Immunotherapies against HER2-Positive Breast Cancer

Immunotherapy; Resistance; VaccinesImmunoteràpia; Resistència; VacunesInmunoterapia; Resistencia; VacunasBreast cancer is the leading cause of cancer-related deaths among women worldwide. HER2-positive breast cancer, which represents 15–20% of all cases, is characterized by the overexpression of the HER2 receptor. Despite the variety of treatments available for HER2-positive breast cancer, both targeted and untargeted, many patients do not respond to therapy and relapse and eventually metastasize, with a poor prognosis. Immunotherapeutic approaches aim to enhance the antitumor immune response to prevent tumor relapse and metastasis. Several immunotherapies have been approved for solid tumors, but their utility for HER2-positive breast cancer has yet to be confirmed. In this review, we examine the different immunotherapeutic strategies being tested in HER2-positive breast cancer, from long-studied cancer vaccines to immune checkpoint blockade, which targets immune checkpoints in both T cells and tumor cells, as well as the promising adoptive cell therapy in various forms. We discuss how some of these new approaches may contribute to the prevention of tumor progression and be used after standard-of-care therapies for resistant HER2-positive breast tumors, highlighting the benefits and drawbacks of each. We conclude that immunotherapy holds great promise for the treatment of HER2-positive tumors, with the potential to completely eradicate tumor cells and prevent the progression of the disease.This research was funded by Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III

Three-dimensional cell culture of chimeric antigen receptor T cells originated from peripheral blood mononuclear cells towards cellular therapies

3D cell culture; CAR T cells; Adoptive cell therapyCultiu cel·lular 3D; Cèl·lules T CAR; Teràpia cel·lular adoptivaCultivo celular 3D; Células T CAR; Terapia celular adoptivaBackground aims With the objective of improving the ex vivo production of therapeutic chimeric antigen receptor (CAR) T cells, we explored the addition of three-dimensional (3D) polystyrene scaffolds to standard suspension cell cultures. Methods We aimed to mimic the structural support given by the lymph nodes during in vivo lymphocyte expansion. Results We observed an increase in cell proliferation compared with standard suspension systems as well as an enhanced cytotoxicity toward cancer cells. Moreover, we directly obtained the CAR T cells from peripheral blood mononuclear cells, thus minimizing the ex vivo manipulation of the therapeutic cells and opening the way to synergies among different cell populations. Conclusions We propose the use of commercially available 3D polystyrene systems to improve the current immune cell cultures and resulting cell products for emerging cellular (immuno)therapies.This research was funded by Instituto de Salud Carlos III through Consorcio Centro de Investigación Biomédica en Red (CIBER) with the projects “Alycia” (Nr. BBN18PI01) and “Gels4ACT” (Nr. BBN20PIV02). The authors are also grateful for the financial support received from the Spanish Ministry of Science and Innovation (PID2020-115296RA-I00, PID2019-105622RBI00 and the “Ramón y Cajal” program [RYC-2017-22614]). The work was supported as well by the Max Planck Society through the Max Planck Partner Group “Dynamic Biomimetics for Cancer Immunotherapy” in collaboration with the Max Planck for Medical Research (Heidelberg, Germany). This research was also supported by the European Union's Horizon 2020 research and innovation programme H2020-MSCA-COFUND-2016 (DOC-FAM, grant agreement Nr. 754397). The authors acknowledge financial support from the Spanish Ministry of Science and Innovation through the “Severo Ochoa” Programme for Centres of Excellence in R&D (CEX2019-000917-S)

The target antigen determines the mechanism of acquired resistance to T cell-based therapies

Cancer; Antigen; ResistanceCáncer; Antígeno; ResistenciaCàncer; Antigen; ResistènciaDespite the revolution of immunotherapy in cancer treatment, patients eventually progress due to the emergence of resistance. In this scenario, the selection of the tumor antigen can be decisive in the success of the clinical response. T cell bispecific antibodies (TCBs) are engineered molecules that include binding sites to the T cell receptor and to a tumor antigen. Using gastric CEA+/HER2+ MKN45 cells and TCBs directed against CEA or HER2, we show that the mechanism of resistance to a TCB is dependent on the tumor antigen. Acquired resistant models to a high-affinity-CEA-targeted TCB exhibit a reduction of CEA levels due to transcriptional silencing, which is reversible upon 5-AZA treatment. In contrast, a HER2-TCB resistant model maintains HER2 levels and exhibit a disruption of the interferon-gamma signaling. These results will help in the design of combinatorial strategies to increase the efficacy of cancer immunotherapies and to anticipate and overcome resistances.This work was supported by Asociación Española Contra el Cancer (AECC), Breast Cancer Research Foundation (BCRF-21-008), and Instituto de Salud Carlos III (PI19/01181). A.M.S. was funded by the Spanish Government (PFIS FI20/00188). B.M. was funded by a fellowship from PERIS (Departament de Salut, Generalitat de Catalunya). M.R.A. was funded by Agency for Management of University and Research Grants (AGAUR, 2022 FI_B2 00080). P.O.R. was funded by the BBVA. E.J.A. was funded by the AECC (POSTD211413AREN). VHIO acknowledges the Cellex Foundation for providing research facilities and equipment, the Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) from the Institute of Health Carlos III (ISCIII), and the Department of Health (Generalitat de Catalunya, SLT008/18/00198 SLT008/18/00205) for their support on this research. The authors acknowledge financial support from the State Agency for Research (Agencia Estatal de Investigación) (CEX2020-001024-S/AEI/10.13039/501100011033) and for the Cancer Immunology and Immunotherapy (CAIMI-2) program funded by BBVA Foundation. We would like to remark the funding from B.M PERIS (Spain). The authors thank Dr. Anne Freimoser-Grundschober and Roche for helping provide the TCBs. The graphical abstract was created with BioRender.com

The Eutherian Armcx genes regulate mitochondrial trafficking in neurons and interact with Miro and Trak2

Producción CientíficaBrain function requires neuronal activity-dependent energy consumption. Neuronal energy supply is controlled by molecular mechanisms that regulate mitochondrial dynamics, including Kinesin motors and Mitofusins, Miro1-2 and Trak2 proteins. Here we show a new protein family that localizes to the mitochondria and controls mitochondrial dynamics. This family of proteins is encoded by an array of armadillo (Arm) repeat-containing genes located on the X chromosome. The Armcx cluster is unique to Eutherian mammals and evolved from a single ancestor gene (Armc10). We show that these genes are highly expressed in the developing and adult nervous system. Furthermore, we demonstrate that Armcx3 expression levels regulate mitochondrial dynamics and trafficking in neurons, and that Alex3 interacts with the Kinesin/Miro/Trak2 complex in a Ca2 + -dependent manner. Our data provide evidence of a new Eutherian-specific family of mitochondrial proteins that controls mitochondrial dynamics and indicate that this key process is differentially regulated in the brain of higher vertebrates.2015-03-3

Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation

Immunotherapy has raised high expectations in the treatment of virtually every cancer. Many current efforts are focused on ensuring the efficient delivery of active cytotoxic cells to tumors. It is assumed that, once these active cytotoxic cells are correctly engaged to cancer cells, they will unfailingly eliminate the latter, provided that inhibitory factors are in check. T cell bispecific antibodies (TCBs) and chimeric antigen receptors (CARs) offer an opportunity to test this assumption. Using TCB and CARs directed against HER2, here we show that disruption of interferon-gamma signaling confers resistance to killing by active T lymphocytes. The kinase JAK2, which transduces the signal initiated by interferon-gamma, is a component repeatedly disrupted in several independently generated resistant models. Our results unveil a seemingly widespread strategy used by cancer cells to resist clearance by redirected lymphocytes. In addition, they open the possibility that long-term inhibition of interferon-gamma signaling may impair the elimination phase of immunoediting and, thus, promote tumor progression

The target antigen determines the mechanism of acquired resistance to T cell-based therapies

Despite the revolution of immunotherapy in cancer treatment, patients eventually progress due to the emergence of resistance. In this scenario, the selection of the tumor antigen can be decisive in the success of the clinical response. T cell bispecific antibodies (TCBs) are engineered molecules that include binding sites to the T cell receptor and to a tumor antigen. Using gastric CEA+/HER2+ MKN45 cells and TCBs directed against CEA or HER2, we show that the mechanism of resistance to a TCB is dependent on the tumor antigen. Acquired resistant models to a high-affinity-CEA-targeted TCB exhibit a reduction of CEA levels due to transcriptional silencing, which is reversible upon 5-AZA treatment. In contrast, a HER2-TCB resistant model maintains HER2 levels and exhibit a disruption of the interferon-gamma signaling. These results will help in the design of combinatorial strategies to increase the efficacy of cancer immunotherapies and to anticipate and overcome resistances

Métodos y mediciones

Actitud y conducta hacia la salud oral en estudiantes de la comuna de AraucoAnálisis de instrumentos de registro odontológicos en la red de APS de la Región MetropolitanaAnálisis de la eficiencia relativa del Hospital de Cabildo mediante la aplicación del análisis de fronteraAnálisis de letalidad intrahospitalaria y acumulada a 30 días de eventos IAM, 2003-2007Análisis del programa de cáncer cervicouterino en Chile con metodología de marco lógicoAños de vida perdidos por muerte prematura: efecto de diferentes criterios de corrección de subregistrosCalidad global de la alimentación de mujeres asistidas por el sistema de salud público chilenoCarga de mortalidad para el estado de Río de Janeiro, BrasilCausas de extracciones permanentes en adultos atendidos en la Posta Central, ChileComparación del consumo de drogas en escolares hombres utilizando metodología de pares y cuestionario autoregistradoCuidado hospitalario de pacientes con accidente cerebrovascular isquémico atendidos bajo régimen GESDescripción de dimensiones del constructo de calidad de vida en niños de 2-5 añosDistribución de benzodiacepinas en establecimientos del SNSS, período 2006-2008Evaluación de calidad, implementación del control odontológico del niño sano en CAP'S, Región del MauleEvaluación de la satisfacción del usuario interno de la Unidad de Cuidados Básicos del Hospital MetropolitanoEvaluación del protocolo de referencia de cefalea tensional y migraña en consultorio Llay-LlayEvaluación económica del Programa de Fluoración del Agua en ChileFactores de riesgo de enfermedad hipertensiva del embarazo en la UCI del H.G EcatepecImpacto de reforma sanitaria en autorizaciones sanitarias y de desempeño en instalaciones de radiodiagnóstico dentalInstitucionalidad de la investigación en salud pública en ChileLetalidad intrahospitalaria y a 30 días de los eventos de accidente cerebrovascular isquémico en ChileLimitaciones y desafíos de la investigación en salud pública en ChileMejora de agudeza visual y utilización cirugía de segundo ojo en pacientes con cataratas GESMortalidad infantil en la Región Metropolitana II del Estado de Río de Janeiro, 1981-2008Mortalidad por cáncer de tiroides en Chile en el período 1985-2007Mortalidad por tumores cerebrales en población infantil y adolescente, ciudad Río de Janeiro, 1980-2007Mortalidad por tumores del sistema nervioso central en adultos, Río de Janeiro, 1980 a 2007Prevalencia de anemia ferropriva en una muestra representativa de beneficiarios del PNACPrevalencia de caries y fluorosis previo a la fluoruración del agua potable en TemucoPrevalencia de traumatismos dentoalveolares en niños del Hospital Dr. Sótero del Río, enero-junio 2010Propuesta de un indicador de la calidad para los centros de salud familiarSalud pública y la emergencia del dispositivo clínico en la modernidad nacionalSatisfacción de funcionalidad familiar en adolescentes entre 12 y 18 años consumidores de drogasValidación cualitativa del cuestionario ASAQ para la determinación de la conducta sedentaria en escolare

Métodos y mediciones

Actitud y conducta hacia la salud oral en estudiantes de la comuna de AraucoAnálisis de instrumentos de registro odontológicos en la red de APS de la Región MetropolitanaAnálisis de la eficiencia relativa del Hospital de Cabildo mediante la aplicación del análisis de fronteraAnálisis de letalidad intrahospitalaria y acumulada a 30 días de eventos IAM, 2003-2007Análisis del programa de cáncer cervicouterino en Chile con metodología de marco lógicoAños de vida perdidos por muerte prematura: efecto de diferentes criterios de corrección de subregistrosCalidad global de la alimentación de mujeres asistidas por el sistema de salud público chilenoCarga de mortalidad para el estado de Río de Janeiro, BrasilCausas de extracciones permanentes en adultos atendidos en la Posta Central, ChileComparación del consumo de drogas en escolares hombres utilizando metodología de pares y cuestionario autoregistradoCuidado hospitalario de pacientes con accidente cerebrovascular isquémico atendidos bajo régimen GESDescripción de dimensiones del constructo de calidad de vida en niños de 2-5 añosDistribución de benzodiacepinas en establecimientos del SNSS, período 2006-2008Evaluación de calidad, implementación del control odontológico del niño sano en CAP'S, Región del MauleEvaluación de la satisfacción del usuario interno de la Unidad de Cuidados Básicos del Hospital MetropolitanoEvaluación del protocolo de referencia de cefalea tensional y migraña en consultorio Llay-LlayEvaluación económica del Programa de Fluoración del Agua en ChileFactores de riesgo de enfermedad hipertensiva del embarazo en la UCI del H.G EcatepecImpacto de reforma sanitaria en autorizaciones sanitarias y de desempeño en instalaciones de radiodiagnóstico dentalInstitucionalidad de la investigación en salud pública en ChileLetalidad intrahospitalaria y a 30 días de los eventos de accidente cerebrovascular isquémico en ChileLimitaciones y desafíos de la investigación en salud pública en ChileMejora de agudeza visual y utilización cirugía de segundo ojo en pacientes con cataratas GESMortalidad infantil en la Región Metropolitana II del Estado de Río de Janeiro, 1981-2008Mortalidad por cáncer de tiroides en Chile en el período 1985-2007Mortalidad por tumores cerebrales en población infantil y adolescente, ciudad Río de Janeiro, 1980-2007Mortalidad por tumores del sistema nervioso central en adultos, Río de Janeiro, 1980 a 2007Prevalencia de anemia ferropriva en una muestra representativa de beneficiarios del PNACPrevalencia de caries y fluorosis previo a la fluoruración del agua potable en TemucoPrevalencia de traumatismos dentoalveolares en niños del Hospital Dr. Sótero del Río, enero-junio 2010Propuesta de un indicador de la calidad para los centros de salud familiarSalud pública y la emergencia del dispositivo clínico en la modernidad nacionalSatisfacción de funcionalidad familiar en adolescentes entre 12 y 18 años consumidores de drogasValidación cualitativa del cuestionario ASAQ para la determinación de la conducta sedentaria en escolare