Combination therapy for pancreatic cancer: anti-PD-(L)1-based strategy

Abstract

Mortality associated with pancreatic cancer is among the highest of all malignancies, with a 5-year overall survival of 5–10%. Immunotherapy, represented by the blocking antibodies against programmed cell death protein 1 or its ligand 1 (anti-PD-(L)1), has achieved remarkable success in a number of malignancies. However, due to the immune-suppressive tumor microenvironment, the therapeutic efficacy of anti-PD-(L)1 in pancreatic cancer is far from expectation. To address such a fundamental issue, chemotherapy, radiotherapy, targeted therapy and even immunotherapy itself, have individually been attempted to combine with anti-PD-(L)1 in preclinical and clinical investigation. This review, with a particular focus on pancreatic cancer therapy, collects current anti-PD-(L)1-based combination strategy, highlights potential adverse effects of accumulative combination, and further points out future direction in optimization of combination, including targeting post-translational modification of PD-(L)1 and improving precision of treatment.

Comprehensive multimodal management of borderline resectable pancreatic cancer: Current status and progress

“…These results contradict the A021501 study, potentially because the A021501 study had low rates of pancreatectomy (35%) and treatment completion (18%). It is worth mentioning that SBRT has a theoretical synergy with emerging immunotherapies, the effectiveness and safety of which have been confirmed by previous basic research and clinical studies[ 47 , 48 ].…”

Advance of T regulatory cells in tumor microenvironment remodeling and immunotherapy in pancreatic cancer

“…56 Currently, pembrolizumab and nivolumab are FDA-approved PD-L1 inhibitors used in clinical trials. 57 Preclinical and clinical trials primarily focus on PD-L1 combined with chemotherapy, radiotherapy, and immunotherapy.…”

B7 Family Members in Pancreatic Ductal Adenocarcinoma: Attractive Targets for Cancer Immunotherapy

“…Although the combination of PD-1/PD-L1 inhibitors with chemotherapy, radiotherapy, or targeted therapy did not produce the expected results in terms of progression-free survival (PFS) and OS, an overall improvement was observed in some clinical trials [ 29 , 30 ]. In a phase Ib clinical trial, 12 patients with metastatic pancreatic cancer were treated with the CD40 agonist APX005M (Sotigalimab, 0.1 mg/kg or 0.3 mg/kg on day 3 or 10), gemcitabine (1000 mg/m 2 on days 1, 8, and 15 every 4 weeks), and nab-paclitaxel (125 mg/m 2 on days 1, 8, and 15 every 4 weeks) in combination with the anti-PD-1 mAb nivolumab (240 mg on day 1, 15 cases every 4 weeks).…”

“…However, PD-L1 with CTLA4 may not be the optimal choice for PDAC, and additional immune checkpoints need to be sought [ 28 , 33 , 34 ]. Furthermore, the combination of multiple immunotherapies, such as TGF-β inhibitors, oncolytic viruses, tumor vaccines, and adoptive cell therapy, has shown a good safety and tolerability profile, but clinical outcomes must be evaluated further [ 29 , 30 , 36 ].…”