazar-Molnar et al., 2000). Melanoma cells are also less efficient in antigen (Ag) presentation to CD4+ T cells, reducing immune detection of melanoma tumors and the effectiveness of some immunotherapy strategies (Norton & Haque, 2009). Multiple defects along the HLA class II pathway are present in melanoma cells, the alteration of which could prove useful in novel tumor targeting and immunotherapeutic vaccination strategies. These defects and the potential to overcome them will be further explained in this chapter. Costimulatory molecules are also altered in melanoma cells, reducing positive cellular interaction with T cells and professional antigen presenting cells (APCs), while promoting immunosuppressive interactions through CD28, CTLA-4, and the B7 family of immune inhibitors (Pardee et al., 2009; Wolchok & Saenger, 2008). Study focused on enhancing these secondary stimulation signals would promote complete T cell stimulation and activation of anti-tumor CD8+ T cells, a current goal of most immunotherapy strategies. Melanoma cells are also capable of modulating the surrounding immune cells including: suppression of tumor infiltrating lymphocytes (TILs), enhancement of CD4+CD25+FoxP3+ T regulatory cells (Tregs), increased immature myeloid suppressor cells, increased protumorigenic m2 macrophages, and generation of melanoma-associated fibroblasts (Oble et al.
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...
Advances in melanoma immunotherapy
2017
Melanoma is considered to be the most immunogenic malignant tumour. This fact is recognized for many years, and certain forms of immunotherapy have been used in melanoma therapy for a considerable time. Treatment options for patients with metastatic melanoma have changed dramatically in the past 5 years, with the FDA approval of eight new therapeutic agents (immunotherapies and targeted therapies). During this period, melanoma immunotherapy has transitioned from cytokine-based treatment to antibody-mediated blockade of the cytotoxic Tlymphocyteassociated antigen4 (CTLA4) and, recently, the programmed cell-death protein 1 (PD1) immune checkpoints. These changes in the treatment options have dramatically improved patient outcomes, with the median overall survival of patients with metastatic melanoma increasing from approximately 9 months before 2011 to at least 2 years, and probably longer. Various types of immunotherapy, like pembrolizumab, nivolumab, ipilimumab, combined therapy wit...