Background Radiotherapy (RT) synergizes with immune checkpoint blockade (ICB), reducing immunosuppression within the tumor microenvironment (TME) and inducing immunogenic cell death (ICD) which can trigger dendritic cell maturation/activation in vitro. CD1c(BDCA-1)⁺/CD141(BDCA-3)⁺ myeloid dendritic cells (myDC) in the TME are indispensable at initiating effector CD8⁺/CD4⁺ T-cell responses, and response to ICB. This ongoing clinical trial investigates efficacy and toxicity of combining stereotactic body radiation therapy (SBRT), ICB, and intratumoral (IT) administration of myDCs in patients with ICB pretreated advanced solid tumors.

Methods This phase II trial recruits oligoprogressive patients with solid tumors refractory to anti-PD-1 ICB. Patients undergo a leukapheresis isolating CD1c(BDCA-1)⁺/CD141(BDCA-3)⁺ myDC’s. Following SBRT (3x8Gy), patients are randomized (3:1) to an immediate treatment arm (A) or contemporary control arm (B). In arm-A IT ipilimumab (10 mg) and avelumab (40 mg) with intravenous (IV) pembrolizumab (200 mg) are administered followed by IT myDC injections. Patients continue to receive IV pembrolizumab Q3w with IT ipilimumab/avelumab. In arm-B, patients receive IV pembrolizumab, with the option to start IT injections upon progressive disease (PD). Follow-up consists of 18F-FDG PET-CT (Q12w), tumor biopsies/blood samples (at treatment cycle).

Results To date, we enrolled 12 patients (9 in arm-A, 3 in arm-B) with 8 non-small cell lung cancer, and 4 melanoma (9 male, median age 62 years). Two patients crossed over (B to A) at PD. In arm-A, all patients except one received IT myDC’s with ICB (median treatment duration 24 weeks [range 3–51]). In arm-A, one pathological complete response was achieved after 4 IT injections. One patient obtained a partial response (PR) (PFS 15.6 months) and one achieved stable disease (SD) as best objective response. Best response in arm-B is one SD. Median PFS is 24 weeks in arm-A vs 21 in arm-B, OS 92 and 44 weeks respectively. Five patients died (4 PD, 1 COVID-infection). Treatment is ongoing in 1 patient (14 weeks after initiating therapy). There were no grade 4–5 TRAE. Grade 3 TRAE included pneumothorax (one) and pneumonitis (one). PBMC showed decrease of LAG-3 on CD4⁺ T-cells in 2 responders, increased expression was noted in non-responders. PD-1 expression on CD8⁺ T-cells decreased in most patients. No consistent changes in CTLA-4, TIM-3, TIGIT, CD39 were found.

Conclusions IT injection of CD1c(BDCA-1)⁺/CD141(BDCA-3)⁺ myDCs with repeated IT ipilimumab and avelumab, and systemic pembrolizumab was feasible and tolerable with early signs of activity in ICB refractory patients in this ongoing phase II trial.

Trial Registration Clinicaltrials.gov: NCT04571632

(EudraCT: 2019–003668-32)

Ethics Approval Initial study was accepted at 18–12-2019 and the amendement at 09–02-2022 at the Ethical committee of Universitair Ziekenhuis Brussel (2019–440)