A randomized phase II clinical trial of stereotactic body radiation therapy (SBRT) and systemic pembrolizumab with or without intratumoral avelumab/ipilimumab plus CD1c (BDCA-1)+/CD141 (BDCA-3)+ myeloid dendritic cells in solid tumors

Abstract

Background: Radiotherapy (RT) synergizes with immune checkpoint blockade (ICB). CD1c(BDCA-1)⁺/CD141(BDCA-3)⁺ myeloid dendritic cells (myDC) in the tumor microenvironment are indispensable at initiating effector T-cell responses and response to ICB.

Methods: In this phase II clinical trial, anti-PD-1 ICB pretreated oligometastatic patients (tumor agnostic) underwent a leukapheresis followed by isolation of CD1c(BDCA-1)⁺/CD141(BDCA-3)⁺ myDC. Following hypofractionated stereotactic body RT (3 × 8 Gy), patients were randomized (3:1). Respectively, in arm A (immediate treatment), intratumoral (IT) ipilimumab (10 mg) and avelumab (40 mg) combined with intravenous (IV) pembrolizumab (200 mg) were administered followed by IT injection of myDC; subsequently, IV pembrolizumab and IT ipilimumab/avelumab were continued (q3W). In arm B (contemporary control arm), patients received IV pembrolizumab, with possibility to cross-over at progression. Primary endpoint was 1-year progression-free survival rate (PFS). Secondary endpoints were safety, feasibility, objective response rate, PFS, and overall survival (OS).

Results: Thirteen patients (10 in arm A, eight non-small cell lung cancer, and five melanoma) were enrolled. Two patients crossed over. One-year PFS rate was 10% in arm A and 0% in arm B. Two patients in arm A obtained a partial response, and one patient obtained a stable disease as best response. In arm B, one patient obtained a SD. Median PFS and OS were 21.8 weeks (arm A) versus 24.9 (arm B), and 62.7 versus 57.9 weeks, respectively. An iatrogenic pneumothorax was the only grade 3 treatment-related adverse event.

Conclusion: SBRT and pembrolizumab with or without IT avelumab/ipilimumab and IT myDC in oligometastatic patients are safe and feasible with a clinically meaningful tumor response rate. However, the study failed to reach its primary endpoint.

Trial registration number: Clinicaltrials.gov: NCT04571632 (09 AUG 2020).

Eudract: 2019-003668-32. Date of registration: 17 DEC 2019, amendment 1: 6 MAR 2021, amendment 2: 4 FEB 2022.

Keywords: Intratumoral immunotherapy; Melanoma; Myeloid dendritic cell therapy; Non-small lung cell carcinoma; Stereotactic body radiation therapy.

Fig. 1

CONSORT diagram: 13 patients were recruited between September 2020 and June 2023

Fig. 2

Swimmer plot (a) of randomized patients, Kaplan–Meier curve of progression-free survival (PFS) (b), and overall survival (OS) (c). Abbreviations: stable disease (SD), partial response (PR), progressive disease (PD), progressive disease after cross-over (PD2)

Fig. 3

Case illustration of patient 2 (arm A), who had a PR at week 25, but encountered IT treatment interruptions (at week 33) due to pain and fibrosis. Hospitalization for fever, elevated inflammatory markers, and widespread lung activity on PET-CT was managed by high-dose corticosteroids. A relapse of the latter followed by a COVID-19 infection led to further treatment interruption with disease progression by week 70. Upper row images: CT, second row: PET/CT maximum intensity projections (MIP) of disease locations, third row (single image): fused PET/CT image illustrating diffuse PET activity in both lungs, suggestive of (ir-)pneumonitis. SD = stable disease, PR = partial response, PD = progressive disease, PEMBRO = pembrolizumab, AVE = avelumab, IPI = ipilimumab