Combination systemic therapies with immune checkpoint inhibitors in pancreatic cancer: overcoming resistance to single‐agent checkpoint blockade

Abstract

Immune checkpoint inhibitors have demonstrated broad single-agent antitumor activity and a favorable safety profile that render them attractive agents to combine with other systemic anticancer therapies. Pancreatic cancer has been fairly resistant to monotherapy blockade of programmed cell death protein 1 receptor, programmed death ligand 1, and cytotoxic T-lymphocyte associated protein 4. However, there is a growing body of preclinical evidence to support the rational combination of checkpoint inhibitors and various systemic therapies in pancreatic cancer. Furthermore, early clinical evidence has begun to support the feasibility and efficacy of checkpoint inhibitor-based combination therapy in advanced pancreatic cancer. Despite accumulating preclinical and clinical data, there remains several questions as to the optimal dosing and timing of administration of respective agents, toxicity of combination strategies, and mechanisms by which immune resistance to single-agent checkpoint blockade are overcome. Further development of biomarkers is also important in the advancement of combination systemic therapies incorporating checkpoint blockade in pancreatic cancer. Results from an impressive number of ongoing prospective clinical trials are eagerly anticipated and will seek to validate the viability of combination immuno-oncology strategies in pancreatic cancer.

Therapeutic challenges and current immunomodulatory strategies in targeting the immunosuppressive pancreatic tumor microenvironment

“…Other mechanisms of resistance to immune checkpoint blockade in pancreatic cancer include aberrant expression of immune checkpoints such as PD-L1 on the tumor cell surface, downregulation of antigen presenting MHC molecules, reduced Fas receptor signaling and therefore a reduction in counterattack by T cells via the expression of Fas ligands [64, 65]. In addition, the establishment of a highly desmoplastic TME by stromal cells creates a therapeutic barrier in treating pancreatic cancer [66].…”

Update on current pancreatic treatments: from molecular pathways to treatment

“…Further studies should be performed towards combined therapies 87. Combination systemic therapies or radiotherapy with immune checkpoint inhibitors in pancreatic cancer can overcome resistance to single‑agent checkpoint blockade 88. Radiotherapy of pancreatic cancer in older patients is feasible and can be used.…”

Durable Response and Good Tolerance to the Triple Combination of Toripalimab, Gemcitabine, and Nab-Paclitaxel in a Patient With Metastatic Pancreatic Ductal Adenocarcinoma

“…Given the predictive role of PD-L1 overexpression in PDAC was still controversial, our case suggested that PD-L1 overexpression may have the potential to select population. Moreover, emerging evidence supported combining systemic therapy on an ICIs backbone to overcome resistance due to the superior safety of ICIs (15). Theoretically, systemic chemotherapy was regarded as an immunogenic approach by stimulating anti-cancer immune effectors or inhibiting immunosuppressive factors (16).…”