Person: Chocarro de Erauso, Luisa
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Chocarro de Erauso
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Luisa
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Ciencias de la Salud
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0000-0001-7384-9847
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TA108719
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Publication Open Access Immune profiling uncovers memory T-cell responses with a Th17 signature in cancer patients with previous SARS-CoV-2 infection followed by mRNA vaccination(MDPI, 2022) Echaide Górriz, Míriam; Labiano, Ibone; Delgado, Marina; Fernández de Lascoiti, Ángela; Ochoa, Patricia; Garnica, Maider; Ramos, Pablo; Chocarro de Erauso, Luisa; Fernández Rubio, Leticia; Arasanz Esteban, Hugo; Bocanegra Gondán, Ana Isabel; Blanco, Ester; Piñeiro Hermida, Sergio; Morente Sancho, Pilar; Vera García, Ruth; Alsina, María; Escors Murugarren, David; Kochan, Grazyna; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako GobernuaIt is unclear whether patients with cancer present inherently impaired responses to COVID-19 and vaccination due to their treatments, neoplastic diseases or both. To address this question, immune profiling was performed in three cohorts of healthy donors and oncologic patients: infected with SARS-CoV-2, BNT162b2-vaccinated, and with previous COVID-19 disease and subsequently vaccinated. Cancer patients showed good antibody responses to vaccination, but poor induction of T-cell responses towards the S protein when compared to infection. Following natural infection, the major targets for T-cells were the SARS-CoV-2 structural proteins M and S, but not the N protein. Similar to antibody titers, the T-cell responses quickly decayed after six months post-vaccination. Significant memory T-cell expansion was observed in vaccinated donors only if previously diagnosed with COVID-19 before undergoing vaccination. Oncologic patients with previous COVID-19 followed by vaccination exhibited potent IL-17+ CD4 and CD8 T-cell responses and elevated numbers of circulating neutrophils in peripheral blood. © 2022 by the authors.Publication Open Access Systemic blood immune cell populations as biomarkers for the outcome of immune checkpoint inhibitor therapies(MDPI, 2020) Hernández, Carlos; Arasanz Esteban, Hugo; Chocarro de Erauso, Luisa; Bocanegra Gondán, Ana Isabel; Zuazo Ibarra, Miren; Ciencias de la Salud; Osasun Zientziak; Universidad Pública de Navarra / Nafarroako Unibertsitate Publikoa; Gobierno de Navarra / Nafarroako GobernuaThe development of cancer immunotherapy in the last decade has followed a vertiginous rhythm. Nowadays, immune checkpoint inhibitors (ICI) which include anti-CTLA4, anti-PD-1 and anti-PD-L1 antibodies are in clinical use for the treatment of numerous cancers. However, approximately only a third of the patients benefit from ICI therapies. Many efforts have been made for the identification of biomarkers allowing patient stratification into potential responders and progressors before the start of ICI therapies or for monitoring responses during treatment. While much attention is centered on biomarkers from the tumor microenvironment, in many cases biopsies are not available. The identification of systemic immune cell subsets that correlate with responses could provide promising biomarkers. Some of them have been reported to influence the response to ICI therapies, such as proliferation and activation status of CD8 and CD4 T cells, the expression of immune checkpoints in peripheral blood cells and the relative numbers of immunosuppressive cells such as regulatory T cells and myeloid-derived suppressor cells. In addition, the profile of soluble factors in plasma samples could be associated to response or tumor progression. Here we will review the cellular subsets associated to response or progression in different studies and discuss their accuracy in diagnosis.Publication Open Access Systemic CD4 immunity and PD-L1/PD-1 blockade immunotherapy(MDPI, 2022) Escors Murugarren, David; Bocanegra Gondán, Ana Isabel; Chocarro de Erauso, Luisa; Blanco, Ester; Piñeiro Hermida, Sergio; Garnica, Maider; Fernández Rubio, Leticia; Vera García, Ruth; Arasanz Esteban, Hugo; Kochan, Grazyna; Ciencias de la Salud; Osasun ZientziakPD-L1/PD-1 blockade immunotherapy has changed the therapeutic approaches for the treatment of many cancers. Nevertheless, the mechanisms underlying its efficacy or treatment failure are still unclear. Proficient systemic immunity seems to be a prerequisite for efficacy, as recently shown in patients and in mouse models. It is widely accepted that expansion of anti-tumor CD8 T cell populations is principally responsible for anti-tumor responses. In contrast, the role of CD4 T cells has been less studied. Here we review and discuss the evidence supporting the contribution of CD4 T cells to anti-tumor immunity, especially recent advances linking CD4 T cell subsets to efficacious PD-L1/PD-1 blockade immunotherapy. We also discuss the role of CD4 T cell memory subsets present in peripheral blood before the start of immunotherapies, and their utility as predictors of response.Publication Open Access PD-L1 in systemic immunity: unraveling its contribution to PD-1/PD-L1 blockade immunotherapy(MDPI, 2020) Bocanegra Gondán, Ana Isabel; Blanco, Ester; Fernández Hinojal, Gonzalo; Chocarro de Erauso, Luisa; Zuazo Ibarra, Miren; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako GobernuaThe use of monoclonal antibodies targeting PD-1/PD-L1 axis completely changed anticancer treatment strategies. However, despite the significant improvement in overall survival and progression-free survival of patients undergoing these immunotherapy treatments, the only clinically accepted biomarker with some prediction capabilities for the outcome of the treatment is PD-L1 expression in tumor biopsies. Nevertheless, even when having PD-L1-positive tumors, numerous patients do not respond to these treatments. Considering the high cost of these therapies and the risk of immune-related adverse events during therapy, it is necessary to identify additional biomarkers that would facilitate stratifying patients in potential responders and non-responders before the start of immunotherapies. Here, we review the utility of PD-L1 expression not only in tumor cells but in immune system cells and their influence on the antitumor activity of immune cell subsets.Publication Open Access Cutting-edge: preclinical and clinical development of the first approved LAG-3 inhibitor(MDPI, 2022) Chocarro de Erauso, Luisa; Bocanegra Gondán, Ana Isabel; Blanco, Ester; Fernández Rubio, Leticia; Arasanz Esteban, Hugo; Echaide Górriz, Míriam; Garnica, Maider; Ramos, Pablo; Piñeiro Hermida, Sergio; Vera García, Ruth; Escors Murugarren, David; Kochan, Grazyna; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako GobernuaImmune checkpoint inhibitors (ICIs) have revolutionized medical practice in oncology since the FDA approval of the first ICI 11 years ago. In light of this, Lymphocyte-Activation Gene 3 (LAG-3) is one of the most important next-generation immune checkpoint molecules, playing a similar role as Programmed cell Death protein 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4). 19 LAG-3 targeting molecules are being evaluated at 108 clinical trials which are demonstrating positive results, including promising bispecific molecules targeting LAG-3 simultaneously with other ICIs. Recently, a new dual anti-PD-1 (Nivolumab) and anti-LAG-3 (Relatimab) treatment developed by Bristol Myers Squibb (Opdualag), was approved by the Food and Drug Administration (FDA) as the first LAG-3 blocking antibody combination for unresectable or metastatic melanoma. This novel immunotherapy combination more than doubled median progression-free survival (PFS) when compared to nivolumab monotherapy (10.1 months versus 4.6 months). Here, we analyze the large clinical trial responsible for this historical approval (RELATIVITY-047), and discuss the preclinical and clinical developments that led to its jump into clinical practice. We will also summarize results achieved by other LAG-3 targeting molecules with promising anti-tumor activities currently under clinical development in phases I, I/II, II, and III. Opdualag will boost the entry of more LAG-3 targeting molecules into clinical practice, supporting the accumulating evidence highlighting the pivotal role of LAG-3 in cancer.Publication Open Access Leading edge: intratumor delivery of monoclonal antibodies for the treatment of solid tumors(MDPI, 2023) Blanco, Ester; Chocarro de Erauso, Luisa; Fernández Rubio, Leticia; Bocanegra Gondán, Ana Isabel; Arasanz Esteban, Hugo; Echaide Górriz, Míriam; Garnica, Maider; Piñeiro Hermida, Sergio; Kochan, Grazyna; Escors Murugarren, David; Ciencias de la Salud; Osasun ZientziakImmunotherapies based on immune checkpoint blockade have shown remarkable clinical outcomes and durable responses in patients with many tumor types. Nevertheless, these therapies lack efficacy in most cancer patients, even causing severe adverse events in a small subset of patients, such as inflammatory disorders and hyper-progressive disease. To diminish the risk of developing serious toxicities, intratumor delivery of monoclonal antibodies could be a solution. Encouraging results have been shown in both preclinical and clinical studies. Thus, intratumor immunotherapy as a new strategy may retain efficacy while increasing safety. This approach is still an exploratory frontier in cancer research and opens up new possibilities for next-generation personalized medicine. Local intratumor delivery can be achieved through many means, but an attractive approach is the use of gene therapy vectors expressing mAbs inside the tumor mass. Here, we summarize basic, translational, and clinical results of intratumor mAb delivery, together with descriptions of non-viral and viral strategies for mAb delivery in preclinical and clinical development. Currently, this is an expanding research subject that will surely play a key role in the future of oncology.Publication Open Access Systemic CD4 immunity: a powerful clinical biomarker for PD-L1/PD-1 immunotherapy(EMBO Press, 2020) Zuazo Ibarra, Miren; Arasanz Esteban, Hugo; Bocanegra Gondán, Ana Isabel; Chocarro de Erauso, Luisa; Vera García, Ruth; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua, BMED 050-2019The search for non-invasive systemic biomarkers of response to PD-L1/PD-1 blockade immunotherapy is currently a priority in oncoimmunology. In contrast to classical tumor biomarkers, the identification of clinically useful immunological biomarkers is certainly a challenge, as anti-cancer immune responses depend on the coordinated action of many cell types. Studies on the dynamics of systemic CD8 T-cell populations have provided indications that such biomarkers may have a place in clinical practice. However, the power of CD8 T-cell subsets to discriminate clinical responses in immunotherapy has so far proven to be limited. The systemic evaluation of CD8 T-cell regulators such as myeloid cells and CD4 T cells may provide the solution. Here we discuss the value of systemic quantification of CD4 T-cell subsets for patient selection in light of the results obtained by Prof. Kagamu′s and our team. Our studies have independently demonstrated that the evaluation of the pre-treatment status of systemic CD4 immunity is a critical factor for the clinical outcome of PD-L1/PD-1 blockade therapy with robust predictive capacities.Publication Open Access Profound reprogramming towards stemness in pancreatic cancer cells as adaptation to AKT inhibition(MDPI, 2020) Arasanz Esteban, Hugo; Hernández, Carlos; Bocanegra Gondán, Ana Isabel; Chocarro de Erauso, Luisa; Zuazo Ibarra, Miren; Ciencias de la Salud; Osasun Zientziak; Universidad Pública de Navarra / Nafarroako Unibertsitate Publikoa; Gobierno de Navarra / Nafarroako GobernuaCancer cells acquire resistance to cytotoxic therapies targeting major survival pathways by adapting their metabolism. The AKT pathway is a major regulator of human pancreatic adenocarcinoma progression and a key pharmacological target. The mechanisms of adaptation to long-term silencing of AKT isoforms of human and mouse pancreatic adenocarcinoma cancer cells were studied. Following silencing, cancer cells remained quiescent for long periods of time, after which they recovered proliferative capacities. Adaptation caused profound proteomic changes largely affecting mitochondrial biogenesis, energy metabolism and acquisition of a number of distinct cancer stem cell (CSC) characteristics depending on the AKT isoform that was silenced. The adaptation to AKT1 silencing drove most de-differentiation and acquisition of stemness through C-MYC down-modulation and NANOG upregulation, which were required for survival of adapted CSCs. The changes associated to adaptation sensitized cancer cells to inhibitors targeting regulators of oxidative respiration and mitochondrial biogenesis. In vivo pharmacological co-inhibition of AKT and mitochondrial metabolism effectively controlled pancreatic adenocarcinoma growth in pre-clinical models.Publication Open Access Clinical landscape of LAG-3-targeted therapy(Elsevier, 2022) Chocarro de Erauso, Luisa; Blanco, Ester; Arasanz Esteban, Hugo; Fernández Rubio, Leticia; Bocanegra Gondán, Ana Isabel; Echaide Górriz, Míriam; Garnica, Maider; Ramos, Pablo; Fernández Hinojal, Gonzalo; Vera García, Ruth; Kochan, Grazyna; Escors Murugarren, David; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako GobernuaLymphocyte-activated gene 3 (LAG-3) is a cell surface inhibitory receptor and a key regulator of immune homeostasis with multiple biological activities related to T-cell functions. LAG-3 is considered a next-generation immune checkpoint of clinical importance, right next to programmed cell death protein 1 (PD-1) and cytotoxic T-cell lymphocyte antigen-4 (CTLA-4). Indeed, it is the third inhibitory receptor to be exploited in human anticancer immunotherapies. Several LAG-3-antagonistic immunotherapies are being evaluated at various stages of preclinical and clinical development. In addition, combination therapies blocking LAG-3 together with other immune checkpoints are also being evaluated at preclinical and clinical levels. Indeed, the co-blockade of LAG-3 with PD-1 is demonstrating encouraging results. A new generation of bispecific PD-1/LAG-3-blocking agents have also shown strong capacities to specifically target PD-1+ LAG-3+ highly dysfunctional T cells and enhance their proliferation and effector activities. Here we identify and classify preclinical and clinical trials conducted involving LAG-3 as a target through an extensive bibliographic research. The current understanding of LAG-3 clinical applications is summarized, and most of the publically available data up to date regarding LAG-3-targeted therapy preclinical and clinical research and development are reviewed and discussed.Publication Open Access The multi-specific VH-based Humabody CB213 co-targets PD1 and LAG3 on T cells to promote anti-tumour activity(Springer Nature, 2021) Edwards, Carolyn J.; Sette, Angelica; Cox, Carl; Di Fiore, Barabara; Wyre, Chris; Sydoruk, Daniela; Yadin, David; Hayes, Philip; Stelter, Szymon; Bartlett, Phillip D.; Zuazo Ibarra, Miren; García Granda, María Jesús; Benedetti, Giovanni; Fiaska, Stratonik; Birkett, Neil R.; Teng, Yumin; Enever, Carrie; Arasanz Esteban, Hugo; Bocanegra Gondán, Ana Isabel; Chocarro de Erauso, Luisa; Fernández, Gonzalo; Vera García, Ruth; Archer, Bethan; Osuch, Isabelle; Lewandowska, Martyna; Surani, Yasmin M.; Kochan, Grazyna; Escors Murugarren, David; Legg, James; Pierce, Andrew J.; Ciencias de la Salud; Osasun Zientziak; Universidad Pública de Navarra / Nafarroako Unibertsitate Publikoa; Gobierno de Navarra / Nafarroako GobernuaBackground: improving cancer immunotherapy long-term clinical benefit is a major priority. It has become apparent that multiple axes of immune suppression restrain the capacity of T cells to provide anti-tumour activity including signalling through PD1/PD-L1 and LAG3/MHC-II. Methods: CB213 has been developed as a fully human PD1/LAG3 co-targeting multi-specific Humabody composed of linked VH domains that avidly bind and block PD1 and LAG3 on dual-positive T cells. We present the preclinical primary pharmacology of CB213: biochemistry, cell-based function vs. immune-suppressive targets, induction of T cell proliferation ex vivo using blood obtained from NSCLC patients, and syngeneic mouse model anti-tumour activity. CB213 pharmacokinetics was assessed in cynomolgus macaques. Results: CB213 shows picomolar avidity when simultaneously engaging PD1 and LAG3. Assessing LAG3/MHC-II or PD1/PD-L1 suppression individually, CB213 preferentially counters the LAG3 axis. CB213 showed superior activity vs. αPD1 antibody to induce ex vivo NSCLC patient T cell proliferation and to suppress tumour growth in a syngeneic mouse tumour model, for which both experimental systems possess PD1 and LAG3 suppressive components. Non-human primate PK of CB213 suggests weekly clinical administration. Conclusions: CB213 is poised to enter clinical development and, through intercepting both PD1 and LAG3 resistance mechanisms, may benefit patients with tumours escaping front-line immunological control.