Table 1.

A list of notable immunotherapies in clinical development for PDAC.

Therapeutic target and agents under investigation for PDAC	Preclinical rationale	Clinical evidence and ongoing trials
PD-1/PD-L1 nivolumab pembrolizumab durvalumab	PD-1/PD-L1 inhibition has activity in a wide number of tumors. PD-L1 expression is upregulated in a subset of PDAC, and is associated with shortened survival (161,162).	Responses were observed in a subset of patients with MMR-deficient pancreatic cancer (≤ 5% of PDAC) (56), and additional trials in MMR-d disease are ongoing NCT01876511, NCT02465060). None of 14 pancreatic patients responded in a study of single-agent nivolumab (22). Multiple combination immunotherapy trials are ongoing (NCT02558894, NCT02268825, NCT02472977, NCT02243371, NCT02777710).
CTLA-4 ipilimumab tremelimumab	Anti-CTLA-4 therapy may reduce intratumoral Tregs and shift the threshold needed for T cell activation. A trial of ipilimumab failed to show convincing clinical activity, but a possible delayed response was observed in one patient (21).	Multiple combination trials are ongoing, including combinations with PD-1 inhibition and/or therapeutic vaccines (NCT02558894, NCT01896869).
IDO1 indoximod	IDO1 mediates tumor immunosuppression in preclinical models (non-PDAC), and PDAC frequently overexpresses IDO as a mechanism of immune escape (132,163,164).	Evidence of clinical activity was observed in combination with chemotherapy (133). A clinical trial is ongoing in combination with gemcitabine-based chemotherapy (NCT02077881).
BTK Ibrutinib	BTK is involved with B cell receptor signaling and is also expressed by macrophages. In preclinical models ibrutinib synergizes with gemcitabine to increase antitumor immunity (137).	Clinical trials are ongoing in combination with gemcitabine-based chemotherapy in PDAC (NCT02562898, NCT02436668)
CD-40 RO7009789 (CP-870,893) JNJ-64457107	CD40 is expressed on B cells, DCs, and other cell types. CD40 agonists inhibit PDAC stroma, increase CCL2 levels and interferon gamma (IFN-g) in the TME, and synergize with chemotherapy (145,165).	Evidence of clinical activity was observed in an early stage clinical trial in PDAC (141). Additional trials of monotherapy or combination with gemcitabine-based chemotherapy are ongoing (NCT02588443, NCT02829099).
CCR2 CCX872 PF-04136309	CCR2 recruits suppressive macrophages to the immunosuppressive TME in PDAC, and CCR2 inhibition depletes tumor infiltrating macrophages and improves survival in a preclinical model (145).	CCR2 inhibition has shown safety and possible evidence of clinical activity in combination with chemotherapy. Clinical trials in combination with chemotherapy in PDAC are ongoing (NCT02345408, NCT02732938)
CSF-1R Cabiralizumab (FPA008) Pexidartinib (PLX3397) BLZ945 AMG 820	CSF1R inhibition reprograms tumor-associated macrophages and upregulates immune checkpoints. Synergistic activity has been observed with immune checkpoint inhibitors in preclinical models of PDAC (146,147).	Multiple agents are in clinical trials in metastatic PDAC in combination with PD-1 inhibitors (NCT02526017, NCT02777710, NCT02829723, NCT02713529)
CXCR4 LY2510924	CXCR4 blockade abrogated metastasis in prelclinical models (151), and synergized with PD-L1 therapy to increase antitumor immunity (158)	CXCR4 inhibitor is in clinical trial in combination with PD-L1 blockade to treat advanced solid tumors, including PDAC (NCT27037072).