Table 1.

A list of notable immunotherapies in clinical development for PDAC

Therapeutic target and agents under investigation for PDACPreclinical rationaleClinical evidence and ongoing trials
PD-1/PD-L1PD-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 (43, 161).Responses were observed in a subset of patients with MMR-deficient pancreatic cancer (56), and additional trials in MMR-deficient disease are ongoing (NCT01876511 and 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, and NCT02777710).
CTLA-4Anti–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 and NCT01896869).
IDO1IDO1 mediates tumor immunosuppression in preclinical models (non-PDAC), and PDAC frequently overexpresses IDO as a mechanism of immune escape (132, 162, 163).Evidence of clinical activity was observed in combination with chemotherapy (133). A clinical trial is ongoing in combination with gemcitabine-based chemotherapy (NCT02077881).
BTKBTK 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 and NCT02436668).
CD40CD40 is expressed on B cells, DCs, and other cell types. CD40 agonists inhibit PDAC stroma, increase CCL2 levels and interferon gamma (IFN-γ) in the TME, and synergize with chemotherapy (145, 164).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 and NCT02829099).
RO7009789 (CP-870,893)
CCR2CCR2 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 and NCT02732938).
CSF1RCSF1R 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, and NCT02713529).
Cabiralizumab (FPA008)
Pexidartinib (PLX3397)
AMG 820
CXCR4CXCR4 blockade abrogated metastasis in preclinical 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).
  • Abbreviations: BTK, Bruton tyrosine kinase; CCL2, chemokine (C-C motif) ligand 2; CCR2, C-C chemokine receptor type 2; CSF1R, colony-stimulating factor-1 receptor; CXCR4, C-X-C chemokine receptor type 4; DC, dendritic cell; MMR, mismatch repair.