Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients

• Published in: Annals of oncology Vol. 29; no. 5; pp. 1312 - 1319
• Main Authors: Rodríguez-Ruiz, M.E., Perez-Gracia, J.L., Rodríguez, I., Alfaro, C., Oñate, C., Pérez, G., Gil-Bazo, I., Benito, A., Inogés, S., López-Diaz de Cerio, A., Ponz-Sarvise, M., Resano, L., Berraondo, P., Barbés, B., Martin-Algarra, S., Gúrpide, A., Sanmamed, M.F., de Andrea, C., Salazar, A.M., Melero, I.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-05-2018; Oxford University Press
• Subjects: Adult; Aged; Antigens, Neoplasm - administration & dosage; Antigens, Neoplasm - immunology; Cancer Vaccines - administration & dosage; Cancer Vaccines - immunology; Carboxymethylcellulose Sodium - administration & dosage; Carboxymethylcellulose Sodium - analogs & derivatives; Combined Modality Therapy - methods; Cyclophosphamide - administration & dosage; Cytokines - immunology; Cytokines - metabolism; dendritic cell vaccination; Dendritic Cells - immunology; Dendritic Cells - transplantation; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - immunology; Humans; Immunotherapy - methods; Injections, Intralesional; intratumoral injections; Leukocytes, Mononuclear - metabolism; Male; Middle Aged; Neoplasms - immunology; Neoplasms - therapy; Poly I-C - administration & dosage; poly-ICLC (Hiltonol); Polylysine - administration & dosage; Polylysine - analogs & derivatives; Radiosurgery - methods; radiotherapy and abscopal effects; Response Evaluation Criteria in Solid Tumors; dendritic cell vaccination; radiotherapy and abscopal effects; poly-ICLC (Hiltonol); intratumoral injections
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1093/annonc/mdy089

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.
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 0.25mg injections of the dsRNA-analogue Hiltonol. Cyclophosphamide 600mg/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.
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.
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.