Tumor vaccines: a role in preventing recurrence in melanoma?

Patients presenting with thick primary melanomas or those with regional nodal metastases have a high risk of recurrence after surgery alone. Chemotherapy has limited efficacy in the adjuvant setting, and while the use of high-dose interferon in the adjuvant setting has been reported to improve survival, treatment with interferon is not without significant cost and toxicity. Mounting evidence suggests a prominent role for the immune system in the natural history of melanoma, and the clinical success of interferon highlights the potential for immunotherapy to prevent recurrence. Many researchers hope to use melanoma vaccines to reduce recurrence without significant toxicity, and many different vaccine strategies are under investigation. Peptide vaccines attempt to induce immunity to melanoma MHC-restricted peptide antigens by delivering the peptide to the patient along with an immune adjuvant meant to induce inflammation and stimulate immunity. While peptide vaccines have advantages with regard to cost and feasibility, it is still unclear whether highly purified peptides will stimulate an adequate immune response. An alternative approach is the use of cellular vaccines. Autologous cellular vaccines present all biologically relevant antigens to the immune system, but this is limited to individuals with sufficient tumor to prepare a vaccine. Allogeneic cellular vaccines are based on the fact that melanoma-associated antigens are shared among a large number of patients, so a vaccine prepared from a cultured cell line could stimulate an anti-tumor immune response in many patients. Allogeneic vaccines are available for all patients, and can be standardized, preserved and distributed in a manner akin to any other therapeutic agent. Because of this, they are more readily available for evaluation in large trials, and there are two major allogeneic vaccines presently being evaluated as an adjuvant therapy for melanoma. Several additional approaches to vaccine therapies are being investigated including among others ganglioside vaccines, viral oncolysates, cytokine gene-modified tumor cell vaccines, dendritic cell vaccines, anti-idiotype antibodies and DNA vaccines. While there appears to be tremendous potential for vaccines, it must be remembered that there has been significant interest in immunotherapy for melanoma for over 50 years and, to date, no large prospective, randomized trial has shown a survival benefit.     

Tumorimmunabwehr und Autoimmunität: Erkenntnisse für die Entwicklung moderner Melanomvakzinen aus tierexperimentellen Studien

Summary: Some patients with advanced melanoma benefit from non‐specific immunotherapy. The molecular identification of melanoma antigens allows for the development of specific vaccines. Animal studies allow for insights into the possibility to generate and maintain immunity against melanoma antigens. It has become clear that the stimulation of melanoma‐specific T cells is limited by mechanisms responsible for peripheral immune tolerance. Novel genetic vaccine strategies are able to circumvent immune tolerance in laboratory mice. This requires the adjuvant application of dendritic cells or the fusion of the antigen‐encoding cDNA with immunostimulatory proteins. Additionally, melanoma‐specific T cells have to be attracted into the tumor tissue with the help of proinflammatory signals in a therapeutic setting. We believe that these lessons learned in the murine system are of great importance for the future development of melanoma vaccines for application in man.     

Immunotherapy for melanoma

The immunogenicity of melanoma and the identification of melanoma-associated antigens is the basis for immunotherapy. This review will discuss the current status of melanoma immunotherapy with a focus on non-specific cytokines and highly specific vaccines, including peptides, viruses, dendritic cells, and whole cell vaccines. The passive transfer of melanoma-specific monoclonal antibodies and T-cells will also be reviewed. The problem of tumor escape and the association of immunotherapy to autoimmunity will be discussed. The use of immunotherapy in combination with other therapeutic agents and genetic profiling to predict responses suggests that immunotherapy will continue to play a role in the treatment of melanoma.     

Possibilities of immunotherapy in malignant melanoma]

The immune response of malignant melanoma bases on evident humoral and cellular defence mechanisms of the host against his tumor. Of special interest is a defective immune response, developing in the course of the disease. Hence, any immunotherapy aims at an immunostimulation and immunoregulation. Local and systemic nonspecific immunotherapy try to raise an immune response against the tumor by stimulating unspecifically the whole immune system. On the contrary, specific immunotherapy tries to stimulate directly the defence mechanisms against the tumor by transfusion of antisera (passive immunotherapy) and sensitized cells (adoptive immunotherapy) and by immunizing the patient with tumor tissue (active immunotherapy). One of the best ways in therapy of melanoma seems to be the combination of immunotherapy with chemotherapy, as yet employed in BCG and DTIC treatment.     

Malignant melanoma--future prospects

As the incidence and already high mortality rates of malignant melanoma have been steadily increasing in recent decades, the early detection and excision of malignant melanoma have imposed as the most important task. Staging of malignant melanoma is determined according to the level of invasion (Clark level) and vertical thickness (Breslow scale). Besides operative therapy, which is the only effective treatment for malignant melanoma, postoperative adjuvant chemotherapy, immunotherapy, radiotherapy, and biologic therapy also are of great importance. In recent years, immunologic strategies including tumor vaccine and adjuvant therapy with interferon-alfa have been attempted to improve survival of patients with more advanced malignant melanoma. A recent melanoma research has focused on target therapy such as immunotherapy (vaccines, monoclonal antibodies, dendritic cells) and gene therapy. Genetic immunization has become an attractive strategy for the development of melanoma vaccines, because a number of antigens recognized by cellular components of the immune system have been identified at the molecular level. Numerous chemotherapeutic agents have shown activity in the treatment of metastatic malignant melanoma, such as dacarbazine (dimethyl triazene imidazole carboxamide); other agents have been used, however, with less success. However, a very modest effect was recorded in advanced malignant melanoma. There are many experimental trials using combined therapy for malignant melanoma, including chemotherapy (dimethyl triazene imidazole carboxamide) and biologic therapy (interleukin (IL)-2, interferon (IFN)-gamma, IFN-alfa). The results obtained open particularly interesting prospects in the field of malignant melanoma with high relevance for its development and progression. Molecular therapeutics and vaccine development will probably be an important focus for the future melanoma treatment.     

Immunotherapy of Melanoma: Current Status and Prospects for the Future

As one of the most immunogenic human malignancies, melanoma has served as a prototype for the development of immunotherapy against human cancer in a number of treatment modalities over the past two decades. These studies have included augmentation of host immunity with lymphokines and other biological response modifiers, lymphokine-activated killer cells, and cytotoxic T-cells; active immunotherapy using purified antigens, tumor cell vaccines, and anti-id antibodies; and passive immunotherapy with monoclonal antibodies. The results of these investigations are discussed as well as the prospect for future treatments of melanoma incorporating immunotherapeutic techniques. A report on a recent trial of gene therapy of human melanoma performed by Dr. Steven Rosenberg is also presented.     

Targeting the PD-1 pathway: a promising future for the treatment of melanoma

Advanced melanoma presents a significant therapeutic challenge to clinicians. Many therapies for metastatic melanoma are limited by low response rates, severe toxicities, and/or relatively short response duration. Cancer immunotherapies that act as immune-checkpoint inhibitors to block the localized immune suppression mechanisms utilized by tumors are undergoing development and clinical trials. A clinically relevant immune escape mechanism in melanoma is the activation of the programmed cell death-1 (PD-1) receptor on infiltrating T cells. Activating PD-1 triggers an immune checkpoint resulting in inhibition of T cells directed against melanoma antigens and prevents the immune system from combating the melanoma. In Phase I clinical trials, two anti-PD1 therapies, Nivolumab and MK-3475, that block the PD-1 receptor to enable T cell killing have demonstrated objective tumor responses in patients with advanced melanoma. The purpose of this review is to present the available clinical evidence on anti-PD-1 and anti-PD-L1 immunotherapy for the treatment of advanced melanoma. We also discuss limitations associated with anti-PD-1 therapy. The blockade of the PD-1–PD-L1 pathway has shown promising results in clinical trials and has revolutionized melanoma immunotherapy.     

Vaccines against advanced melanoma

Research shows that cancers are recognized by the immune system but that the immune recognition of tumors does not uniformly result in tumor rejection or regression. Quantitating the success or failure of the immune system in tumor elimination is difficult because we do not really know the total numbers of encounters of the immune system with the tumors. Regardless of that important issue, recognition of the tumor by the immune system implicitly contains the idea of the tumor antigen, which is what is actually recognized. We review the molecular identity of all forms of tumor antigens (antigens with specific mutations, cancer-testis antigens, differentiation antigens, over-expressed antigens) and discuss the use of these multiple forms of antigens in experimental immunotherapy of mouse and human melanoma. These efforts have been uniformly unsuccessful; however, the approaches that have not worked or have somewhat worked have been the source of many new insights into melanoma immunology. From a critical review of the various approaches to vaccine therapy we conclude that individual cancer-specific mutations are truly the only sources of cancer-specific antigens, and therefore, the most attractive targets for immunotherapy.     

恶性黑素瘤免疫逃逸机制与对策

恶性黑素瘤治疗困难,免疫治疗是治疗本病的新型策略,治疗性疫苗则是其最为重要的形式.目前黑素瘤治疗性疫苗开发远未成功,究其原因与肿瘤具有多种免疫逃逸机制有关,主要包括两类:①肿瘤低免疫原性、肿瘤相关抗原及MHC Ⅰ类分子表达缺失、免疫隔离等所导致的免疫识别障碍;②抑制性树突状细胞、PD-1等抑制性配体、调节性T细胞、抑制性细胞因子等造成的免疫效应障碍.对其深入研究有利于开发更为合理有效的对策.     

Dendritic Cell‐Based Immunotherapy of Malignant Melanoma: Success and Limitations

Dendritic cells (DC) are professional antigen‐presenting cells in the immune system which are able to induce primary T‐cell responses. Because of their central role in the initiation of immune responses, DC are an important tool for tumor‐antigen‐specific immunotherapy of cancer. DC vaccination using tumor‐antigen‐loaded DC has led to tumor regression in individual advanced‐stage cancer patients. However, there is a discrepancy between strong and antigen‐specific T cell responses in vaccinated cancer patients detectable ex vivo and only weak clinical responses. In most cases the immune system of advanced stage IV cancer patients allows only a temporary anti‐tumor response and increasing evidence exists that active suppressive mechanisms of the immune system as well as of the tumor itself ultimately prevent “autoaggressive“ immune reactions against the tumor. Active counter‐regulation of effector T cells by tumor‐antigen‐specific regulatory T‐cell (Treg) populations play a central role in limiting the efficacy of the vaccines. Nevertheless, recent studies have shown that DC,additionally activated byToll‐Like‐receptor ligands (TLRL) can neutralize these suppressive effects of Treg and facilitate the induction of long‐lasting effector T cell responses even in the presence of activated Treg. These studies open a new way for “conditioning“ of DC by TLRL and might significantly enhance the efficiency of DC‐based melanoma vaccines in the future.     

RNA as a tumor vaccine: a review of the literature

Many approaches have been attempted to harness the host immune system to act against malignant tumors. These have included animal and clinical trials with agents to non-specifically boost immunity, factors to augment specific immunity, transfer of lymphokine-activated killer cells and transfer of expanded populations of tumor-infiltrating lymphocytes. Therapeutic vaccination strategies have been employed using tumor extracts, purified tumor antigens, recombinant peptide tumor antigens and specific DNA sequences coding for a tumor antigen (genetic vaccination) both through direct administration to the host and by administration of antigen presenting cells exposed to these materials ex vivo. Recently, the use of RNA has been proposed for use in tumor vaccination protocols. The use of RNA has several potential advantages. Since total cellular RNA or mRNA can be utilized, it is not necessary to know the molecular nature of the putative tumor antigen(s). RNA can be effectively amplified; thus, unlike tumor-extract vaccines, only a small amount of tumor is needed to prepare the material for vaccination. Also, unlike DNA-based vaccines, there is little danger of incorporation of RNA sequences into the host genome. The possible utility of RNA-based vaccines for tumor immunotherapy should be further explored to determine whether such approaches are clinically useful.     

树突状细胞疫苗治疗恶性黑素瘤的作用

近年恶性黑素瘤发病率不断增高，而且缺乏理想的治疗方法。树突状细胞疫苗是近年发展起来的一项新的免疫治疗技术。它是利用恶性黑素瘤细胞或恶性黑素瘤的抗原物质来诱导机体产生特异性细胞免疫和体液免疫应答，增强机体的抗癌能力，阻止肿瘤的生长、扩散和复发，从而达到治疗肿瘤的目的。目前抗恶性黑素瘤免疫治疗已进入Ⅰ～Ⅲ期临床研究，疗效可观，但仍待进一步研究以推广使用。     

Activated melanoma vessels: A sticky point for successful immunotherapy

Metastatic melanoma is a devastating disease with a marginal—albeit increasing—hope for cure. Melanoma has a high mutation rate which correlates to the expression of numerous neo-antigens and thus is associated with the potential to induce and strengthen effective antitumoral immunity. However, the incomplete and potentially insufficient response to established immunotherapies (response rates usually do not markedly exceed 60%) already points to the need of further studies to improve treatment strategies. Multiple tumor escape mechanisms that allow melanoma to evade from antitumoral immune responses have been characterized and must be overcome to achieve a better clinical efficacy of immunotherapies. Recently, promising progress has been made in targeting tumor vasculature to control and increase the infiltration of tumors with effector lymphocytes. It has been hypothesized that amplified lymphocytic infiltrates in melanoma metastases result in a switch of the tumor microenvironment from a non-inflammatory to an inflammatory state. In this view point essay, we discuss the requirements for successful homing of lymphocytes to melanoma tissue and we present a mouse melanoma xenograft model that allows the investigation of human tumor vessels in vivo. Furthermore, current clinical studies dealing with the activation of melanoma vasculature for enhanced effectiveness of immunotherapy protocols are presented and open questions for routine clinical application are addressed.     

Immunology of melanoma

It can be safely said that human melanomas are immunogenic. Virtually all the major principles of “tumor immunology” have been experimentally established in this model. It is now amply clear that melanoma cells display multiple antigens and peptide epitopes that are targetable by the host immune system and that patients with melanoma are capable of responding to these antigens and epitopes serologically as well as through the cell-mediated mechanisms. The immune responses against melanoma are, however, subject to regulation by the regulatory processes within the immune system itself and melanoma cells can resort to overt evasive activities. Indeed, the intrinsic as well as the extrinsic mechanisms within the immune system that are designed to control the magnitude as well as the duration of immune responses at times act as constraints against generating a robust and long-lasting antimelanoma response and melanoma cells are capable of using all the tricks (eg, downregulation of targetable molecules, elaboration of immunosuppressive cytokines) available to living organisms so as to evade immune recognition and destruction. As a result, the immune system often fails to protect the host against melanoma development and progression. The cumulative knowledge over the years on melanoma-associated antigens and epitopes, on methods of immunization, and on technologies for generating melanoma antigen-specific T cells, natural or engineered, have led to the development of immunotherapeutic strategies with “melanoma vaccines” and with T-cell–based adoptive immunotherapy for melanoma. Although these strategies have not been uniformly successful in all cases, durable complete regressions of metastatic melanoma can at times be obtained with active specific immunization or adoptive cell therapy. There is reason for hope that continued research in the field is likely to improve the outcome of melanoma immunotherapy: the ultimate goal of tumor immunology.     

Management of malignant melanoma: new developments in immune and gene therapy

Thus far, the use of classical anti-cancer treatment modalities had only rarely a beneficial impact on the prognosis of patients with metastatic melanoma. We as physicians have therefore the obligation as well as the chance to develop and test new therapeutic strategies. Our growing knowledge about the genetic basis of melanoma provides one platform to fulfil this task. Another one comes from our increasing understanding of the molecular and cellular mechanisms involved in the induction/modulation of immune responses, as well as the progress made in the field of identification of melanoma antigens, and allows for the development of a new generation of vaccines. The aim of this article is to discuss several of these new concepts towards the use of immune and gene therapy of melanoma.     

HLA-A(*)0201(+) Plasmacytoid Dendritic Cells Provide a Cell-Based Immunotherapy for Melanoma Patients

Several sources of evidence suggest that tumor-specific T cells have the potential to control melanoma tumors. Current active and adoptive therapeutic approaches to elicit such T cells are either not sufficiently clinically efficient or require fastidious processes that impede their extensive clinical use. As plasmacytoid dendritic cells (pDCs) have a crucial role in triggering antitumor immunity especially in melanoma, we explored their potential as a cell-based approach for melanoma immunotherapy. An irradiated human HLA-A(*)0201(+) pDC line loaded with peptides derived from the major melanoma tumor antigens, MelA/MART-1, gp100/pmel17, tyrosinase, and MAGE-A3, was used to trigger functional multi-specific T cells ex vivo from peripheral blood mononuclear cells and tumor-infiltrating lymphocytes from stage I-IV HLA-A(*)0201(+) melanoma patients. pDCs loaded with melanoma-derived peptides promptly induced high levels of melanoma tumor-specific T cells from both sources. pDC-primed central/effector memory antitumor T cells were highly functional as indicated by the specific IFNγ secretion and membrane CD107 expression upon stimulation. Cells also exhibited strong cytotoxicity toward semi-allogeneic melanoma cells and patient-derived tumor cells. The simple design and potent efficacy of this promising approach provides a preclinical basis for the development of a pDC-based vaccine and an alternative means to produce tumor-specific T cells for adoptive cellular immunotherapy in melanoma patients.     

Radiation‐induced melanoma‐associated leucoderma,systemic antimelanoma immunity and disease‐free survival in a patient with advanced‐stage melanoma: a case report and immunological analysis

Background Melanoma is an immunogenic tumour. The development of skin depigmentation or melanoma‐associated leucoderma (MAL) has been associated with favourable clinical outcome in patients with metastatic melanoma, especially after immunotherapy. Evidence for clinically meaningful enhancement of melanoma‐directed autoimmunity, as indicated by MAL, after radiotherapy without immunotherapy has not yet been published. Objectives We investigated whether a patient with stage IV melanoma, who developed leucoderma in the irradiated skin areas following radiotherapy and experienced exceptional disease‐free survival of 3 years despite brain metastasis, possessed antimelanoma immunity that could be linked to the favourable disease course. Methods A detailed immunological analysis was performed consisting of immunohistochemistry of several melanoma tissues, and analyses of T cells isolated from the blood and MAL skin tissue for melanocyte/melanoma specificity and functionality, as well as the presence of a melanoma‐specific antibody response. Results Immunological analyses showed the presence of CD8+ T cells and antibody responses directed against melanocyte differentiation antigens expressed in the primary tumour, lymph node and brain metastasis, indicating adequate tumour recognition by activated T cells. Conclusion The immune responses found in this patient, probably enhanced by radiotherapy, are thought to have contributed to his favourable clinical course. Radiotherapy may act as local immunotherapy in patients with melanoma by destroying melanocytes, leading to the induction, or enhancement, of already existent antimelanoma immunity. As in patients treated with immunotherapy, this may lead to MAL, also at distant sites from the treated area. This patient is a clear example of the positive prognostic value of MAL, which is possibly induced by radiotherapy, for patients with melanoma.     

光动力疗法诱导抗肿瘤免疫的研究进展

光动力疗法不仅直接杀死局部肿瘤细胞,还可以激活局部与系统性抗肿瘤的免疫反应,其机制涉及通过热休克蛋白等促进肿瘤抗原释放和增强免疫细胞在炎症反应中的作用.免疫佐剂和其他免疫疗法与光动力疗法联合使用,可提高光动力疗法治疗肿瘤的疗效.利用上述免疫机制建立肿瘤疫苗,能够抑制肿瘤原发灶和转移灶的生长,有望成为光动力疗法抗肿瘤免疫领域的新热点.     

光动力疗法诱导抗肿瘤免疫的研究进展

光动力疗法不仅直接杀死局部肿瘤细胞,还可以激活局部与系统性抗肿瘤的免疫反应,其机制涉及通过热休克蛋白等促进肿瘤抗原释放和增强免疫细胞在炎症反应中的作用.免疫佐剂和其他免疫疗法与光动力疗法联合使用,可提高光动力疗法治疗肿瘤的疗效.利用上述免疫机制建立肿瘤疫苗,能够抑制肿瘤原发灶和转移灶的生长,有望成为光动力疗法抗肿瘤免疫领域的新热点.     

Immunotherapeutic possibilities for treatment of malignant melanomas]

Principles, possibilities and limits of an immunotherapy of malignant melanoma are discussed. On account of the results of immunological investigations in melanoma patients and in animal models the immunogenicity of melanoma cells and the stage dependent immune reactivity of tumor bears seem to be certain. These facts have been the rational basis for the evaluation of an immunotherapy in malignant melanoma. Netherless these therapy trials are still in the state of clinical testing. Controlled long term studies of immunotherapy schedules under observation of the immune profile of the patients in vivo and in vitro are necessary in order to determine the place of immunotherapy within the range of oncological therapeutic possibilities.