Intratumoral Combinatorial Administration of CD1c (BDCA-1)+ Myeloid Dendritic Cells Plus Ipilimumab and Avelumab in Combination with Intravenous Low-Dose Nivolumab in Patients with Advanced Solid Tumors: A Phase IB Clinical Trial.

Julia Katharina Schwarze,Gil Awada,Louise Cras,Bart Neyns,Inès Dufait,Jens Tijtgat,Sandra Tuyaerts,Ramses Forsyth,Ivan Van Riet

doi:10.3390/vaccines8040670

Julia Katharina Schwarze, Gil Awada + Show 7 more

Open Access

https://doi.org/10.3390/vaccines8040670

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Journal: Vaccines	Publication Date: Nov 10, 2020
Citations: 21	License type: CC BY 4.0

Affiliation: Universitair Ziekenhuis Brussel

Abstract

Intratumoral (IT) myeloid dendritic cells (myDCs) play a pivotal role in re-licensing antitumor cytotoxic T lymphocytes. IT injection of the IgG1 monoclonal antibodies ipilimumab and avelumab may induce antibody-dependent cellular cytotoxicity, thereby enhancing the release of tumor antigens that can be captured and processed by CD1c (BDCA-1)+ myDCs. Patients with advanced solid tumors after standard care were eligible for IT injections of ≥1 lesion with ipilimumab (10 mg) and avelumab (40 mg) and intravenous (IV) nivolumab (10 mg) on day 1, followed by IT injection of autologous CD1c (BDCA-1)+ myDCs on day 2. IT/IV administration of ipilimumab, avelumab, and nivolumab was repeated bi-weekly. Primary objectives were safety and feasibility. Nine patients were treated with a median of 21 × 106 CD1c (BDCA-1)+ myDCs, and a median of 4 IT/IV administrations of ipilimumab, avelumab, and nivolumab. The treatment was safe with mainly injection-site reactions, but also immune-related pneumonitis (n = 2), colitis (n = 1), and bullous pemphigoid (n = 1). The best response was a durable partial response in a patient with stage IV melanoma who previously progressed on checkpoint inhibitors. Our combinatorial therapeutic approach, including IT injection of CD1c (BDCA-1)+ myDCs, is feasible and safe, and it resulted in encouraging signs of antitumor activity in patients with advanced solid tumors.

Highlights

Remarkable antitumoral activity has been achieved in various cancer types by blocking the inhibitory T-cell receptor cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or the programmed cell death protein 1 (PD-1/progressive disease (PD)-L1) axis [1]
PD-L1 are not expected to become neutralized upon exposure to avelumab [39]. In this phase IB clinical trial, we investigate the safety and feasibility of a combined immunotherapeutic approach that includes the intralesional administration of autologous, non-substantially manipulated CD1c (BDCA-1)+ myeloid dendritic cells (myDCs) plus ipilimumab and avelumab in combination with intravenous low-dose nivolumab in patients with advanced solid tumors who progressed on standard of care treatment options
Between 6 February 2018 and 9 July 2019, nine patients with pretreated advanced solid tumors were enrolled in this clinical trial and initiated study treatment

Summary

Introduction

Remarkable antitumoral activity has been achieved in various cancer types by blocking the inhibitory T-cell receptor cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or the programmed cell death protein 1 (PD-1/PD-L1) axis [1]. A pivotal role in initiating antigen-specific antitumoral immunity has recently been attributed to specific types of myeloid dendritic cells (myDCs) [14,16]. It has been shown in mouse models that myDCs are essential for priming antitumor T-cell responses, with type 1 conventional dendritic cells (cDC1), being characterized by the expression of CD103 and dependent on the transcription factor Batf, mediating CD8+ cytotoxic T lymphocytes (CTL), and type 2 conventional dendritic cells (cDC2) mediating CD4+ T-cell responses against tumor cells [17]

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