Molina, C. (Carmeen)
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- Immunotherapeutic effects of intratumoral nanoplexed poly I:C(BMC, 2019) Planelles, M. (María); Etxeberria, I. (Iñaki); Perez-Gracia, J.L. (Jose Luis); Rodriguez, I. (Inmaculada); Bolaños, E. (Elixabet); Rodriguez-Ruiz, M.E. (María Esperanza); Aznar, M.A. (María Ángela); Marquez-Rodas, I. (Iván); Garasa, S. (Saray); Quintero, M. (Marisol); Lopez-Casas, P. (Pedro); Molina, C. (Carmeen); Melero, I. (Ignacio); Perez, G. (Guiomar); Perez-Olivares, M. (Mercedes); Teijeira, A. (Álvaro)Poly I:C is a powerful immune adjuvant as a result of its agonist activities on TLR-3, MDA5 and RIG-I. BO-112 is a nanoplexed formulation of Poly I:C complexed with polyethylenimine that causes tumor cell apoptosis showing immunogenic cell death features and which upon intratumoral release results in more prominent tumor infiltration by T lymphocytes. Intratumoral treatment with BO-112 of subcutaneous tumors derived from MC38, 4 T1 and B16- F10 leads to remarkable local disease control dependent on type-1 interferon and gamma-interferon. Some degree of control of non-injected tumor lesions following BO-112 intratumoral treatment was found in mice bearing bilateral B16-OVA melanomas, an activity which was enhanced with co-treatment with systemic anti-CD137 and anti-PD-L1 mAbs. More abundant CD8+ T lymphocytes were found in B16-OVA tumor-draining lymph nodes and in the tumor microenvironment following intratumoral BO-112 treatment, with enhanced numbers of tumor antigen-specific cytotoxic T lymphocytes. Genome-wide transcriptome analyses of injected tumor lesions were consistent with a marked upregulation of the type-I interferon pathway. Inspired by these data, intratumorally delivered BO-112 is being tested in cancer patients (NCT02828098).
- Repurposing the yellow fever vaccine for intratumoral immunotherapy(EMBO, 2020) Berraondo, P. (Pedro); Ríus-Rocabert, S. (Sergio); Etxeberria, I. (Iñaki); Azpilikueta, A. (Arantza); Sanchez-Paulete, A.R. (Alfonso R.); Rodriguez, I. (Inmaculada); Nistal-Villan, E. (Estanislao); Aznar, M.A. (María Ángela); Cordeiro-Minute, L. R (Luna Ridan); Garasa, S. (Saray); Molina, C. (Carmeen); Melero, I. (Ignacio); Álvarez, M. (Maite); Teijeira, A. (Álvaro)Live 17D is widely used as a prophylactic vaccine strain for yellow fever virus that induces potent neutralizing humoral and cellular immunity against the wild-type pathogen. 17D replicates and kills mouse and human tumor cell lines but not non-transformed human cells. Intratumoral injections with viable 17D markedly delay transplanted tumor progression in a CD8 T-cell-dependent manner. In mice bearing bilateral tumors in which only one is intratumorally injected, contralateral therapeutic effects are observed consistent with more prominent CD8 T-cell infiltrates and a treatment-related reduction of Tregs. Additive efficacy effects were observed upon co-treatment with intratumoral 17D and systemic anti-CD137 and anti-PD-1 immunostimulatory monoclonal antibodies. Importantly, when mice were preimmunized with 17D, intratumoral 17D treatment achieved better local and distant antitumor immunity. Such beneficial effects of prevaccination are in part explained by the potentiation of CD4 and CD8 T-cell infiltration in the treated tumor. The repurposed use of a GMP-grade vaccine to be given via the intratumoral route in prevaccinated patients constitutes a clinically feasible and safe immunotherapy approach.
- Human CD8 T cells are susceptible to TNF-mediated activation-induced cell death(2020) Berraondo, P. (Pedro); Etxeberria, I. (Iñaki); Azpilikueta, A. (Arantza); Miguéliz-Basterra, I. (Itziar); Otano, I. (Itziar); Molina, C. (Carmeen); Ochoa, M.C. (María Carmen); Melero, I. (Ignacio); Andrea, C.E. (Carlos Eduardo) de; Álvarez, M. (Maite); Minute, L. (Luna); Fernandez-Sanmamed, M. (Miguel); Teijeira, A. (Álvaro)Activation-induced cell death (AICD) is a complex immunoregulatory mechanism that causes the demise of a fraction of T-lymphocytes upon antigen-driven activation. In the present study we investigated the direct role of TNF in AICD of CD8 T lymphocytes. Methods: Human peripheral mononuclear cells were isolated from healthy donors and fresh tumor-infiltrating lymphocytes were obtained from cancer patients undergoing surgery. T cells were activated with anti-CD3/CD28 mAbs or with a pool of virus peptides, in combination with clinicalgrade TNF blocking agents. Results: A portion of CD8 T cells undergoes apoptosis upon CD3/CD28 activation in a manner that is partially prevented by the clinically used anti-TNF agents infliximab and etanercept. TNF-mediated AICD was also observed upon activation of virus-specific CD8 T cells and tumor-infiltrating CD8 T lymphocytes. The mechanism of TNF-driven T cell death involves TNFR2 and production of mitochondrial oxygen free radicals which damage DNA. Conclusion: The use of TNF blocking agents reduces oxidative stress, hyperpolarization of mitochondria, and the generation of DNA damage in CD8 T celss undergoing activation. The fact that TNF mediates AICD in human tumor-reactive CD8 T cells suggests that the use of TNF-blocking agents can be exploited in immunotherapy strategies.
- Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy(Springer Science and Business Media LLC, 2019) Berraondo, P. (Pedro); Llacer, C. (Casilda); Perez-Gracia, J.L. (Jose Luis); Perez-Ruiz, E. (Elisabeth); Rodriguez-Ruiz, M.E. (María Esperanza); Luque, V. (Vanesa) de; Marquez-Rodas, I. (Iván); Otano, I. (Itziar); Molina, C. (Carmeen); Ochoa, M.C. (María Carmen); Melero, I. (Ignacio); Andrea, C.E. (Carlos Eduardo) de; Belsue, V. (Virginia); Álvarez, M. (Maite); Álvarez, M. (Martina); Minute, L. (Luna); Teijeira, A. (Álvaro)Combined PD-1 and CTLA-4-targeted immunotherapy with nivolumab and ipilimumab is effective against melanoma, renal cell carcinoma and non-small-cell lung cancer1-3. However, this comes at the cost of frequent, serious immune-related adverse events, necessitating a reduction in the recommended dose of ipilimumab that is given to patients4. In mice, co-treatment with surrogate anti-PD-1 and anti-CTLA-4 monoclonal antibodies is effective in transplantable cancer models, but also exacerbates autoimmune colitis. Here we show that treating mice with clinically available TNF inhibitors concomitantly with combined CTLA-4 and PD-1 immunotherapy ameliorates colitis and, in addition, improves anti-tumour efficacy. Notably, TNF is upregulated in the intestine of patients suffering from colitis after dual ipilimumab and nivolumab treatment. We created a model in which Rag2-/-Il2rg-/- mice were adoptively transferred with human peripheral blood mononuclear cells, causing graft-versus-host disease that was further exacerbated by ipilimumab and nivolumab treatment. When human colon cancer cells were xenografted into these mice, prophylactic blockade of human TNF improved colitis and hepatitis in xenografted mice, and moreover, immunotherapeutic control of xenografted tumours was retained. Our results provide clinically feasible strategies to dissociate efficacy and toxicity in the use of combined immune checkpoint blockade for cancer immunotherapy.
- Intratumoral co-injection of the poly I:C-derivative BO-112 and a STING agonist synergize to achieve local and distant anti-tumor efficacy(2021) Glez-Vaz, J. (Javier); Berraondo, P. (Pedro); Fan, X. (X.); Fernández-Sendín, M. (Myriam); NO USAR de Andrea, C. E. (Carlos E.); González-Gomariz, J. (José); Rodriguez-Ruiz, M.E. (María Esperanza); Villalba, M. (María); Quintero, M. (Marisol); Aranda, F. (Fernando); Molina, C. (Carmeen); Ochoa, M.C. (María Carmen); Melero, I. (Ignacio); Álvarez, M. (Maite); Shen, W. H. (Wen H.); Fernandez-Sanmamed, M. (Miguel); Teijeira, A. (Álvaro)Background BO-112 is a nanoplexed form of polyinosinic:polycytidylic acid that acting on toll-like receptor 3 (TLR3), melanoma differentiation-associated protein 5 (MDA5) and protein kinase RNA-activated (PKR) elicits rejection of directly injected transplanted tumors, but has only modest efficacy against distant untreated tumors. Its clinical activity has also been documented in early phase clinical trials. The 5,6-dimethylxanthenone-4-acetic acid (DMXAA) stimulator of interferon genes (STING) agonist shows a comparable pattern of efficacy when used via intratumoral injections. Methods Mice subcutaneously engrafted with bilateral MC38 and B16.OVA-derived tumors were treated with proinflammatory immunotherapy agents known to be active when intratumorally delivered. The combination of BO-112 and DMXAA was chosen given its excellent efficacy and the requirements for antitumor effects were studied on selective depletion of immune cell types and in gene-modified mouse strains lacking basic leucine zipper ATF-like transcription factor 3 (BATF3), interferon-α/β receptor (IFNAR) or STING. Spatial requirements for the injections were studied in mice bearing three tumor lesions. Results BO-112 and DMXAA when co-injected in one of the lesions of mice bearing concomitant bilateral tumors frequently achieved complete local and distant antitumor efficacy. Synergistic effects were contingent on CD8 T cell lymphocytes and dependent on conventional type 1 dendritic cells, responsiveness to type I interferon (IFN) and STING function in the tumor-bearing host. Efficacy was preserved even if BO-112 and DMXAA were injected in separate lesions in a manner able to control another untreated third-party tumor. Efficacy could be further enhanced on concurrent PD-1 blockade. Conclusion Clinically feasible co-injections of BO-112 and a STING agonist attain synergistic efficacy able to eradicate distant untreated tumor lesions.
- Depletion of conventional type-1 dendritic cells in established tumors suppresses immunotherapy efficacy(AACR, 2022) Egea, J. (Josune); Berraondo, P. (Pedro); Kaisho, T. (Tsuneyasu); Cirella, A. (Assunta); Azpilikueta, A. (Arantza); Sancho, D. (David); Verkhusha, V. (Vladislav); Rouzaut, A. (Ana); Gato-Cañas, M. (María); Rodriguez, I. (Inmaculada); Wculek, S.K. (Stefanie K.); Garasa, S. (Saray); Molina, C. (Carmeen); Melero, I. (Ignacio); Valencia, K. (Karmele); Andrea, C.E. (Carlos Eduardo) de; Olivera, I. (Irene); Luri-Rey, C. (Carlos); Teijeira, A. (Álvaro)The ability of conventional type-1 dendritic cells (cDC1) to cross-present tumor antigens to CD8+ T cells is critical for the induction of antitumor CTLs. Mice that are constitutively deficient in cDC1 cells have been reported to fail to respond to immunotherapy strategies based on checkpoint inhibitors. However, further work is needed to clarify the precise time during immunotherapy treatment that cDC1 cells are required for the beneficial effect of treatment. Here, we used a refined XCR1-DTR-Venus transgenic mouse model to acutely deplete cDC1 cells and trace their behavior using intravital microscopy. Diphtheria toxin-mediated cDC1 depletion prior to immunotherapy treatment with anti-PD-1 and/or anti-CD137 immunostimulatory mAbs completely ablated antitumor efficacy. The efficacy of adoptive T-cell therapy was also hampered by prior cDC1 depletion. After the onset of immunotherapy treatment, depletion of cDC1s only moderately reduced the therapeutic efficacy of anti-PD-1 and anti-CD137 mAbs. Intravital microscopy of liver-engrafted tumors revealed changes in the intratumoral behavior of cDC1 cells in mice receiving immunotherapy, and treatment with diphtheria toxin to deplete cDC1s impaired tumor T-cell infiltration and function. These results reveal that the functional integrity of the cDC1 compartment is required at the onset of various immunotherapies to successfully treat established tumors.
- The search for a role of the caudal intralaminar nuclei in the pathophysiology of Parkinson's disease(Elsevier, 2009) Tuñon, M.T. (María Teresa); Erro-Aguirre, M.E (María Elena); Gonzalo, N. (Nancy); Conte-Perales, L. (L.); Lanciego, J.L. (José Luis); Rico, A.J. (Alberto J.); Castle, M. (M.); Combarro, C. (C.); Aymerich-Soler, M.S. (María Soledad); Roda, E. (Elvira); Lopez, I.P. (Iciar P.); Molina, C. (Carmeen); Barroso-Chinea, P. (P.); Perez-Manso, M. (Mónica)The situation of the caudal intralaminar thalamic nuclei within basal ganglia circuits has gained increased attention over the past few years. Although initially considered as a "non-specific" thalamic nuclei, tract-tracing studies carried out over the past two decades have demonstrated that the centromedian-parafascicular thalamic complex (CM-Pf) is connected to virtually all basal ganglia components and related nuclei. Although the anatomical basis sustaining the thalamic modulation of basal ganglia circuits has long been characterized, the functional significance of these transverse circuits still remain to be properly accommodated within the basal ganglia model, both under normal conditions as well as in situations of dopaminergic depletion. However, the recent demonstration of primary (e.g., non-dopamine related) neurodegenerative phenomena restricted to the CM-Pf in Parkinson's disease (PD) has renewed interest in the role played by the caudal intralaminar nuclei in the pathophysiology of PD. Concomitantly, evidence has become available of increased metabolic activity in the caudal intralaminar nuclei in rodent models of PD. Finally, CM-Pf neurosurgery in patients suffering from PD has produced contrasting outcomes, indicating that a consensus is still to be reached regarding the potential usefulness of targeting the caudal intralaminar nuclei to treat movement disorders of basal ganglia origin.