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

Cutaneous Melanoma: A Test Field for Immunotherapy and a Medical Challenge

Cutaneous melanoma (CM) is the fourth tumor in frequency, and that whose incidence increases faster. In half of the cases, CM arises from pre-existing nevi. CM is a highly heterogeneous tumor, whose degree of differentiation varies among different hosts, and such heterogeneity is probably based on the accumulation of mutations that determine transitions from normal melanocytic stem cells mutated benign melanocytic stem cells malignant melanocytic stem cells clonogenic melanocytic cells. These populations may express different antigens and would therefore trigger the proliferation of different T and B cell clones. Early diagnosis is the clue for the cure of CM; when visceral metastatic disease is established, the prognosis is somber. This is especially so since CM is quite resistant to chemotherapy, and some of the reasons for such resistance will be discussed here. However, CM has proved to be sensitive to immunological effectors, although the mechanism of such sensitivity is still being investigated. These effectors range from therapeutic vaccines, in vitro expanded cytotoxic lymphocytes, cytokines, and monoclonal antibodies. Finally, we will discuss new therapeutic approaches that include the combination of immune modulators and vaccines which are being assayed in light of recent tumor immunology research.Fil: Aris, Mariana. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Barrio, Maria Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; ArgentinaFil: Mordoh, Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentin

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

Cetuximab and IL-15 Promote NK and Dendritic Cell Activation In Vitro in Triple Negative Breast Cancer

Triple Negative Breast Cancer (TNBC) treatment is still challenging, and immunotherapy is a potential approach in this tumor subtype. Cetuximab is an IgG1 monoclonal antibody (mAb) directed against Epidermic Growth Factor Receptor (EGFR), a protein overexpressed in a subgroup of TNBC patients and associated with poor prognosis. Previously, we demonstrated in vitro that Cetuximab triggers Ab-dependent cell cytotoxicity against TNBC cells. In this study, using co-cultures including TNBC cells, and NK and Dendritic Cells (DCs) from healthy donors, we studied the effect of Cetuximab-activated NK cells on DC function. Given that we already demonstrated that TNBC has an immunosuppressive effect on NK cells, we also tested Cetuximab combination with IL-15. We determined that Cetuximab opsonization of TNBC cells increased IFN-γ and TNF-α production by NK cells co-cultured with DCs. Moreover, we showed that NK cells activated by TNBC cells opsonized with Cetuximab promoted tumor material uptake and maturation of DCs, as well as their ability to produce IL-12. Furthermore, the stimulation with IL-15 increased the activation of NK cells and the maturation of DCs. These results suggest that IL-15 may enhance the efficacy of Cetuximab in the treatment of TNBC by promoting activation of both NK cells and DCs.Fil: Juliá, Estefanía Paula. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Mordoh, Jose. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Fundación Instituto Leloir; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Levy, Estrella Mariel. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Vacuna terapéutica CSF-470 para melanoma cutáneo

El melanoma cutáneo es la patología tumoral con mayor incidencia de crecimiento. Una vez que hace metástasis, es resistente a los tratamientos convencionales, con pronóstico reservado. Recientemente han surgido nuevas estrategias terapéuticas con resultados alentadores, incluyendo la inmunoterapia. En esta nota nos centraremos en el uso de vacunas, en particular en la vacuna alogeneica irradiada CSF-470, coadyuvada con BCG y Molgramostim (GM-CSF), para el tratamiento adyuvante de pacientes con melanoma cutáneo estadios IIB, IIC o III post-cirugía. Describiremos los resultados del estudio clínico de fase I y el diseño del estudio actual de fase II-III activoFil: Aris, Mariana. Fundacion Cancer. Centro de Investigaciones Oncologicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Barrio, Maria Marcela. Fundacion Cancer. Centro de Investigaciones Oncologicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Mordoh, Jose. Fundacion Cancer. Centro de Investigaciones Oncologicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

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

Standardization of molecular monitoring for chronic myeloid leukemia in Latin America using locally produced secondary cellular calibrators

Residual disease in chronic myeloid leukemia (CML) patients undergoing therapy with tyrosine kinase inhibitors (TKIs) is measured by assessing the quantity of transcripts of the BCR-ABL1 fusion gene in peripheral white blood cells. This analysis is based on reverse-transcription quantitative PCR (RT–qPCR) technology; however, the wide array of methods used worldwide has led to large variation in quantitative BCR-ABL1 measurements, which hamper inter-laboratory comparative studiesFil: Ruiz, María Sol. Fundación Cáncer. Centro de Investigaciones Oncológicas; ArgentinaFil: Medina, M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Tapia, I.. Fundación Cáncer. Centro de Investigaciones Oncológicas; ArgentinaFil: Mordoh, Jose. Fundación Cáncer. Centro de Investigaciones Oncológicas; ArgentinaFil: Cross, N. C. P.. Universidad de Southampton Uk; Reino UnidoFil: Larripa, Irene Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Bianchini, Michele. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentin

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

Monocyte chemoattractant protein correlates with angiogenesis in metastatic melanoma

Se analizaron biopsias de melanoma metastásico humano para elucidar la relación entre la expresión de la quimioquina MCP-1/CCL2 (monocyte chemoattractant protein-1), la angiogénesis y la agresividad del tumor. Se encontró que esta quimioquina se expresa en el 100% de los casos, con heterogeneidad en el porcentaje de células positivas dentro del tumor. Estos tumores presentaron gran cantidad de macrófagos infiltrantes, particularmente asociados a las áreas de más activa angiogénesis. Se obtuvo correlación positiva entre el porcentaje de células que expresan MCP-1 y el grado de vascularización. Asimismo, se encontró asociación entre una mayor angiogénesis y la proliferación tumoral evaluada como índice mitótico. Estos resultados sugieren que el aumento en la vascularización podría ser predictivo de metástasis más agresivas, donde la expresión de MCP-1 estaría estrechamente vinculada al desarrollo de vasos a través del reclutamiento de macrófagos.Biopsies from human metastatic melanomas were analyzed in order to elucidate the relationship between MCP-1/CCL-2 (monocyte chemoattractant protein-1) chemokine expression by tumor cells, angiogenesis and aggressiveness in tumor development. The chemokine was expressed in 100% of the cases, with heterogeneity in the percentage of positive cells within the tumor mass. Tumors presented an important infiltration of macrophages, particularly associated to areas of active angiogenesis. Microvascular development, assessed by immunohistochemistry, correlated with the high percentage of cells expressing MCP-1/CCL-2. There was also significant correlation with vascularization and mitotic index. These results suggest that vascularization could be predictive of more aggressive melanoma metastasis, where the MCP-1/CCL-2 expression would be closely associated to vessel development through macrophages recruitment.Fil: Gazzaniga, Silvina Noemí. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Bravo, Alicia Ines. Hospital Eva Perón; ArgentinaFil: Mordoh, Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Wainstok, Rosa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentin