Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients
Mené sur 15 patients atteints d'un cancer de stade avancé, cet essai de phase I évalue la sécurité et la tolérabilité d'un traitement combinant une injection intratumorale de l'immunostimulant poly-ICLC, une vaccination à base de cellules dendritiques et une radiothérapie stéréotaxique ablative
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 24h 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 one 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 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 were studied by IFN
γ 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 stable disease (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 stable disease (SD). IFNγ-ELISPOT reactivity to tumor lysates was observed in two patients experiencing durable SD. CONCLUSIONS
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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.
Annals of Oncology 2018