Mejías-Sosa, L.D. (Luis D.)
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- Modification of breast cancer milieu with chemotherapy plus dendritic cell vaccine: an approach to select best therapeutic strategies(2023) Hato-Álvaro, L. (Laura); Espinos, J. (Jaime); Lozano, M.D. (María Dolores); Pérez-Solans, B. (Belén); Lopez-Diaz-de-Cerio, A. (Ascensión); Córdoba-Iturriagagoitia, A. (Alicia); Santisteban, M. (Marta); Inoges, S. (Susana); Guillen-Grima, F. (Francisco); Mejías-Sosa, L.D. (Luis D.); Idoate, M.A. (Miguel Ángel); Sala-Elarre, P. (Pablo); Cruz, S. (S.) de la; López-Janeiro, Á. (Álvaro)Background: The addition of dendritic cell vaccines (DCV) to NAC could induce immune responses in those patients with residual disease (RD) by transforming the tumor microenvironment. Methods: Core diagnostic biopsies and surgical specimens from 80 patients (38 in the vaccinated group plus NAC (VG) and 42 in the control group (CG, treated only with NAC) were selected. We quantify TILs (CD8, CD4 and CD45RO) using immunohistochemistry and the automated cellular imaging system (ACIS III) in paired samples. Results: A CD8 rise in TNBC samples was observed after NAC plus DCV, changing from 4.48% in the biopsy to 6.70% in the surgical specimen, not reaching statistically significant differences (p = 0.11). This enrichment was seen in up to 67% of TNBC patients in the experimental arm as compared with the CG (20%). An association between CD8 TILs before NAC (4% cut-off point) and pathological complete response in the VG was found in the univariate and multivariate analysis (OR = 1.41, IC95% 1.05-1.90; p = 0.02, and OR = 2.0, IC95% 1.05-3.9; p = 0.03, respectively). Conclusion: Our findings suggest that patients with TNBC could benefit from the stimulation of the antitumor immune system by using DCV together with NAC.
- Final results regarding the addition of dendritic cell vaccines to neoadjuvant chemotherapy in early HER2-negative breast cancer patients: clinical and translational analysis(Sage Journals, 2021) Hato-Álvaro, L. (Laura); Rodríguez-Espiteri, N. (Natalia); Pérez-Solans, B. (Belén); Sanchez-Bayona, R. (Rodrigo); Lopez-Diaz-de-Cerio, A. (Ascensión); Urrizola-Martínez, A. (Amaia); Toledo, E. (Estefanía); Santisteban, M. (Marta); Inoges, S. (Susana); Salgado, E. (Esteban); Mejías-Sosa, L.D. (Luis D.); Idoate, M.A. (Miguel Ángel); Olartecoechea, B. (Begoña)Background:Primary breast cancer (BC) has shown a higher immune infiltration than the metastatic disease, justifying the optimal scenario for immunotherapy. Recently, neoadjuvant chemotherapy (NAC) combined with immune checkpoint inhibitors has demonstrated a gain in pathological complete responses (tpCR) in patients with BC. The aim of our study is to evaluate the safety, feasibility, and efficacy of the addition of dendritic cell vaccines (DCV) to NAC in HER2-negative BC patients. Methods:Thirty-nine patients with early BC received DCV together with NAC conforming the vaccinated group (VG) and compared with 44 patients as the control group (CG). All patients received anthracyclines and taxanes-based NAC (ddECx4→Dx4) followed by surgery ± radiotherapy ± hormonotherapy. Results:The tpCR rate was 28.9% in the VG and 9.09% in the CG (p = 0.03). Pathological CR in the triple negative (TN) BC were 50.0% versus 30.7% (p = 0.25), 16.6% versus 0% in luminal B (p = 0.15), and none among luminal A patients in VG versus CG, respectively. Impact of DCV was significantly higher in the programmed cell death ligand 1 (PD-L1) negative population (p < 0.001). PD-L1 expression was increased in patients with residual disease in the VG as compared with the CG (p < 0.01). No grade ⩾3 vaccine-related adverse events occurred. With a median follow-up of 8 years, no changes were seen in event-free survival or overall survival. Phenotypic changes post DCV in peripheral blood were observed in myeloid-derived suppressor cells (MDSC), NK, and T cells. Increase in blood cell proliferation and interferon (IFN)-γ production was detected in 69% and 74% in the VG, respectively. Humoral response was also found. Clonality changes in TCR-β repertoire were detected in 67% of the patients with a drop in diversity index after treatment. Conclusion:The combination of DCV plus NAC is safe and increases tpCR, with a significant benefit among PD-L1-negative tumors. DCV modify tumor milieu and perform cellular and humoral responses in peripheral blood with no impact in outcome. Trial registration:ClinicalTrials.gov number: NCT01431196. EudraCT 2009-017402-36.
- Anti-PD1 associated fulminant myocarditis after a single pembrolizumab dose: the role of occult pre-existing autoimmunity(Ferrata Storti Foundation, 2018) Martinez-Calle, N. (Nicolas); Villar-Fernández, S. (Sara); Mejías-Sosa, L.D. (Luis D.); Melero, I. (Ignacio); Rodriguez-Otero, P. (Paula); Idoate, M.A. (Miguel Ángel); Paiva, B. (Bruno); Marinello, P. (Patricia); Prosper-Cardoso, F. (Felipe); San-Miguel, J.F. (Jesús F.)Multiple myeloma is a promising candidate for anti-PD1 checkpoint inhibitor therapy.1–3 Results of phase I trials of pembrolizumab, in combination with lenalidomide or pomalidomide in relapsed/refractory patients have shown encouraging results. These trials showed a 35% and 65% response rate in patients already refractory to IMIDs with a median PFS of 7.2 and 14 months for the lenalidomide and pomalidomide combinations, respectively.4,5 These positive results prompted the activation of phase III trials, which are currently underway in relapsed (clinicaltrials.gov identifier 02576977) and first-line setting (clinicaltrials.gov identifier 02579863). Immune-related adverse events (irAE) as a result of uncontrolled activation of autoreactive T-cells,6 are the most important emerging safety issues of checkpoint inhibitors. Myocarditis is rare among the irAE; however, several cases of lethal immune-related myocarditis have recently been published.7–9 The Nivolumab patient database has revealed an incidence of myocarditis of 0.09% in over 20,000 patients already treated;7 however, this figure may be an underestimation since only symptomatic cases were recorded. Myocarditis seems to be frequent with the nivolumab-ipilimumab combination (0.27%), with two reports of a lethal outcome.8 To the best of our knowledge, no fatal cases have been reported with pembrolizumab or nivolumab as single checkpoint inhibitor agents. Here, we report a newly diagnosed multiple myeloma patient who developed a lethal immune-related myocarditis after a single dose of pembrolizumab, which was combined with lenalidomide and dexamethasone, not with other checkpoint inhibitors.
- Use of Machine-Learning Algorithms in Intensified Preoperative Therapy of Pancreatic Cancer to Predict Individual Risk of Relapse(MDPI AG, 2019) Chopitea, A. (Ana); Larrea-Leoz, B. (Blanca); Rotellar, F. (Fernando); Benito-Boíllos, A. (Alberto); Baudin, V. (Vicky); Carranza, O. (Omar); Arbea-Moreno, L. (Leire); Pardo, F. (Fernando); Subtil, J.C. (José Carlos); Ponz-Sarvise, M. (Mariano); Mejías-Sosa, L.D. (Luis D.); Sala-Elarre, P. (Pablo); Rodríguez-Rodríguez, J. (Javier); Iragorri-Barberena, Y. (Yohana); Yu, K.H. (Kenneth H.); Oyaga-Iriarte, E. (Esther)Background: Although surgical resection is the only potentially curative treatment for pancreatic cancer (PC), long-term outcomes of this treatment remain poor. The aim of this study is to describe the feasibility of a neoadjuvant treatment with induction polychemotherapy (IPCT) followed by chemoradiation (CRT) in resectable PC, and to develop a machine-learning algorithm to predict risk of relapse. Methods: Forty patients with resectable PC treated in our institution with IPCT (based on mFOLFOXIRI, GEMOX or GEMOXEL) followed by CRT (50 Gy and concurrent Capecitabine) were retrospectively analyzed. Additionally, clinical, pathological and analytical data were collected in order to perform a 2-year relapse-risk predictive population model using machine-learning techniques. Results: A R0 resection was achieved in 90% of the patients. After a median follow-up of 33.5 months, median progression-free survival (PFS) was 18 months and median overall survival (OS) was 39 months. The 3 and 5-year actuarial PFS were 43.8% and 32.3%, respectively. The 3 and 5-year actuarial OS were 51.5% and 34.8%, respectively. Forty-percent of grade 3-4 IPCT toxicity, and 29.7% of grade 3 CRT toxicity were reported. Considering the use of granulocyte colony-stimulating factors, the number of resected lymph nodes, the presence of perineural invasion and the surgical margin status, a logistic regression algorithm predicted the individual 2-year relapse-risk with an accuracy of 0.71 (95% confidence interval [CI] 0.56-0.84, p = 0.005). The model-predicted outcome matched 64% of the observed outcomes in an external dataset. Conclusion: An intensified multimodal neoadjuvant approach (IPCT + CRT) in resectable PC is feasible, with an encouraging long-term outcome. Machine-learning algorithms might be a useful tool to predict individual risk of relapse. A small sample size and therapy heterogeneity remain as potential limitations.
- Assessing the impact of the addition of dendritic cell vaccination to neoadjuvant chemotherapy in breast cancer patients: A model-based characterization approach(Wiley, 2019) Espinos, J. (Jaime); Pérez-Solans, B. (Belén); Lopez-Diaz-de-Cerio, A. (Ascensión); Troconiz, I.F. (Iñaki F.); Santisteban, M. (Marta); Elizalde, A. (Arlette); Inoges, S. (Susana); Pina-Insausti, L. (Luis); Salgado, E. (Esteban); Mejías-Sosa, L.D. (Luis D.)Aims: Immunotherapy is a rising alternative to traditional treatment in breast cancer (BC) patients in order to transform cold into hot immune enriched tumours and improve responses and outcome. A computational modelling approach was applied to quantify modulation effects of immunotherapy and chemotherapy response on tumour shrinkage and progression-free survival (PFS) in naïve BC patients. Methods: Eighty-three Her2-negative BC patients were recruited for neoadjuvant chemotherapy with or without immunotherapy based on dendritic cell vaccination. Sequential tumour size measurements were modelled using nonlinear mixed effects modelling and linked to PFS. Data from another set of patients (n = 111) were used to validate the model. Results: Tumour size profiles over time were linked to biomarker dynamics and PFS. The immunotherapy effect was related to tumour shrinkage (P < .05), with the shrinkage 17% (95% confidence interval: 2-23%) being higher in vaccinated patients, confirmed by the finding that pathological complete response rates in the breast were higher in the vaccinated compared to the control group (25.6% vs 13.6%; P = .04). The whole tumour shrinkage time profile was the major prognostic factor associated to PFS (P < .05), and therefore, immunotherapy influences indirectly on PFS, showing a trend in decreasing the probability of progression with increased vaccine effects. Tumour subtype was also associated with PFS (P < .05), showing that luminal A BC patients have better prognosis. Conclusions: Dendritic cell-based immunotherapy is effective in decreasing tumour size. The semi-mechanistic validated model presented allows the quantification of the immunotherapy treatment effects on tumour shrinkage and establishes the relationship between the dynamics of tumour size and PFS.
- Cytology smears in the era of molecular biomarkers in non-small cell lung cancer: doing more with less(American Medical Association, 2018) Lozano, M.D. (María Dolores); Mejías-Sosa, L.D. (Luis D.); Abengozar-Muela, M. (Marta); Echeveste, J.I. (José I.); Idoate, M.A. (Miguel Ángel); Andrea, C.E. (Carlos Eduardo) de; Calvo-González, A. (Alfonso)Context: - The rapid advances in targeted therapies in non-small cell lung cancer (NSCLC) make the optimization and implementation of cytology specimens for molecular testing a priority. Up to 70% of patients with NSCLC are diagnosed at advanced stages and tissue biopsies often cannot be taken. Although cytology samples provide high-quality material for molecular testing, molecular cytopathology is not yet well known or widely used. Objective: - To report the many advances in molecular cytopathology and the suitability and utility of cytology samples in molecular and genetic testing of NSCLC. Data sources: - Data sources comprised published peer-reviewed literature and personal experience of the authors. Conclusions: - Molecular testing can be performed on cytologic specimens, especially on direct smears. Rapid on-site evaluation by cytopathologists has improved the adequacy and the management of cytology samples for molecular testing. Mutational profiling of NSCLC using next-generation sequencing can be performed on cytology samples from very small amounts of DNA. Fluorescence in situ hybridization assays on cytology specimens, including stained direct smear, offer some distinct advantages over their histologic counterpart, and are used to detect ALK and ROS1 rearrangements in NSCLC. Cytology specimens allow assessment of the entire tumor cell nucleus, avoiding signal loss from truncation artifacts. The use of cytology samples for assessing programmed death ligand-1 protein expression is currently being developed. Protocols for bisulfite conversion and DNA droplet digital polymerase chain reaction assays have been optimized for cytology smear to investigate aberrant DNA methylation of several NSCLC-related genes.