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Ann Oncol. 2018 May 1;29(5):1312-1319. doi: 10.1093/annonc/mdy089.

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

Author information

1
Department of Oncology, Clínica Universidad de Navarra, Pamplona.
2
Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona.
3
CIBERONC, Centro de Investigación Biomédica en Red de Cáncer, Madrid.
4
Navarra Health Research Insititute (IDISNA), Pamplona.
5
Departments of Immunology.
6
Radiology.
7
Physics, Clínica Universidad de Navarra, Pamplona, Spain.
8
Immunobiology Department, Yale University School of Medicine, New Haven, USA.
9
Department of Pathology, Clínica Universidad de Navarra, Pamplona, Spain.
10
Oncovir, Washington, USA.

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.

PMID:
29554212
DOI:
10.1093/annonc/mdy089

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