Tumor microenvironment in pancreatic ductal adenocarcinoma: Implications in immunotherapy

Table 1 Complete immune checkpoint inhibitor-based clinical trials in pancreatic ductal adenocarcinoma

Strategy	Treatment	Phase	Number	Cancer stage	Outcomes
Immune checkpoint inhibitor (target) monotherapy	Tremelimumab (CTLA-4)	II	NCT02527434	Advanced/metastatic PDAC	Tremelimumab monotherapy is ineffective for metastatic PDAC.
	Ipilimumab (CTLA-4)	II	NCT00112580	Advanced PDAC	Ipilimumab monotherapy is ineffective for advanced PDAC.
	Atezolizumab (PD-L1)	I/II	NCT03829501	Advanced PDAC	No results reported yet
Immune checkpoint inhibitor (target) + immune checkpoint inhibitor(target)	Tremelimumab (CTLA-4) + Durvalumab (PD-L1)	II	NCT02558894	Metastatic PDAC	ORR 3.1% for combination therapy. (ORR 0% for monotherapy).
	Nivolumab (PD-1) + Ipilimumab (CTLA-4)	I/II	NCT01928394	Advanced/metastatic PDAC	No results reported yet
Immune checkpoint inhibitor (target) + chemotherapy	Tremelimumab (CTLA-4) + Gemcitabine	I	NCT00556023	Advanced PDAC	Median OS 7.4 mo (95%CI: 5.8-9.4 mo)
	Ipilimumab(CTLA-4) + Gemcitabine	Ib	NCT01473940	Advanced/metastatic PDAC	Median OS 6.90 mo (95%CI: 2.63–9.57 mo)
	Pembrolizumab (PD-1) + Gemcitabine and Nab-paclitaxel	Ib/II	NCT02331251	Advanced/metastatic PDAC	Median OS 15.0 mo (95%CI: 6.8–22.6 mo)
Immune Checkpoint Inhibitor (Target) + Target therapy	Durvalumab (PD-L1) + Galunisertib	I	NCT02734160	Metastatic PDAC	Median PFS 1.9 mo (95%CI: 1.5-2.2 mo); median OS was NR (95%CI: 3.6 mo, NR)
	Durvalumab (PD-L1) + Pexidartinib	I	NCT02777710	Advanced/metastatic PDAC	No results reported yet
Immune Checkpoint Inhibitor (Target) + Radiation Therapy	Tremelimumab (CTLA-4) + Durvalumab (PD-1) + SBRT	I/II	NCT02311361	Advanced/metastatic PDAC	ORR of 9.6% including 2 patients who achieved a durable partial response lasting over 12 mo

https://clinicaltrials.gov/. PDAC: Pancreatic ductal adenocarcinoma; CTLA-4: Cytotoxic T lymphocyte-associated antigen-4; PD-1: Programmed cell death protein 1; PD-L1: Programmed cell death ligand 1; OS: Overall survival; PFS: Progression-free survival; ORR: Overall response rate; NR: Not reached.

Table 2 Complete vaccine immunotherapy-based clinical trials in pancreatic ductal adenocarcinoma

Treatment	Phase	Number	Cancer stage	Outcomes
GVAX, 5-FU, chemoradiation	II	NCT00084383	Resected stage I/II PDAC	Median OS 24.8 mo (95%CI: 21.2-31.6 mo)
GVAX, cyclophosphamide, CRS-207	II	NCT01417000	Metastatic PDAC	Cy/GVAX and CRS-207 extended OS for PDAC patients, with minimal toxicity
GVAX, cyclophosphamide, CRS-207	II	NCT02004262	Metastatic PDAC	Cy/GVAX and CRS-207 did not show survival benefit over chemotherapy in patients with previously treated metastatic PDAC
GVAX, Ipilimumab, FOLFIRINOX	II	NCT01896869	Metastatic PDAC	Ipilimumab + GVAX group did not show survival benefit over chemotherapy [median OS 9.38 mo (95% CI, 5.0-12.2 mo) vs 14.7 mo (95%CI: 11.6-20.0 mo)]
Algenpantucel-L	II	NCT00569387	Surgically resected PDAC	The addition of algenpantucel-L to standard adjuvant therapy for resected pancreatic cancer may improve survival (12-mo DFS 62%, 12-mo OS 86%)
Gemcitabine, 5FU Chemoradiation, Algenpantucel-L	III	NCT01072981	Surgically Resected PDAC	No results reported yet
Dendritic cells pulsed with MUC-1/WT-1	I/II	NCT03114631	PDAC	Dendritic cells immunotherapy provided a favorable outcome in PDAC patents (12-mo OS 78.2% vs 33.8%)
GI-4000 (KRAS), Gemcitabine	II	NCT00300950	Non-metastatic, Post-resection PDAC	Overall, GI-4000 group showed a similar pattern of recurrence-free survival and OS compared with the placebo group. For stratified R1 resection subgroup, there was a trend in 1 year OS (72% vs 56%), an improvement in OS (523.5 vs 443.5 d (hazard ratio: 1.06; 95%CI: 0.53–2.13, P = 0.872), and increased frequency of immune responders (40% vs 8%; P = 0.062) for GI-4000 vs placebo.
Ras-peptide vaccine, IL-2, GM-CSF	II	NCT00019331	Metastatic PDAC	No results reported yet
GV1001 (telomerase peptide vaccine), Gemcitabine, Capecitabine	III	NCT00425360	Locally Advanced or Metastatic PDAC	Adding GV1001 vaccination to chemotherapy did not improve OS.

https://clinicaltrials.gov/. PDAC: Pancreatic ductal adenocarcinoma; Cy: cyclophosphamide; DFS: Disease-free survival; OS: Overall survival.

Table 3 Complete adoptive cell transfer-based clinical trials in pancreatic ductal adenocarcinoma

Treatment	Phase	Number	Cancer stage	Outcomes
MORAb-009, Gemcitabine	II	NCT00570713	Advanced PDAC	MORAb-009 did not show survival benefit over placebo group [median OS 6.5 mo, 95%CI: 4.5–8.10 mo vs 6.9 mo 95%CI: 5.4–8.8 mo]
MORAb-009	I	NCT00325494	PDAC	No results reported yet
Radiolabeled Amatuximab (MORAb-009)	I	NCT01521325	PDAC	No results reported yet
Autologous Redirected RNA Mesothelin CAR T cells	I	NCT01897415	PDAC	No results reported yet
CART-133 T cells	I/II	NCT02541370	Relapsed and/or Chemotherapy Refractory Advanced PDAC	No results reported yet

https://clinicaltrials.gov/. PDAC: Pancreatic ductal adenocarcinoma; OS: Overall survival.

Table 4 Ongoing clinical trials with immunotherapy plus agents targeting the tumor microenvironment in pancreatic ductal adenocarcinoma

Strategy	Treatment	Phase	Number	Cancer stage
Immune checkpoint inhibitor (target) + CAFs/CXCL12 targeted agents	Pembrolizumab(PD-1) + Olaptesed pegol	I/II	NCT03168139	Metastatic PDAC
Immune checkpoint inhibitor (target)+ CSF1R targeted agent	Durvalumab (PD-L1) + Pexidartinib	I	NCT02777710	Metastatic/Advanced PDAC
	Nivolumab (PD-1) + Cabiralizumab	I	NCT02526017	Advanced PDAC
	Nivolumab (PD-1) + Cabiralizumab + Gemcitabine	II	NCT03697564	Advanced PDAC (Stage IV)
Immune checkpoint inhibitor (target) + FAK targeted agent	Pembrolizumab(PD-1) + Defactinib	I/IIa	NCT02758587	Advanced PDAC
	Pembrolizumab(PD-1) + Defactinib + Gemcitabine	I	NCT02546531	Advanced PDAC
	Pembrolizumab (PD-1) + Defactinib	II	NCT03727880	Resectable PDAC

https://clinicaltrials.gov/. PDAC: Pancreatic ductal adenocarcinoma; CTLA-4: Cytotoxic T lymphocyte-associated antigen-4; PD-1: Programmed cell death protein 1; PD-L1: Programmed cell death ligand 1; CAFs: Cancer-associated fibroblasts; CXCL12: CXC motif chemokine ligand 12; CSF1R: Colony-stimulating factor 1 receptor; FAK: Focal adhesion kinase.