Immunotherapy for Melanoma
The incidence of malignant melanoma, the most lethal skin cancer, has been steadily increasing in the last 30 years and prognosis for patients is poor. The well-documented interface between the immune response and melanoma represents an attempt by the host to suppress tumor growth, but also constitutes a key parameter in the natural history of the disease. Systemic adjuvant therapies, such as IFN-α2b, have validated the merits of activating immune responses to oppose tumor development. Cutting-edge research efforts into targeting key T-cell immune check points, such as CTLA-4, aiming to overcome tolerance and enhance immune responses to melanoma, are now yielding novel therapeutics. We review the key areas of research activity in melanoma immunotherapy, the clinical experiences with immune therapeutics and discuss the most promising agents that are now driving the field.
Melanoma is a major public health issue in that incidence and mortality are currently rising. Melanoma is a highly aggressive form of skin cancer that arises from malignantly transformed melanocytes in the basal layer of the epidermis. Although for melanomas presenting at an early stage, surgical excision is associated with over a 95% 5-year survival rate, overall 20% of patients with melanoma will go on to develop metastatic disease for which the prognosis is extremely poor. The poor prognosis is in part due to the fact that agents currently used for the treatment of metastatic disease have limited efficacy, highlighting the need for further research in this field.
It is well documented that melanoma is an immunogenic tumor, and this hypothesis is further supported by clinical observations, such as spontaneous complete remissions, incomplete or complete regression of melanoma lesions and the occurrence of vitiligo-like depigmentation and halo nevi in a small number of patients. Similarly, pathological evidence suggests that the presence of T-cell infiltrates within melanoma lesions may correlate positively with longer patient survival. The involvement of the immune system in protection against melanoma is supported by increased prevalence of melanoma in immunosuppressed patients and partial success of immunotherapies, such as the immune activators IFN-α2b and IL-2, both of which have been approved for the treatment of patients with melanoma. Emerging evidence demonstrating clinical responses to anti-CTLA-4 antibody therapies also suggest the merit of selectively targeting regulatory elements of the immune response to achieve clinical benefits.
Although cancer cells are known to elicit immune responses, the interplay between the immune system and cancer most often does not result in eradication of tumors. Solid tumors are associated with inflammatory responses resulting in infiltration of macrophages, T lymphocytes, mast cells, B lymphocytes, neutrophils, natural killer (NK) cells, dendritic cells (DCs) and eosinophils within the tumor mass and in the periphery. These cells are recruited by a variety of cytokines and chemokines expressed by local inflammatory cells, stromal cells and also by tumor cells. Evidence of host–antigen-mediated cellular immune responses has been reported in healthy skin, but enhanced immune responses are well documented in many cancers, including melanoma. These are documented by tumor antigen-specific CD8 cytotoxic T cells activated via recognition of MHC class I/tumor antigen complexes presented on professional antigen-presenting cells (APCs; e.g., DCs, macrophages and B cells). The presence of tumors is also known to induce secretion of mediators such as IFN-γ and TNF-α by CD4 helper T cells, as well as to trigger antitumor antibody responses, which may have tumor-neutralizing potential.
Despite the recruitment and activation of immune cells both locally and in the circulation, the immune system of cancer patients fails to tackle tumor growth and spread (Figure 1). It has been proposed that the immune system battles to strike a fine balance between a sustained immune response and the development of autoimmunity against self and altered self-proteins expressed on tumor cells. Furthermore, immune cells are modulated by tumors to exert powerful tumor-promoting functions. This is mediated by facilitating genomic instability and promoting angiogenesis, as well as regulating the growth, migration and differentiation of neoplastic cells, endothelial cells and fibroblasts in the tumor microenvironment. Neoplastic cells also divert immune and other inflammatory mediators, such as matrix metalloproteinases, cytokines and chemokines, to favor tumor growth and metastasis.
(Enlarge Image)
Figure 1.
Shifting the balance of antitumor immunity. mAb: Monoclonal antibody.
Tumors devise a number of immunomodulatory mechanisms to evade antitumoral immune responses (Figure 1). Tumor cells secrete immune inhibitory cytokines (e.g., IL-10 and TGF-β) or induce immune cells, such as Tregs and macrophages, in tumor lesions to secrete these cytokines. The result is impaired T-cell responses and induction of apoptosis or reduced tumor killing capacity in cytolytic effector cells (CD8 T and NK cells). Other mechanisms include loss or altered expression of MHC class I expression on the surface of tumor cells, making them relatively 'invisible' to the immune response. Inhibition of antigen-presenting functions and DC maturation is also contributory. Tumor cells also express T-cell inhibitory molecules such as the glycoprotein PD-L1 that functions through recognition of PD-1 on T cells. These mechanisms translate into impaired antigen presentation and subsequent T-cell anergy in melanoma. Tumors also induce upregulation of Tregs through mechanisms such as indoleamine 2,3-dioxygenase expression by APCs.
The need for development of new and novel therapeutics is highlighted by the fact that standard chemotherapeutic regimes have little impact on survival for advanced disease. Recent promise for the use of immunotherapy in the treatment of melanoma has been highlighted by the use of the anti-CTLA-4 drug ipilimumab, demonstrating the therapeutic potential for drugs targeting the immune response. In addition to promise shown with some immunotherapies, newly emerging therapeutics that target oncogenes thought to be critical in the pathogenesis of melanoma are currently under evaluation and have shown promising results in clinical trials, including those that target B-Raf and c-kit mutations, although the duration of response to these agents is often limited.
Abstract and Introduction
Abstract
The incidence of malignant melanoma, the most lethal skin cancer, has been steadily increasing in the last 30 years and prognosis for patients is poor. The well-documented interface between the immune response and melanoma represents an attempt by the host to suppress tumor growth, but also constitutes a key parameter in the natural history of the disease. Systemic adjuvant therapies, such as IFN-α2b, have validated the merits of activating immune responses to oppose tumor development. Cutting-edge research efforts into targeting key T-cell immune check points, such as CTLA-4, aiming to overcome tolerance and enhance immune responses to melanoma, are now yielding novel therapeutics. We review the key areas of research activity in melanoma immunotherapy, the clinical experiences with immune therapeutics and discuss the most promising agents that are now driving the field.
Introduction
Melanoma is a major public health issue in that incidence and mortality are currently rising. Melanoma is a highly aggressive form of skin cancer that arises from malignantly transformed melanocytes in the basal layer of the epidermis. Although for melanomas presenting at an early stage, surgical excision is associated with over a 95% 5-year survival rate, overall 20% of patients with melanoma will go on to develop metastatic disease for which the prognosis is extremely poor. The poor prognosis is in part due to the fact that agents currently used for the treatment of metastatic disease have limited efficacy, highlighting the need for further research in this field.
It is well documented that melanoma is an immunogenic tumor, and this hypothesis is further supported by clinical observations, such as spontaneous complete remissions, incomplete or complete regression of melanoma lesions and the occurrence of vitiligo-like depigmentation and halo nevi in a small number of patients. Similarly, pathological evidence suggests that the presence of T-cell infiltrates within melanoma lesions may correlate positively with longer patient survival. The involvement of the immune system in protection against melanoma is supported by increased prevalence of melanoma in immunosuppressed patients and partial success of immunotherapies, such as the immune activators IFN-α2b and IL-2, both of which have been approved for the treatment of patients with melanoma. Emerging evidence demonstrating clinical responses to anti-CTLA-4 antibody therapies also suggest the merit of selectively targeting regulatory elements of the immune response to achieve clinical benefits.
Although cancer cells are known to elicit immune responses, the interplay between the immune system and cancer most often does not result in eradication of tumors. Solid tumors are associated with inflammatory responses resulting in infiltration of macrophages, T lymphocytes, mast cells, B lymphocytes, neutrophils, natural killer (NK) cells, dendritic cells (DCs) and eosinophils within the tumor mass and in the periphery. These cells are recruited by a variety of cytokines and chemokines expressed by local inflammatory cells, stromal cells and also by tumor cells. Evidence of host–antigen-mediated cellular immune responses has been reported in healthy skin, but enhanced immune responses are well documented in many cancers, including melanoma. These are documented by tumor antigen-specific CD8 cytotoxic T cells activated via recognition of MHC class I/tumor antigen complexes presented on professional antigen-presenting cells (APCs; e.g., DCs, macrophages and B cells). The presence of tumors is also known to induce secretion of mediators such as IFN-γ and TNF-α by CD4 helper T cells, as well as to trigger antitumor antibody responses, which may have tumor-neutralizing potential.
Despite the recruitment and activation of immune cells both locally and in the circulation, the immune system of cancer patients fails to tackle tumor growth and spread (Figure 1). It has been proposed that the immune system battles to strike a fine balance between a sustained immune response and the development of autoimmunity against self and altered self-proteins expressed on tumor cells. Furthermore, immune cells are modulated by tumors to exert powerful tumor-promoting functions. This is mediated by facilitating genomic instability and promoting angiogenesis, as well as regulating the growth, migration and differentiation of neoplastic cells, endothelial cells and fibroblasts in the tumor microenvironment. Neoplastic cells also divert immune and other inflammatory mediators, such as matrix metalloproteinases, cytokines and chemokines, to favor tumor growth and metastasis.
(Enlarge Image)
Figure 1.
Shifting the balance of antitumor immunity. mAb: Monoclonal antibody.
Tumors devise a number of immunomodulatory mechanisms to evade antitumoral immune responses (Figure 1). Tumor cells secrete immune inhibitory cytokines (e.g., IL-10 and TGF-β) or induce immune cells, such as Tregs and macrophages, in tumor lesions to secrete these cytokines. The result is impaired T-cell responses and induction of apoptosis or reduced tumor killing capacity in cytolytic effector cells (CD8 T and NK cells). Other mechanisms include loss or altered expression of MHC class I expression on the surface of tumor cells, making them relatively 'invisible' to the immune response. Inhibition of antigen-presenting functions and DC maturation is also contributory. Tumor cells also express T-cell inhibitory molecules such as the glycoprotein PD-L1 that functions through recognition of PD-1 on T cells. These mechanisms translate into impaired antigen presentation and subsequent T-cell anergy in melanoma. Tumors also induce upregulation of Tregs through mechanisms such as indoleamine 2,3-dioxygenase expression by APCs.
The need for development of new and novel therapeutics is highlighted by the fact that standard chemotherapeutic regimes have little impact on survival for advanced disease. Recent promise for the use of immunotherapy in the treatment of melanoma has been highlighted by the use of the anti-CTLA-4 drug ipilimumab, demonstrating the therapeutic potential for drugs targeting the immune response. In addition to promise shown with some immunotherapies, newly emerging therapeutics that target oncogenes thought to be critical in the pathogenesis of melanoma are currently under evaluation and have shown promising results in clinical trials, including those that target B-Raf and c-kit mutations, although the duration of response to these agents is often limited.
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