Nuestros investigadores

Felipe Calvo Manuel

Publicaciones científicas más recientes (desde 2010)

Autores: Rodriguez, I.; et al.
ISSN 1535-7163  Vol. 18  Nº 3  2019  págs. 621 - 631
Radiotherapy can be synergistically combined with immunotherapy in mouse models, extending its efficacious effects outside of the irradiated field (abscopal effects). We previously reported that a regimen encompassing local radiotherapy in combination with anti-CD137 plus anti-PD-1 mAbs achieves potent abscopal effects against syngeneic transplanted murine tumors up to a certain tumor size. Knowing that TGF beta expression or activation increases in irradiated tissues, we tested whether TGF beta blockade may further enhance abscopal effects in conjunction with the anti-PD-1 plus anti-CD137 mAb combination. Indeed, TGF beta blockade with 1D11, a TGF beta-neutralizing mAb, markedly enhanced abscopal effects and overall treatment efficacy against subcutaneous tumors of either 4T1 breast cancer cells or large MC38 colorectal tumors. Increases in CD8 T cells infiltrating the nonirradiated lesion were documented upon combined treatment, which intensely expressed Granzyme-B as an indicator of cytotoxic effector capability. Interestingly, tumor tissue but not healthy tissue irradiation results in the presence of higher concentrations of TGF beta in the nonirradiated contralateral tumor that showed smad2/3 phosphorylation increases in infiltrating CD8 T cells. In conclusion, radiotherapy-induced TGF beta hampers abscopal efficacy even upon combination with a potent immunotherapy regimen. Therefore, TGF beta blockade in combination with radioimmunotherapy results in greater efficacy.
Autores: Garcia-Vazquez, V., (Autor de correspondencia); Sese-Lucio, B.; Calvo, Felipe Ángel; et al.
ISSN 1748-717X  Vol. 13  2018 
BackgroundDose calculations in intraoperative electron radiation therapy (IOERT) rely on the conventional assumption of water-equivalent tissues at the applicator end, which defines a flat irradiation surface. However, the shape of the irradiation surface modifies the dose distribution. Our study explores, for the first time, the use of surface scanning methods for three-dimensional dose calculation of IOERT.MethodsTwo different three-dimensional scanning technologies were evaluated in a simulated IOERT scenario: a tracked conoscopic holography sensor (ConoProbe) and a structured-light three-dimensional scanner (Artec). Dose distributions obtained from computed tomography studies of the surgical field (gold standard) were compared with those calculated under the conventional assumption or from pseudo-computed tomography studies based on surfaces.ResultsIn the simulated IOERT scenario, the conventional assumption led to an average gamma pass rate of 39.9% for dose values greater than 10% (two configurations, with and without blood in the surgical field). Results improved when considering surfaces in the dose calculation (88.5% for ConoProbe and 92.9% for Artec).ConclusionsMore accurate three-dimensional dose distributions were obtained when considering surfaces in the dose calculation of the simulated surgical field. The structured-light three-dimensional scanner provided the best results in terms of dose distributions. The findings obtained in this specific experimental setup warrant further research on surface scanning in the IOERT context owing to the clinical interest of improving the documentation of the actual IOERT scenario.
Autores: Rodríguez, I.; Leaman, O.; et al.
ISSN 1879-016X  Vol. 196  2018  págs. 195 - 203
Radiotherapy of cancer has been traditionally considered as a local therapy without noticeable effects outside the irradiated fields. However, ionizing radiation exerts multiple biological effects on both malignant and stromal cells that account for a complex spectrum of mechanisms beyond simple termination of cancer cells. In the era of immunotherapy, interest in radiation-induced inflammation and cell death has considerably risen, since these mechanisms lead to profound changes in the systemic immune response against cancer antigens. Immunotherapies such as immunomodulatory monoclonal antibodies (anti-PD-1, anti-CTLA-4, anti-CD137, anti-OX40, anti-CD40, anti-TGFß), TLR-agonists, and adoptive T-cell therapy have been synergistically combined with radiotherapy in mouse models. Importantly, radiation and immunotherapy combinations do not only act against the irradiated tumor but also against distant non-irradiated metastases (abscopal effects). A series of clinical trials are exploring the beneficial effects of radioimmunotherapy combinations. The concepts of crosspriming of tumor neoantigens and immunogenic cell death are key elements underlying this combination efficacy. Proinflamatory changes in the vasculature of the irradiated lesions and in the cellular composition of the leukocyte infiltrates in the tumor microenvironment contribute to raise or dampen cancer immunogenicity. It should be stressed that not all effects of radiotherapy favor antitumor immunity as there are counterbalancing mechanisms such as TGFß and VEGFs that inhibit the efficacy of the antitumor immune response, hence offering additional therapeutic targets to suppress. All in all, radiotherapy and immunotherapy are compatible and often synergistic approaches against cancer that jointly target irradiated and non-irradiated malignant lesions in the same patient.
Autores: Cambeiro, Felix Mauricio; Calvo, Felipe Ángel;
ISSN 1576-8260  Vol. 71  Nº 3  2018  págs. 298-305
Autores: Sole, Claudio V.; Calvo, Felipe Ángel; Alvarez, Eduardo; et al.
ISSN 1879-0887  Vol. 119  Nº 1  2016  págs. 30-34
Purpose To assess long-term outcomes and toxicity of adjuvant radiotherapy in the post-surgical management of patients with resected high-grade skeletal osteosarcomas. Methods and materials Seventy-two patients with primary resected osteosarcomas underwent adjuvant radiotherapy after neoadjuvant chemotherapy from December 1984 to December 2008. Local control (LC), overall survival (OS) and disease-free survival (DFS) were estimated using Kaplan¿Meier methods. For survival outcomes potential associations were assessed in univariate and multivariate analyses using the Cox proportional hazards model. Results After a median follow-up of 174 months (range, 33¿363 months), 10-year LC, DFS, and OS rates were 82%, 58%, and 73%, respectively. In the multivariate analysis only R1 margin status (p = 0.02) remained significantly associated with LC. Patients with tumor necrosis <90% (p = 0.04) and R1 resection margin (p = 0.05) remained at a significantly higher risk of mortality on multivariate analysis. Six patients (8%) developed grade ¿3 treatment-related chronic toxicity events. No grade 5 toxicities were reported. Conclusions A multimodal radiotherapy-containing approach is a well-tolerated component of treatment for patients with osteosarcomas undergoing programed resection, allowing low toxicity rates while maintaining high local control rates.