Combination immunotherapies are emerging as a promising strategy to combat pancreatic cancer (PC), a disease characterized by a dense stroma and immunosuppressive microenvironment. Researchers are exploring various combinations of agents targeting different aspects of the tumor microenvironment to enhance the efficacy of anti-PD-(L)1 therapies.
Targeting the Extracellular Stroma
Pancreatic cancer's dense fibrous stroma, composed of collagen, hyaluronic acid (HA), and fibronectin, impedes blood flow, inhibits drug delivery, and suppresses the anti-tumor immune response. High levels of HA are associated with decreased survival in PC patients. Preclinical studies have shown that depleting HA with hyaluronidase can remodel the stroma and enhance the effects of anti-PD-(L)1 antibodies. For instance, combining an anti-PD-L1 antibody with PEGylated recombinant hyaluronidase PH20 significantly inhibited tumor growth in a PC mouse model with high HA levels (79% inhibition, p < 0.0001). A clinical trial is underway to investigate the use of PEGPH20 with pembrolizumab in patients with HA-high refractory metastatic PC.
Targeting Membrane Receptors
Pancreatic stellate cells (PSCs) express high levels of vitamin D receptors (VDRs) in the tumor stroma. Treatment with VDR ligands may convert activated PSCs to a quiescent state, inducing stromal remodeling and improving drug delivery. A clinical trial combining gemcitabine, albumin-bound paclitaxel, cisplatin, nivolumab, and paricalcitol in metastatic PC patients showed promising results, with 19 out of 24 patients displaying partial response (PR) and a median overall survival (mOS) of 15.3 months. However, the role of paricalcitol in improving anti-tumor effects remains unknown due to the lack of a control group.
Transforming growth factor-β (TGF-β) promotes immunosuppression and metastasis. Preclinical trials have demonstrated that combined blockade of TGF-β signaling and PD-(L)1 checkpoint increases CD8+ T cell infiltration and reduces immune suppression. In a phase I trial of advanced PC patients, one patient with mismatch repair-deficient (dMMR) disease achieved durable PR with the bifunctional fusion protein M7824 (anti-PD-L1 antibody fused to the extracellular domain of TGF-β receptor II). Another patient displayed prolonged stable disease (SD) for 4.5 months. A phase Ib study combining the TGF-β receptor I kinase inhibitor galunisertib and durvalumab in recurrent or refractory metastatic PC patients showed a disease control rate (DCR) of 25% and a median progression-free survival (mPFS) of 1.9 months.
Targeting Tumor Microenvironment
Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) actively suppress the anti-tumor immune response. Colony-stimulating factor 1 (CSF1) signaling regulates their differentiation and survival. A phase I study combining the anti-CSF1R antibody cabiralizumab and nivolumab in PC patients showed that 3 patients experienced PR, with a 6-month DCR of 13% and an ORR of 10%. Another study combining the anti-CSF1R antibody lacnotuzumab with the anti-PD-1 antibody spartalizumab resulted in one patient experiencing PR and two displaying durable SD.
CD40, a member of the tumor necrosis factor (TNF) receptor superfamily, allows dendritic cells (DCs) to promote antitumor T cell activation. Combining a CD40 agonist with PD-L1 blockade improved overall survival in an orthotopic Pan02 tumor mouse model. In a clinical phase Ib study combining the CD40 agonist APX005M (sotigalimab), gemcitabine, nab-paclitaxel, and nivolumab to treat metastatic PC patients, 8 achieved PR while 3 displayed SD. Median PFS was 10.8 months (in the cohort receiving 0.1 mg/kg APX005M) and 12.4 months (in the cohort receiving 0.3 mg/kg APX005M).
To counter anti-tumor immunity, PC cells release high-mobility group protein B1 (HMGB1), which combines with CXC-chemokine ligand 12 (CXCL12) produced by fibroblast activation protein (FAP)-positive CAFs to activate CXC-chemokine receptor 4 (CXCR4) on Teffs. In a syngeneic subcutaneous PC mouse model, the addition of anti-PD-L1 antibodies to a CXCR4 inhibitor significantly decreased tumor volume. In a clinical study, administration of the CXCL12 inhibitor NOX-A12 and pembrolizumab resulted in 25% of patients experiencing SD. A similar DCR of 21.4% was achieved using BL-8040 and pembrolizumab in metastatic PC patients. Furthermore, in a phase IIa two-cohort study, metastatic PC patients received BL-8040, pembrolizumab, liposomal irinotecan, fluorouracil, and leucovorin, finding that the ORR, DCR, and the median duration of response were 32, 77%, and 7.8 months, respectively.
CXCR2 is a G-protein-coupled receptor that regulates neutrophil and MDSC migration in the TME of PC, which drives tumor invasion and metastasis. In an experiment using KPC mice, survival was significantly extended in mice that received the CXCR2 inhibitor AZ13381758 followed by the administration of anti-PD-1 antibodies compared with mice treated with vehicle plus anti-PD-1. In addition, using the KP2 orthotopic PC mouse model, triple therapy with the CXCR1/2 inhibitor SX-682, FOLFIRINOX, and checkpoint inhibition (anti-PD-1/anti-CTLA-4) resulted in significantly increased survival compared with other groups.
CD73 is an ectoenzyme that catalyzes the hydrolysis of adenosine monophosphate (AMP) to immune-suppressive adenosine (ADO). In C57BL/6 J mice bearing established KP4662-G12C tumors, coadministration of CD73 inhibitor A0001421 and anti-PD-1 antibodies was superior to anti-PD-1 alone in limiting PC growth.
Targeting Intracellular Regulators
Focal adhesion kinases (FAKs) translate signals from the extracellular matrix into intracellular pro-inflammatory pathway regulation and cytokine production. FAK inhibitor VS-4718 was found to promote responsiveness to a PD-1 antagonist, demonstrated by reduced tumor burden and improved OS. In a phase I study that combined the FAK inhibitor defactinib, pembrolizumab, and gemcitabine, PR was observed in a patient who had progressed when treated with gemcitabine and nab-paclitaxel.
Bruton’s tyrosine kinase (BTK) is a non-receptor enzyme of the Tec kinase family expressed by B cells and macrophages. A phase II study evaluated the BTK inhibitor acalabrutinib alone or in combination with pembrolizumab in advanced PC patients. The ORR and DCR values of 0 and 14.3% were observed with monotherapy, and 7.9 and 21.1% for combination therapy.
Poly (ADP-ribose) polymerase (PARP) recognizes and binds to single-stranded DNA breaks, and recruits proteins to perform DNA damage repair (DDR). A study in which PARP 1/2 inhibitor BGB-290 was combined with the anti-PD-1 antibody BGB-A317 to treat advanced PC patients found that 1 subject experienced PR while 2 achieved SD.
