Immunomodulatory Monoclonal Antibodies in Combined Immunotherapy Trials for Cutaneous Melanoma

In the last few years, there has been a twist in cancer treatment toward immunotherapy thanks to the impressive results seen in advanced patients from several tumor pathologies. Cutaneous melanoma is a highly mutated and immunogenic tumor that has been a test field for the development of immunotherapy. However, there is still a way on the road to achieving complete and long-lasting responses in most patients. It is desirable that immunotherapeutic strategies induce diverse immune reactivity specific to tumor antigens, including the so-called neoantigens, as well as the blockade of immunosuppressive mechanisms. In this review, we will go through the role of promising monoclonal antibodies in cancer immunotherapy with immunomodulatory function, especially blocking of the inhibitory immune checkpoints CTLA-4 and PD-1, in combination with different immunotherapeutic strategies such as vaccines. We will discuss the rational basis for these combinatorial approaches as well as different schemes currently under study for cutaneous melanoma in the clinical trials arena. In this way, the combination of “push and release” immunomodulatory therapies can contribute to achieving a more robust and durable antitumor immune response in patients

Vacunas celulares terapéuticas para melanoma : descubrir al enemigo oculto

Fil: Mordoh, José. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil: Barrio, María Marcela. Fundación Cáncer; Argentina.Un equipo de científicos argentinos logró desarrollar exitosamente en ratones una vacuna\nexperimental contra el melanoma, un cáncer de piel altamente agresivo y que además es el más\nfrecuente entre las personas de 15 a 44 años. La lógica del hallazgo consiste en inyectar a los\nanimales unas células particulares llamadas "dendríticas", extraídas de los propios ratones y\n"cargadas" con células tumorales muertas. Al aplicarse la vacuna, los linfocitos T, principales agentes\ndel sistema inmune, comienzan a reconocer y atacar el tumor. Ya ha sido aprobado su ensayo en\nseres humanos

Melanoma Vaccines and Modulation of the Immune System in the Clinical Setting: Building from New Realities

To endow the immune system with the capacity to fight cancer has always attracted attention, although the clinical results obtained have been until recently disappointing. Cutaneous melanoma is a highly immunogenic tumor; therefore most of the attempts to produce cancer vaccines have been addressed to this disease. New advances in the comprehension of the mechanisms of antigen presentation by dendritic cells, in the immune responses triggered by adjuvants, as well as the understanding of the role of immunosuppressor molecules such as cytotoxic T-lymphocyte antigen-4 (CTLA-4), which led to the recent approval of the anti-CTLA-4 monoclonal antibody ipilimumab, have opened new hopes about the installment of immunotherapy as a new modality to treat cancer

Editorial: “Cancer Immunotherapy: Lights and Shadows”

Cancer immunotherapy has recently emerged as the fourth treatment modality, in addition to surgery, chemotherapy, and radiotherapy. These advances are the result of important discoveries in the field of regulation of the immune response, especially on the mechanisms which turn “on” and “off” immune responses (1, 2). A disease which has proved to be a canonical model to test therapeutic immunotherapy is the immunogenic cutaneous melanoma (3). So far, “passive” immunotherapy with monoclonal antibodies has outpaced “active” immunotherapy with antitumor vaccines (4, 5), and monoclonal antibodies which antagonize the “off” responses have been recently introduced in clinical practice (6, 7) ...Fil: Barrio, Maria Marcela. Fundacion Cancer. Centro de Investigaciones Oncologicas; ArgentinaFil: Levy, Estrella Mariel. Fundacion Cancer. Centro de Investigaciones Oncologicas; ArgentinaFil: Mordoh, Jose. Fundacion Cancer. Centro de Investigaciones Oncologicas; Argentina. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentin

Natural Killer Cells in Human Cancer: From Biological Functions to Clinical Applications

Natural killer (NK) cells are central components of the innate immunity. In murine models, it has been shown that NK cells can control both local tumor growth and metastasis due to their ability to exert direct cellular cytotoxicity without prior sensitization and to secrete immunostimulatory cytokines like IFN-γ. The latter participates in cancer elimination by inhibiting cellular proliferation and angiogenesis, promoting apoptosis, and stimulating the adaptive immune system, and it is instrumental for enhancing Ag processing and presentation. Nevertheless, NK cells display impaired functionality and capability to infiltrate tumors in cancer patients. Also, NK cells are feasible targets of stimulation to participate in immunotherapeutic approaches like antibody-based strategies and adoptive cell transfer. Thus, multiple attempts currently aim to manipulate NK for utilization in the immunotherapy of cancer

Dissecting the Immune Stimulation Promoted by CSF-470 Vaccine Plus Adjuvants in Cutaneous Melanoma Patients: Long Term Antitumor Immunity and Short Term Release of Acute Inflammatory Reactants

As cutaneous melanoma (CM) currently remains with a bleak prognosis, thorough investigation of new treatment options are of utmost relevance. In the phase II/III randomized clinical trial (CASVAC-0401), the repeated immunization of stages IIB-III CM patients with the irradiated, allogeneic cellular CSF-470 vaccine plus the adjuvants bacillus Calmette-Guerin (BCG) and recombinant human granulocyte macrophage colony-stimulating factor (rhGM-CSF) demonstrated a significant benefit over IFN-alpha2B treatment in distant metastasis-free survival. Here we present on the short and long term immune monitoring results after completing the 2-year protocol; a continuation of the previous report by Mordoh et al. (1). We demonstrate that the repeated CSF-470 vaccinations stimulated a long term cellular and humoral immunity response directed against the vaccine antigens. In the case of 2 patients, we are able to show that a similar immune response was generated against autologous antigens. Evaluation of inhibitory receptor co-expression on patient's T cells indicates that the vaccination protocol did not stimulate T cell exhaustion. In order to better understand the basis for the efficacious vaccine responses observed, we investigated the short term immune events following vaccine injection. A significant increase in C-reactive protein (CRP) and IL-6 was observed 24 h after vaccination, with in vitro studies suggesting IL-6 production occurs in the vaccine site. We demonstrate that CRP enhances the cytotoxicity of peripheral blood mononuclear cells (PBMC) against melanoma cells in an in vitro model. Additionally, CRP stimulates the release of pro and anti-inflammatory cytokines from PBMC. As our results demonstrate that successive vaccinations with CSF-470 plus adjuvants promoted an increase in both anti-tumor innate and adaptive immunity, we propose a subsequent model of action

In vitro synthesis of particulate glycogen from uridine diphosphate glucose

originalFil: Parodi, Armando José A.. Instituto de Investigaciones Bioquímicas Fundación Campomar; ArgentinaFil: Mordoh, Jose. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Krisman, Clara R.. Instituto de Investigaciones Bioquímicas Fundación Campomar; ArgentinaFil: Leloir, Luis Federico. Instituto de Investigaciones Bioquímicas Fundación Campomar; ArgentinaBlanco y negro6 páginas en pdfLFL-PI-O-ART. Artículos científicosUnidad documental simpleAR-HYL-201

Action patterns of phosphorylase and glycogen synthetase on glycogen

originalFil: Parodi, Armando José A.. Instituto de Investigaciones Bioquímicas Fundación Campomar; ArgentinaFil: Mordoh, Jose. Instituto de Investigaciones Bioquímicas Fundación Campomar; ArgentinaFil: Krisman, Clara R.. Instituto de Investigaciones Bioquímicas Fundación Campomar; ArgentinaFil: Leloir, Luis Federico. Instituto de Investigaciones Bioquímicas Fundación Campomar; ArgentinaBlanco y negro9 páginas en pdfLFL-PI-O-ART. Artículos científicosUnidad documental simpleAR-HYL-201

Targeting tumor-associated macrophages and inhibition of MCP-1 reduce angiogenesis and tumor growth in a human melanoma xenograft

Chemokines such as monocyte chemoattractant protein (MCP)-1 are key agonists that attract macrophages to tumors. In melanoma, it has been previously shown that variable levels of MCP-1/CCL2 appear to correlate with infiltrating macrophages and tumor fate, with low to intermediate levels of the chemokine contributing to melanoma development. To work under such conditions, a poorly tumorigenic human melanoma cell line was transfected with an expression vector encoding MCP-1. We found that M2 macrophages are associated to MCP-1+ tumors, triggering a profuse vascular network. To target the protumoral macrophages recruitment and reverting tumor growth promotion, clodronate-laden liposomes (Clod-Lip) or bindarit were administered to melanoma-bearing mice. Macrophage depletion after Clod-Lip treatment induced development of smaller tumors than in untreated mice. Immunohistochemical analysis with an anti-CD31 antibody revealed scarce vascular structures mainly characterized by narrow vascular lights. Pharmacological inhibition of MCP-1 with bindarit also reduced tumor growth and macrophage recruitment, rendering necrotic tumor masses. We suggest that bindarit or Clod-Lip abrogates protumoral-associated macrophages in human melanoma xenografts and could be considered as complementary approaches to antiangiogenic therapy.Facultad de Ciencias Veterinaria

Monocyte-derived dendritic cells loaded with a mixture of apoptotic/necrotic melanoma cells efficiently cross-present gp100 and MART-1 antigens to specific CD8(+ )T lymphocytes

BACKGROUND: In the present study, we demonstrate, in rigorous fashion, that human monocyte-derived immature dendritic cells (DCs) can efficiently cross-present tumor-associated antigens when co-cultured with a mixture of human melanoma cells rendered apoptotic/necrotic by γ irradiation (Apo-Nec cells). METHODS: We evaluated the phagocytosis of Apo-Nec cells by FACS after PKH26 and PKH67 staining of DCs and Apo-Nec cells at different times of coculture. The kinetics of the process was also followed by electron microscopy. DCs maturation was also studied monitoring the expression of specific markers, migration towards specific chemokines and the ability to cross-present in vitro the native melanoma-associated Ags MelanA/MART-1 and gp100. RESULTS: Apo-Nec cells were efficiently phagocytosed by immature DCs (iDC) (55 ± 10.5%) at 12 hs of coculture. By 12–24 hs we observed digested Apo-Nec cells inside DCs and large empty vacuoles as part of the cellular processing. Loading with Apo-Nec cells induced DCs maturation to levels achieved using LPS treatment, as measured by: i) the decrease in FITC – Dextran uptake (iDC: 81 ± 5%; DC/Apo-Nec 33 ± 12%); ii) the cell surface up-regulation of CD80, CD86, CD83, CCR7, CD40, HLA-I and HLA-II and iii) an increased in vitro migration towards MIP-3β. DC/Apo-Nec isolated from HLA-A*0201 donors were able to induce >600 pg/ml IFN-γ secretion of CTL clones specific for MelanA/MART-1 and gp100 Ags after 6 hs and up to 48 hs of coculture, demonstrating efficient cross-presentation of the native Ags. Intracellular IL-12 was detected in DC/Apo-Nec 24 hs post-coculture while IL-10 did not change. CONCLUSION: We conclude that the use of a mixture of four apoptotic/necrotic melanoma cell lines is a suitable source of native melanoma Ags that provides maturation signals for DCs, increases migration to MIP-3β and allows Ag cross-presentation. This strategy could be exploited for vaccination of melanoma patients