Pastor, F. (Fernando)
- Publications
- item.page.relationships.isContributorAdvisorOfPublication
- item.page.relationships.isContributorOfPublication
14 results
Search Results
Now showing 1 - 10 of 14
- Aptamers, a new therapeutic opportunity for the treatment of multiple myeloma(2022) Amundarain, A. (Ane); Pastor, F. (Fernando); Aguirre-Ena, X. (Xabier); Prosper-Cardoso, F. (Felipe)Simple Summary Multiple Myeloma (MM) remains incurable due to high relapse rates and fast development of drug resistances. Monoclonal antibodies (mAb) have revolutionized MM treatment, opening the door to chemotherapy-free yet curative treatments. Nevertheless, antibody-based therapies face several difficulties which could be overcome by nucleic acid aptamers. Aptamers are short oligonucleotide ligands that bind their targets with great affinity and specificity, and can be easily conjugated to different cargoes for their cell-specific delivery. This review summarizes the aptamers that have been tested in MM so far with promising results, and proposes various strategies for the further development of aptamer-based strategies against MM. Multiple Myeloma (MM) remains an incurable disease due to high relapse rates and fast development of drug resistances. The introduction of monoclonal antibodies (mAb) has caused a paradigm shift in MM treatment, paving the way for targeted approaches with increased efficacy and reduced toxicities. Nevertheless, antibody-based therapies face several difficulties such as high immunogenicity, high production costs and limited conjugation capacity, which we believe could be overcome by the introduction of nucleic acid aptamers. Similar to antibodies, aptamers can bind to their targets with great affinity and specificity. However, their chemical nature reduces their immunogenicity and production costs, while it enables their conjugation to a wide variety of cargoes for their use as delivery agents. In this review, we summarize several aptamers that have been tested against MM specific targets with promising results, establishing the rationale for the further development of aptamer-based strategies against MM. In this direction, we believe that the study of novel plasma cell surface markers, the development of intracellular aptamers and further research on aptamers as building blocks for complex nanomedicines will lead to the generation of next-generation targeted approaches that will undoubtedly contribute to improve the management and life quality of MM patients.
- Modulating T Cell Responses by Targeting CD3(2023) Menon, A.P. (Ashwathi Puravankara); Nonatelli, F. (Francesca); Pastor, F. (Fernando); Moreno, B. (Beatriz); Villanueva-Ruiz, M.E. (María Elena); Meraviglia-Crivelli, D. (Daniel); van-Santen, H.M. (Hisse M.); Barainka, M. (Martin); Zheleva, A. (Angelina)Simple Summary CD3 complex provides the first signal sensed by the TCR of the lymphocyte to trigger its activation. Thus, it becomes a very attractive receptor to determine the fate of the immune response in different contexts from tolerance induction to immune activation. We discuss CD3-TCR complex assembly and the current and emerging approaches to harvest CD3 activity for immunotherapy. Harnessing the immune system to fight cancer has become a reality with the clinical success of immune-checkpoint blockade (ICB) antibodies against PD(L)-1 and CTLA-4. However, not all cancer patients respond to ICB. Thus, there is a need to modulate the immune system through alternative strategies for improving clinical responses to ICB. The CD3-T cell receptor (TCR) is the canonical receptor complex on T cells. It provides the first signal that initiates T cell activation and determines the specificity of the immune response. The TCR confers the binding specificity whilst the CD3 subunits facilitate signal transduction necessary for T cell activation. While the mechanisms through which antigen sensing and signal transduction occur in the CD3-TCR complex are still under debate, recent revelations regarding the intricate 3D structure of the CD3-TCR complex might open the possibility of modulating its activity by designing targeted drugs and tools, including aptamers. In this review, we summarize the basis of CD3-TCR complex assembly and survey the clinical and preclinical therapeutic tools available to modulate CD3-TCR function for potentiating cancer immunotherapy.
- Therapeutic strategies to enhance tumor antigenicity: making the tumor detectable by the immune system(2022) Pastor, F. (Fernando); Moreno, B. (Beatriz); Villanueva-Ruiz, M.E. (María Elena); Meraviglia-Crivelli, D. (Daniel); Barainka, M. (Martin); Zheleva, A. (Angelina)Cancer immunotherapy has revolutionized the oncology field, but many patients still do not respond to current immunotherapy approaches. One of the main challenges in broadening the range of responses to this type of treatment is the limited source of tumor neoantigens. T cells constitute a main line of defense against cancer, and the decisive step to trigger their activation is mediated by antigen recognition. Antigens allow the immune system to differentiate between self and foreign, which constitutes a critical step in recognition of cancer cells and the consequent development or control of the malignancy. One of the keystones to achieving a successful antitumor response is the presence of potent tumor antigens, known as neoantigens. However, tumors develop strategies to evade the immune system and resist current immunotherapies, and many tumors present a low tumor mutation burden limiting the presence of tumor antigenicity. Therefore, new approaches must be taken into consideration to overcome these shortcomings. The possibility of making tumors more antigenic represents a promising front to further improve the success of immunotherapy in cancer. Throughout this review, we explored different state-of-the-art tools to induce the presentation of new tumor antigens by intervening at protein, mRNA or genomic levels in malignant cells.
- Clinical benefit associated with idiotypic vaccination in patients with follicular lymphoma.(Oxford University Press, 2006) Garcia-Muñoz, R. (R.); Pastor, F. (Fernando); Orfao, A. (Alberto); Lopez-Diaz-de-Cerio, A. (Ascensión); Rodriguez-Caballero, A. (Arancha); Rocha, E. (Eduardo); Panizo, C. (Carlos); Inoges, S. (Susana); Perez-Calvo, J. (Javier); Villanueva, H. (Helena); Melero, I. (Ignacio); Bendandi, M. (Maurizio); Suarez, L. (Lilia); Soria, E. (Elena); Zabalegui, N. (Natalia); Rodriguez-Calvillo, M. (Mercedes)BACKGROUND: Follicular lymphoma is considered incurable, although cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy can induce sequential remissions. A patient's second complete response is typically shorter than that patient's first complete response. Idiotype vaccines can elicit specific immune responses and molecular remissions in patients with follicular lymphoma. However, a clinical benefit has never been formally proven. METHODS: Thirty-three consecutive follicular lymphoma patients in first relapse received six monthly cycles of CHOP-like chemotherapy. Patients who achieved a second complete response were vaccinated periodically for more than 2 years with autologous lymphoma-derived idiotype protein vaccine. Specific humoral and cellular responses were assessed, and patients were followed for disease recurrence. Statistical tests were two-sided. RESULTS: Idiotype vaccine could be produced for 25 patients who had a second complete response. In 20 patients (80%), a humoral (13/20) and/or a cellular (18/20) idiotype-specific response was detected. The median duration of the second complete response has not been reached, but it exceeds 33 months (range = 20+ to 51+ months). None of the 20 responders relapsed while undergoing active vaccination. All responders with enough follow-up for the comparison to be made experienced a second complete response that was statistically significantly (P<.0001) longer than both their first complete response (18 of 18 patients) and than the median duration of a CHOP-induced second complete response, i.e., 13 months (20 of 20 patients). The five nonresponders all had a second complete response that was shorter (median = 10 months; range = 8-13 months) than their first complete response (median = 17 months; range = 10-39 months). CONCLUSIONS: Idiotypic vaccination induced a specific immune response in the majority of patients with follicular lymphoma. Specific immune response was associated with a dramatic and highly statistically significant increase in disease-free survival. This is the first formal demonstration of clinical benefit associated with the use of a human cancer vaccine.
- Aptamer-iRNAs as therapeutics for cancer treatment(MDPI AG, 2018) Menon, A.P. (Ashwathi Puravankara); Pastor, F. (Fernando); Meraviglia-Crivelli, D. (Daniel); Martínez-Soldevilla, M. (Mario)Aptamers are single-stranded oligonucleotides (ssDNA or ssRNA) that bind and recognize their targets with high affinity and specificity due to their complex tertiary structure. Aptamers are selected by a method called SELEX (Systematic Evolution of Ligands by EXponential enrichment). This method has allowed the selection of aptamers to different types of molecules. Since then, many aptamers have been described for the potential treatment of several diseases including cancer. It has been described over the last few years that aptamers represent a very useful tool as therapeutics, especially for cancer therapy. Aptamers, thanks to their intrinsic oligonucleotide nature, present inherent advantages over other molecules, such as cell-based products. Owing to their higher tissue penetrability, safer profile, and targeting capacity, aptamers are likely to become a novel platform for the delivery of many different types of therapeutic cargos. Here we focus the review on interfering RNAs (iRNAs) as aptamer-based targeting delivered agents. We have gathered the most reliable information on aptamers as targeting and carrier agents for the specific delivery of siRNAs, shRNA, microRNAs, and antisense oligonucleotides (ASOs) published in the last few years in the context of cancer therapy.
- IL-6/STAT3 signaling in tumor cells restricts the expression of frameshift-derived neoantigens by SMG1 induction(2022) Menon, A.P. (Ashwathi Puravankara); Pastor, F. (Fernando); Moreno, B. (Beatriz); Villanueva-Ruiz, M.E. (María Elena); Meraviglia-Crivelli, D. (Daniel); Villalba-Esparza, M. (María); Cebollero, J. (Javier); Calvo-González, A. (Alfonso); Ruiz-de-los-Mozos, I. (Igor); Barainka, M. (Martin); Zheleva, A. (Angelina); Huesa-Berral, C. (Carlos)
- ICOS costimulation at the tumor site in combination with CTLA-4 blockade therapy elicits strong tumor immunity(Elsevier BV, 2019) Menon, A.P. (Ashwathi Puravankara); Pastor, F. (Fernando); Lozano-Moreda, T. (Teresa); Moreno, B. (Beatriz); Meraviglia-Crivelli, D. (Daniel); Ruiz, M. (Marta); Villalba, M. (María); Villanueva, H. (Helena); Pejenaute-Martínez-de-Lizarrondo, Á. (Álvaro); Martínez-Soldevilla, M. (Mario); Llopiz, D. (Diana); Cebollero, J. (Javier); Sarobe, P. (Pablo)Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) blockade therapy is able to induce long-lasting antitumor responses in a fraction of cancer patients. Nonetheless, there is still room for improvement in the quest for new therapeutic combinations. ICOS costimulation has been underscored as a possible target to include with CTLA-4 blocking treatment. Herein, we describe an ICOS agonistic aptamer that potentiates T cell activation and induces stronger antitumor responses when locally injected at the tumor site in combination with anti-CTLA-4 antibody in different tumor models. Furthermore, ICOS agonistic aptamer was engineered as a bi-specific tumor-targeting aptamer to reach any disseminated tumor lesions after systemic injection. Treatment with the bi-specific aptamer in combination with CTLA-4 blockade showed strong antitumor immunity, even in a melanoma tumor model where CTLA-4 treatment alone did not display any significant therapeutic benefit. Thus, this work provides strong support for the development of combinatorial therapies involving anti-CTLA-4 blockade and ICOS agonist tumor-targeting agents.
- Stem Cell Transplant and Idiotypic Vaccination for B-Cell Malignancies(Bentham Science Publishers, 2011) Pastor, F. (Fernando); Lopez-Diaz-de-Cerio, A. (Ascensión); Nieto, J. (José); Sampol, A. (Antonia); Inoges, S. (Susana); Villanueva, H. (Helena); Bendandi, M. (Maurizio); Soria, E. (Elena)Several types of B-cell malignancy, including but not limited to multiple myeloma and follicular lymphoma, are still considered incurable. In a substantial number of cases, patients must undergo either autologous or allogeneic stem cell transplantation as a standard of care procedure for their disease. Among experimental treatments for multiple myeloma and follicular lymphoma, idiotypic vaccination has been attempted over the last two decades with variable degrees of success. Few clinical trials have combined stem cell transplant procedures with idiotypic vaccination, and they are the subject of this review, which will also include some of our original data, as well as our overall evaluation of this field of clinical investigation. Although apparently at the opposite extremes of the therapeutic option array, toxicity-burdened stem cell transplantation and virtually innocuous idiotypic vaccination might well offer a sound curative opportunity to some patients with otherwise incurable B-cell malignancies, provided that the latter treatment first succeeds at obtaining regulatory approval.
- Decoy-based, targeted inhibition of STAT3: A new step forward for B cell lymphoma immunotherapy(Cell Press, 2018) Pastor, F. (Fernando); Martínez-Soldevilla, M. (Mario)Increasing evidence has linked the aggressiveness of non-Hodgkin’s lymphoma, in particular activated B cell-like type diffuse large B cell lymphomas (ABC-DLBCL), to signaling by toll-like receptor 9 (TLR9)/ MyD88 and STAT3. In this issue of Molecular Therapy, Zhao et al.1 describe a dual function molecule comprising a clinically-relevant TLR9 agonist (CpG7909) fused to a STAT3 inhibitor in the form of a high-affinity decoy oligodeoxynucleotide (dODN). CpG-STAT3dODN blocked STAT3 DNA binding and activity, thus reducing expression of downstream target genes, such as MYC and BCL2L1, in human and mouse lymphoma cells. These effects led to the generation of lymphoma cell-specific CD8/ CD4-dependent T cell immunity that could protect mice from tumor rechallenge.
- Idiotype vaccines for human B-cell malignancies(Bentham Science Publishers, 2010) Pastor, F. (Fernando); Lopez-Diaz-de-Cerio, A. (Ascensión); Inoges, S. (Susana); Villanueva, H. (Helena); Bendandi, M. (Maurizio); Soria, E. (Elena)After twenty years of use in humans, customized idiotypic vaccination yet remains a non-approved, experimental therapeutic option for patients with lymphoma and myeloma. Potentially applicable to all B-cell malignancies whose cells express a clonal immunoglobulin or its epitopes on their surface, this treatment is designed to prevent disease recurrence or progression. Mostly used in follicular lymphoma patients so far, idiotype vaccines have clearly shown biological efficacy, clinical efficacy and clinical benefit in this setting, although no study aiming at regulatory approval of the procedure has been able to meet its main clinical endpoints. In mantle cell lymphoma, only biological efficacy has been proven for idiotypic vaccination, while in multiple myeloma a limited number of studies support the notion of biological and perhaps even clinical efficacy, although no credible evidence of clinical benefit has still emerged. Idiotype vaccines have been produced and administered in a number of substantially different manners. Therefore, the results of most clinical trials cannot be easily compared, and even less pooled together in meaningful meta-analyses. A more creative and yet scientifically sound way to design clinical trials of customized active immunotherapies will be key to the future development of idiotype vaccines, particularly considering that we currently lack any clinical or biological indicator to possibly predict which patients are more likely to respond to idiotypic vaccination from an immunologic point of view. This review aims at summarizing the multifaceted success achieved by idiotype vaccines, as well as at outlining the challenges awaiting them in the near future: how to improve feasibility, immunogenicity and efficacy, as well as how to confirm benefit and gain regulatory approval.