M E Rodríguez-Ruiz1, J L Perez-Gracia2, I Rodríguez3, C Alfaro3, C Oñate3, G Pérez3, I Gil-Bazo1, A Benito4, S Inogés5, A López-Diaz de Cerio5, M Ponz-Sarvise6, L Resano7, P Berraondo8, B Barbés9, S Martin-Algarra10, A Gúrpide2, M F Sanmamed11, C de Andrea12, A M Salazar13, I Melero14. 1. Department of Oncology, Clínica Universidad de Navarra, Pamplona; Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona; CIBERONC, Centro de Investigación Biomédica en Red de Cáncer, Madrid; Navarra Health Research Insititute (IDISNA), Pamplona. 2. Department of Oncology, Clínica Universidad de Navarra, Pamplona; CIBERONC, Centro de Investigación Biomédica en Red de Cáncer, Madrid; Navarra Health Research Insititute (IDISNA), Pamplona. 3. Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona; CIBERONC, Centro de Investigación Biomédica en Red de Cáncer, Madrid; Departments of Immunology, Pamplona. 4. Radiology, Pamplona. 5. Navarra Health Research Insititute (IDISNA), Pamplona; Departments of Immunology, Pamplona. 6. Department of Oncology, Clínica Universidad de Navarra, Pamplona; Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona; Navarra Health Research Insititute (IDISNA), Pamplona. 7. Department of Oncology, Clínica Universidad de Navarra, Pamplona. 8. Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona; CIBERONC, Centro de Investigación Biomédica en Red de Cáncer, Madrid; Navarra Health Research Insititute (IDISNA), Pamplona. 9. Navarra Health Research Insititute (IDISNA), Pamplona; Physics, Clínica Universidad de Navarra, Pamplona, Spain. 10. Department of Oncology, Clínica Universidad de Navarra, Pamplona; Navarra Health Research Insititute (IDISNA), Pamplona. 11. Department of Oncology, Clínica Universidad de Navarra, Pamplona; Immunobiology Department, Yale University School of Medicine, New Haven, USA. 12. CIBERONC, Centro de Investigación Biomédica en Red de Cáncer, Madrid; Navarra Health Research Insititute (IDISNA), Pamplona; Department of Pathology, Clínica Universidad de Navarra, Pamplona, Spain. 13. Oncovir, Washington, USA. 14. Department of Oncology, Clínica Universidad de Navarra, Pamplona; Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona; CIBERONC, Centro de Investigación Biomédica en Red de Cáncer, Madrid; Navarra Health Research Insititute (IDISNA), Pamplona; Departments of Immunology, Pamplona. Electronic address: imelero@unav.es.
Abstract
Background: Combination immunotherapy has the potential to achieve additive or synergistic effects. Combined local injections of dsRNA analogues (mimicking viral RNA) and repeated vaccinations with tumor-lysate loaded dendritic cells shows efficacy against colon cancer mouse models. In the context of immunotherapy, radiotherapy can exert beneficial abscopal effects. Patients and methods: In this two-cohort pilot phase I study, 15 advanced cancer patients received two 4-week cycles of four intradermal daily doses of monocyte-derived dendritic cells preloaded with autologous tumor lysate and matured for 24 h with poly-ICLC (Hiltonol), TNF-α and IFN-α. On days +8 and +10 of each cycle, patients received intratumoral image-guided 0.25 mg injections of the dsRNA-analogue Hiltonol. Cyclophosphamide 600 mg/m2 was administered 1 week before. Six patients received stereotactic ablative radiotherapy (SABR) on selected tumor lesions, including those injected with Hiltonol. Expression of 25 immune-relevant genes was sequentially monitored by RT-PCR on circulating peripheral blood mononuclear cell (PBMCs) and serum concentrations of a cytokine panel were sequentially determined before and during treatment. Pre- and post-treatment PBMC from patients achieving durable stable disease (SD) were studied by IFNγ ELISPOT-assays responding to tumor-lysate loaded DC and by TCRβ sequencing. Results: Combined treatment was, safe and well tolerated. One heavily pretreated castration-resistant prostate cancer patient experienced a remarkable mixed abscopal response to SABR+ immunotherapy. No objective responses were observed, while nine patients presented SD (five of them in the six-patient radiotherapy cohort). Intratumoral Hiltonol increased IFN-β and IFN-α mRNA in circulating PBMC. DC vaccination increased serum IL-12 and IL-1β concentrations, especially in patients presenting SD. IFNγ-ELISPOT reactivity to tumor lysates was observed in two patients experiencing durable SD. Conclusions: This radio-immunotherapy combination strategy, aimed at resembling viral infection in tumor tissue in combination with a dendritic-cell vaccine and SABR, is safe and shows immune-associated activity and signs of preliminary clinical efficacy.
Background: Combination immunotherapy has the potential to achieve additive or synergistic effects. Combined local injections of dsRNA analogues (mimicking viral RNA) and repeated vaccinations with tumor-lysate loaded dendritic cells shows efficacy against colon cancermouse models. In the context of immunotherapy, radiotherapy can exert beneficial abscopal effects. Patients and methods: In this two-cohort pilot phase I study, 15 advanced cancerpatients received two 4-week cycles of four intradermal daily doses of monocyte-derived dendritic cells preloaded with autologous tumor lysate and matured for 24 h with poly-ICLC (Hiltonol), TNF-α and IFN-α. On days +8 and +10 of each cycle, patients received intratumoral image-guided 0.25 mg injections of the dsRNA-analogue Hiltonol. Cyclophosphamide 600 mg/m2 was administered 1 week before. Six patients received stereotactic ablative radiotherapy (SABR) on selected tumor lesions, including those injected with Hiltonol. Expression of 25 immune-relevant genes was sequentially monitored by RT-PCR on circulating peripheral blood mononuclear cell (PBMCs) and serum concentrations of a cytokine panel were sequentially determined before and during treatment. Pre- and post-treatment PBMC from patients achieving durable stable disease (SD) were studied by IFNγ ELISPOT-assays responding to tumor-lysate loaded DC and by TCRβ sequencing. Results: Combined treatment was, safe and well tolerated. One heavily pretreated castration-resistant prostate cancerpatient experienced a remarkable mixed abscopal response to SABR+ immunotherapy. No objective responses were observed, while nine patients presented SD (five of them in the six-patient radiotherapy cohort). Intratumoral Hiltonol increased IFN-β and IFN-α mRNA in circulating PBMC. DC vaccination increased serum IL-12 and IL-1β concentrations, especially in patients presenting SD. IFNγ-ELISPOT reactivity to tumor lysates was observed in two patients experiencing durable SD. Conclusions: This radio-immunotherapy combination strategy, aimed at resembling viral infection in tumor tissue in combination with a dendritic-cell vaccine and SABR, is safe and shows immune-associated activity and signs of preliminary clinical efficacy.
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