Safety and Efficacy of Allogeneic Natural Killer Cells in Combination with Pembrolizumab in Patients with Chemotherapy-Refractory Biliary Tract Cancer: A Multicenter Open-Label Phase 1/2a Trial

Abstract

Background and Aim: This study investigated the administration of combination therapy, allogeneic natural killer (NK) cells and pembrolizumab in the treatment of advanced biliary tract cancer to determine the safety and tolerability (phase 1) and the efficacy and safety (phase 2a). Methods: Forty patients (phase 1, n = 6; phase 2a, n = 34) were enrolled between December 2019 and June 2021. The patients received highly activated allogeneic NK cells (“SMT-NK”) on weeks 1 and 2 and pembrolizumab on week 1. This 3-week schedule (one cycle) was repeated until confirmed disease progression, intolerable adverse events (AEs), patient withdrawal, or finishing the maximum treatment schedule. The tumor response was evaluated after every three cycles. Results: In phase 1, four patients (66.7%) experienced seven AEs, but no severe AE was observed. In phase 2a, 126 AEs occurred in 29 patients (85.3%). Severe AEs (≥grade 3) were reported in 16 patients (47.1%). The overall response rate (ORR) was 17.4% in the full analysis set and 50.0% in the per-protocol set. Conclusions: SMT-NKs plus pembrolizumab resulted in no severe AEs directly related to the drug combination. The combination therapy also exerted antitumor activity with improved efficacy compared to the recent monotherapy with pembrolizumab in patients with advanced biliary tract cancer.

Focusing on the Immune Cells: Recent Advances in Immunotherapy for Biliary Tract Cancer

“…Data from the 23 patients who can be obtained efficacy evaluation for highlight its therapeutic potential. 201 Meanwhile, ociperlimab, a TIGIT inhibitor, in combination with tislelizumab and GemCis, are being tested in an ongoing phase II trial (NCT05023109).…”

Immunotherapy in Biliary Tract Cancers: Current Standard-of-Care and Emerging Strategies

“…A number of additional CAR-T trials for BTCs are currently open, targeting mesothelin (NCT05568680, NCT05373147, and NCT05779917), HER2 (NCT04650451 and NCT04660929), MUC1 (NCT03633773), GPC3 (NCT04951141), and CEA (NCT05415475). Beyond CAR-T therapy, a phase I/IIa trial (NCT03358849) studying allogeneic NK cells (SMT-NK) plus pembrolizumab in the second line for advanced/metastatic BTCs demonstrated an ORR of 17.4% in the full analysis and 50.0% in the per-protocol analysis [ 63 ]. A direct comparison of this combination approach to pembrolizumab monotherapy is planned.…”

Tumor immune microenvironment and the current immunotherapy of cholangiocarcinoma (Review)

“…As aforementioned, increasing the number of NK cells can inhibit tumor growth. A phase 1/2a trial explored the safety and efficacy of pembrolizumab combining allogeneic NK cells in chemotherapy-refractory BTC patients ( 158 ). That study reported an overall ORR and DCR of 17.4 and 30.4%, all without severe TRAEs.…”

“…That study reported an overall ORR and DCR of 17.4 and 30.4%, all without severe TRAEs. That study demonstrated that pembrolizumab plus allogeneic NK cells represents a promising therapeutic approach, exhibiting an improved efficacy and a favorable safety profile ( 158 ).…”