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.
CONCLUSIONS: 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.
BACKGROUND: Clinicaltrials.gov: NCT04571632 (09 AUG 2020).
UNASSIGNED: 2019-003668-32. Date of registration: 17 DEC 2019, amendment 1: 6 MAR 2021, amendment 2: 4 FEB 2022.

Amyloid precursor protein (APP) is a well-known to be involved in the development of Alzheimer\'s disease and harbors several phosphorylation sites in its cytoplasmic domain. APP has been also proposed as one of the molecules involved in cell proliferation and invasion in several human malignancies. However, the roles of APP including its phosphorylated form (p-APP) have remained largely unexplored in non-small cell lung carcinoma (NSCLC). Therefore, in this study, we first examined both APP and p-APP expressions and then explored the association between p-APP/APP status and clicopathological parameters in NSCLC. The number of APP-positive cases was 24/91 (26%) in adenocarcinomas (Ad) and 16/35 (46%) in squamous cell carcinomas (Sq), respectively. p-APP-positive cases in Ad and Sq were 28 (31%) and 17 (49%), respectively. In Ad cases, both APP and p-APP were significantly associated with clinical stages (APP and p-APP), pathologic T (p-APP), and pathologic N (APP and p-APP) of the cases examined. In Sq cases, there were no significant associations between APP status and any of the clinicopathological parameters examined with an exception of the significant correlation of p-APP with lymphatic invasion. APP status was not significantly associated with overall survival (OS) of Ad patients but a significant association was detected between p-APP-positive cases and OS of these patients (p < 0.0001). In Sq cases, both APP- (p = 0.01) and p-APP-positive (p = 0.04) groups were also significantly associated with adverse clinical outcome. These results did firstly demonstrate that APP, in particular, p-APP, is considered a potent prognostic factor for both Ad and Sq lung carcinoma patients. However, APP signaling including its phosphorylation signal are considered different between these two types of NSCC cells and further investigations are required for clarification.