Immunotherapy in Combination with Well-Established Treatment Strategies in Pancreatic Cancer: Current Insights

Figures & data

Figure 1 Therapeutic strategies target components of the tumor microenvironment in PDAC. Tumor microenvironment creates a barrier for immunotherapy and cytotoxic drugs in pancreatic cancer. Inhibition of the resistance mechanisms in pancreatic cancer by vaccine therapy and checkpoint inhibitors lead in activation of T-cells and tumor cell destruction. Adoptive cell transfer (ACT) lead to immune destruction of tumor cells while cytotoxic drugs and radiotherapy improve the efficacy of anticancer therapy. Adapted with permission from Schizas D, Charalampakis N, Kole C, et al. Immunotherapy for pancreatic cancer: a 2020 update. Cancer Treat Rev. 2020;86:102016.⁹

Abbreviations: ECM, extracellular matrix; PDAC, pancreatic adenocarcinoma; CAF, carcinoma- associated fibroblasts; MDSC, myeloid-derived suppressive cells; TAM, tumor-associated macrophages; CTL, cytotoxic T-lymphocytes; PSC, pancreatic stellate cells; CCL2/CCR2, C-C motif chemokine ligand/receptor.

Table 1 Adjuvant Immunotherapy in Surgically Resected Pancreatic Adenocarcinoma

Intervention		Cancer Stage	Clinical Phase/ Identifier	Outcomes: Disease Free Survival (Months) (95% CI)	Outcomes: Median Overall Survival (Months) (95% CI)	Reference
GVAX/5-FU/radiation	Whole-cell vaccine, Cytotoxic drugs	Resected stage I or II pancreatic adenocarcinoma	Phase II, NCT00084383	17.3 (14.6–22.8)	24.8 (21.2–31.6)	Lutz et al 2011^Citation60
GVAX/Chemoradiation	Whole-cell vaccine, Cytotoxic drugs	Stage II or III Positive/nevative margins	Phase I	13	20	Jaffee et al 2001^Citation61
Algenpantucel-L/Chemoradiation	Multi-peptide vaccine, Chemoradiation	Surgically Resected Pancreatic Cancer	Phase ΙΙ, NCT00569387	62% 12-month DFS	86% 12-month OS	Hardacre, Mulcahy et al 2013^Citation62
Algenpantucel-L, Gemcitabine/5-FU/Rradiation	Multi-peptide vaccine, Cytotoxic drugs, radiation	Surgically resected pancreatic cancer	Phase III, NCT01072981	Completed No results posted	Completed No results posted	McCormick et al 2016^Citation64
K-Ras vaccine/GM-CSF	Peptide vaccine, Costimulatory molecule	Surgically resected and advanced disease patients	Phase I/II CTNRAS95002 CTNRAS97004	No results posted	25.6 (10–39) for Res 10.2 (3–28) for NonRes	Gjertsen et al 2001^Citation66
Ras-peptide/GM-CSF/Chemotherapy	Peptide vaccine, Costimulatory molecules, chemotherapy	Resected KRAS mutant pancreatic cancer	NA	No results posted	20.3 (95% CI, 11.6–45.3)	Abou-Alfa et al 2011^Citation67
TG01/GM-CSF/Gemcitabine	Vaccine, Costimulatory molecules, chemotherapy	Resected pancreatic cancer	Phase I/II NCT02261714	16.1 (11.1–19.6)	33.3 (24.0–40.0)	ASA 2012^Citation68
GI-4000/Gemcitabine Placebo/Gemcitabine	Mutated RAS Protein vaccine, Cytotoxic drugs	Resected pancreatic cancer/ KRAS mutant	Phase II	9.4 8.3	17.22 14.5	Muscarella et al 2012^Citation69
Nivolumab/GVAX/CRS-207/CY GVAX/CRS-207/CY	PD-1 inhibitor, Whole-cell vaccine, Listeria vaccine, Cytotoxic drugs	Previously treated metastatic pancreatic adenocarcinoma	Phase II, NCT02243371	2.23 (2.14–2.33) 2.17 (2.00–2.30)	5.88 (4.73–8.64) 6.11 (3.52–7.00)	Hopkins et al 2015^Citation77
KIF20A/VEGFR1/VEGFR2/Gemcitabine	Peptide cocktail vaccine, Cytotoxic drugs	Resected pancreatic cancer patients	Phase II	15.8 (11.1–20.6)	NR	Miyazawa et al 2017^Citation70
Nivolumab, MS-813160, GVAX	PD-1 inhibitor, CCR2/CCR5 dual antagonist, Whole-cell vaccine	Locally advanced pancreatic cancer	Phase I/II, NCT03767582	Recruiting	Recruiting	Hopkins 2019^Citation71
Nivolumab, MS-813160, Gemcitabine, Nab-paclitaxel	PD-1 inhibitor, CCR2/CCR5 dual antagonist, Cytotoxic drugs	Resectable and locally advanced pancreatic cancer	Phase I/II, NCT03496662	Recruiting	Recruiting	Medicine WUSo et al 2018^Citation72

Abbreviations: 5-FU, fluorouracil; GM-CSF, granulocyte-macrophage colony-stimulating factor; CY, cyclophosphamide; KIF20A, kinesin family member 20A; VEGFR1/R2, vascular endothelial growth factor receptor ½; CI, confidence interval; Res, resected; NonRes, non-resected; NR, not reached; NA, not applicable.

Table 2 Neoadjuvant Immunotherapy in Resectable or Borderline Resectable Pancreatic Adenocarcinoma

Intervention		Cancer Stage	Clinical Phase/ Identifier	Outcomes: Disease Free Survival (Months) (95% CI)	Outcomes: Median Overall Survival (Months) (95% CI)	Reference
Pembrolizumab/Capecitabine/Radiation Capecitabine/Radiation	PD-1 inhibitor, Cytotoxic drugs,	Resectable or Borderline Resectable Adenocarcinoma	Phase Ib/II, NCT02305186	18.2 14.1 (p 0.41)	27.8 24.3 (p 0.68)	Rahma et al. 2021^Citation37
Pembrolizumab/Defactinib	PD-1 inhibitor, Kinase inhibitor	Resectable Adenocarcinoma	Phase II, NCT03727880	Recruiting	Recruiting	Hopkins et al 2019^Citation41
Pembrolizumab/GVAX/IMC-CS4/CY	PD-1 inhibitor, Whole-cell vaccine, Antineoplastic agent, Cytotoxic drug	Borderline Resectable Adenocarcinoma	Early Phase I, NCT03153410	Active, not recruiting	Active, not recruiting	Hopkins et al 2018^Citation47
GVAX/CY GVAX	Whole-cell vaccine, Cytotoxic drugs	Resectable or Borderline Resectable Adenocarcinoma	Phase II, NCT00727441	8.54 (2.66–17.1) 18.92 (13.87–34.1)	15.4 (13.2–26.5) 34.2 (21.6–45.7)	Hopkins 2008^Citation44
Nivolumab/GVAX/CY/Urelumab	PD-1 inhibitor, Whole-cell vaccine, Cytotoxic drugs, Antineoplastic agent	Resectable Adenocarcinoma	Phase I, II, NCT02451982	Recruiting	Recruiting	Hopkins et al 2016^Citation51
Nivolumab/FOLFRINOX (FFX)	PD-1 inhibitor, chemotherapy regimen	Borderline Resectable Adenocarcinoma	Phase 1/2, NCT03970252	Recruiting	Recruiting	Center, Squibb et al 2019^Citation52
Nivolumab/GVAX/BMS-813160/SBRT	PD-1 inhibitor, Whole-cell vaccine, Antineoplastic agent, Radiation	Locally Advanced Adenocarcinoma	Phase 1/2, NCT03767582	Recruiting	Recruiting	Hopkins 2019^Citation54
GMCI/Chemotherapy/Radiation	Adenoviral vector, Chemoradiation	Advanced Non-Metastatic Pancreatic Adenocarcinoma	Phase 1/2, NCT02446093	Recruiting	Recruiting	Candel Therapeutics and University 2015^Citation53
M7824/ M9241/ SBRT	PD-L1 inhibitor, Immunocytokine	Advanced Pancreas Cancer	Phase ½, NCT04327986	Recruiting	Recruiting	Institute and Center 2021^Citation48
Algenpantucel-L/FOLFRINOX/Gemcitabine/5-FU	Multi-peptide vaccine, Cytotoxic drugs	Borderline resectable pancreatic cancer	Phase II, NCT02405585	Study terminated No results posted	Study terminated No results posted	Corporation and Pharma 2015^Citation49
Algenpantucel-L/FOLFRINOX/Gemcitabine/Nab-paclitaxel/Capecitabine/5-FU	Multi-peptide vaccine, Cytotoxic drugs	Resectable (stage II), Unresectable (stage III)	Phase III, NCT01836432	Study terminated No results posted	Study terminated No results posted	Corporation and Pharma 2013^Citation50
CCX872-B/FOLFIRINOX	CCR2 Inhibitor, Cytotoxic drugs	Patients With Pancreatic Adenocarcinoma	Phase 1b, NCT02345408	Active, not recruiting	No results posted	ChemoCentryx^Citation55
CCX872-B/SBRT	CCR2 Inhibitor, Radiation	Resectable pancreatic cancer	Phase 1b, NCT03778879	Withdrawn No results posted	No results posted	Katz and Rochester 2019^Citation56
PF-04136309/FOLFIRINOX	CCR2 Inhibitor, Cytotoxic drugs	Borderline resectable and locally advanced pancreatic cancer	Phase 1, NCT01413022	CCR2-targeted therapy plus FOLFIRINOX is safe and tolerable		Nywening et al 2016^Citation58 Medicine, W. U. S. o., and Institute, N. C.^Citation57

Abbreviations: CY, cyclophosphamide; FOLFIRINOX (FFX), oxaliplatin, leucovorin, irinotecan, 5-fluorouracil; SBRT, stereotactic body radiation; GMCI, gene mediated cytotoxic immunotherapy (aglatimagene besadenovec plus valacyclovir); 5-FU, fluorouracil; CI, confidence interval.

Table 3 Clinical Trials in Locally Advanced or Metastatic Pancreatic Adenocarcinoma

Intervention		Cancer Stage	Clinical Phase/ Identifier	Outcomes: Disease Free Survival (Months) (95% CI)	Outcomes: Median Overall Survival (Months) (95% CI)	Reference
Ipilimumab/Gemcitabine	CTLA-4 inhibitor, Cytotoxic drugs	Unresectable (Stage III/ IV) or metastatic pancreatic cancer	Phase Ib, NCT01473940	3.8 (0.7–22.4)	8.9 (0.7–30.0)	University and Center 2012^Citation73
Ipilimumab/Nivolumab/Cobimetinib	CTLA-4 inhibitor, PD-1 inhibitor, MEK inhibitor	Advanced/metastatic Tumor	Phase I/II, NCT01928394	ORR 6.7 (95% CI 0.8–22.1) months		Squibb 2013^Citation75
Ipilimumab/GVAX Ipilimumab	CTLA-4 inhibitor, Whole-cell vaccine	Locally advanced, unresectable or metastatic pancreatic	Phase I, NCT00836407	No results posted	5.7 (4.3–14.7) 3.6 (2.5–9.2)	Le et al 2013^Citation76
Tremelimumab/Durvalumab Tremelimumab Durvalumab	CTLA-4 inhibitor, PD-1 inhibitor	Advanced/Metastatic Tumor	Phase II, NCT02527434	2.86 (1.87–3.52) 1.77 (1.38–2.92) 1.84 (1.84–1.84)	7.18 (3.98–18.76) 3.98 (2.83–5.13) 4.14 (NA–NA)	AstraZeneca 2015^Citation27
Tremelimumab/Durvalumab Durvalumab	CTLA-4 inhibitor, PD-1 inhibitor	Metastatic adenocarcinoma/ progression after fluoropyrimidine or gemcitabine first-line chemotherapy	Phase II, NCT02558894	1.5 (1.2–1.5) 1.5 (1.3–1.5)	3.1 (2.2–6.1) 3.6 (2.7–6.1)	AstraZeneca 2015^Citation27
Tremelimumab/Gemcitabine	CTLA-4 inhibitor, Cytotoxic drugs	Advanced Metastatic Pancreatic Cancer	Phase I, NCT00556023	No results posted	7.4 (5.8–9.4)	Aglietta et al 2014^Citation78
Pembrolizumab/Gemcitabine/Nab-paclitaxel	PD-1 inhibitor, Cytotoxic drugs	Advanced Metastatic Pancreatic Cancer	Phase Ib/II, NCT02331251	9.1 (4.9–13/3)	15.0 (6.8–22.6)	Weiss et al 2019^Citation79 Weiss et al 2018^Citation80
Nivolumab/OSE2101/FOLFIRI	PD-1 inhibitor, multi-neoepitope vaccine, Cytotoxic drugs	Locally Advanced or Metastatic	Phase 2, NCT03806309	Recruiting	Recruiting	Group, Immunotherapeutics et al 2019^Citation148
Atezolizumab, KY1044	PD-L1 inhibitor, Inducible T cell co-stimulator	Advanced Metastatic Pancreatic Cancer	Phase I/II, NCT03829501	Recruiting	Recruiting	Limited and Sanofi 2019^Citation149
GVAX/CRS-207/CY GVAX/CY	Whole-cell vaccine, Listeria vaccine, Cytotoxic drugs	Metastatic pancreatic adenocarcinoma	Phase 2a, NCT01417000	No results posted	6.28 (4.47–9.40) 4.07 (3.32–5.42)	Whiting et al 2015^Citation91
GVAX/CRS-207/CY CRS-207 CY	Whole-cell vaccine, Listeria vaccine, Cytotoxic drugs	Previously treated metastatic pancreatic adenocarcinoma	Phase IIb, NCT02004262	No results posted	3.7 (2.9–5.3) 5.4 (4.2–6.4) 4.6 (4.2–5.7)	Le et al 2019^Citation92
KIF20A-66 BSC	Peptide vaccine	Metastatic pancreatic adenocarcinoma, previously treated with gemcitabine	Phase I/II, UMIN000004919	No results posted	4.7 ± 0.8 2.7 ± 1.1	Asahara et al 2013^Citation93
KIF20A/VEGFR1/VEGFR2/Gemcitabine	Peptide vaccine, Peptide vaccine, Peptide vaccine, Cytotoxic drugs	Advanced and/or metastatic pancreatic cancer	Phase II, UMIN000008082	4.7, HLA‐matched 5.2, HLA‐unmatched	9.0, HLA‐matched 10.0, HLA‐unmatched	Suzuki et al 2017^Citation94
MUC1, HLA-A2, ICAM-1, LFA-3, GM-CSF	Vaccinia virus-tumor antigens, Costimulatory molecules	Unresectable or metastatic pancreatic cancer	Phase I	No results posted	15.3, anti CEA/MUC-1 positive 3.9, anti CEA/MUC-1 negative	Kaufman et al 2007^Citation95
w/ Poly-ICLC plus peptide- pulsed DC-CIK	Immunostimulant DC-CIK vaccination	Metastatic, unresectable pancreatic cancer	Phase I NCT01410968	No results posted	7.7 months	Mehrotra et al 2017^Citation150
DC-CIK/Chemotherapy S-1 DC-CIK Chemotherapy S-1 BSC	DC-CIK vaccination, Cytotoxic drugs	Metastatic, unresectable pancreatic cancer	Phase I /II, NCT01781520	4.5 2.8 3 1.4	7 4.2 4.7 1.73	Jiang et al 2017^Citation97
GV1001/Gemcitabine/Capecitabine Gemcitabine/Capecitabine	Peptide vaccine, Cytotoxic drugs	Locally advanced or metastatic pancreatic cancer	Phase III, NCT02854072	No results posted	6.9 (6.4–7.6) 7.9 (7.1–8.8)	Middleton et al 2014^Citation96
MORAb-009, Gemcitabine Placebo/Gemtacibine	Monoclonal antibody, Cytotoxic drugs	Unresectable (stage III or IV)	Phase II, NCT00570713	No results posted	6.5 (4.5–8.10) 6.9 (5.4–8.8)	Morphotek 2007^Citation151

Abbreviations: FOLFIRI, fluorouracil, leucovorin, irinotecan, and oxaliplatin; BSC, best supportive care; CY, cyclophosphamide; KIF20A, kinesin family member 20A; VEGFR1/R2, vascular endothelial growth factor receptor 1/2; MUC1, mucin 1; ICAM-1, intercellular adhesion molecule 1; LFA-3, lymphocyte function-associated antigen 3; GM-CSF, granulocyte-macrophage colony-stimulating factor; CI, confidence interval; ORR, objective response rate; NR, not reached.

Table 4 Clinical Trials in Pancreatic Cancer Patients with High Microsatellite Instability

Intervention		Cancer Stage	Clinical Phase/ Identifier	Outcomes: Disease Free Survival (Months) (95% CI)	Outcomes: Median Overall Survival (Months) (95% CI)	Reference
Pembrolizumab	PD-1 inhibitor	MSI High/advanced pancreatic cancer	Phase II, NCT02628067	Recruiting/2.1 (1.9–3.4)	1395 participants 4.0 (2.1–9.8)	Marabelle et al 2020^Citation136
Pembrolizumab/Sonidegib	PD-1 inhibitor, Hh-pathway inhibitor	MSI High/ advanced pancreatic cancer	Phase I, NCT04007744	Recruiting	Recruiting	Clinic and Institute 2020^Citation152
Pembrolizumab/DEBIO1143	PD-1 inhibitor, IAP inhibitor	Non-MSI-high/ advanced/metastatic	Phase I, NCT03871959	Recruiting	Recruiting	Berard et al 2019^Citation153
Pembrolizumab/XmAb^®22841	PD-1 inhibitor, CTLA-4/LAG-3 inhibitor	MSI High/advanced or metastatic pancreatic cancer	Phase I, NCT03849469	Recruiting	Recruiting	Xencor and Research 2019^Citation154
Nivolumab/Ipilimumab/Radiation	PD-1 inhibitor, CTLA-4 inhibitor, Radiation	MSI High/pancreatic adenocarcinoma	Phase II, NCT03104439	Recruiting	Recruiting	Hospital and Squibb 2017^Citation155
Nivolumab/Pembrolizumab/Atezolizumab/FT500/CY/Fludarabine	PD-1 inhibitor, PD-1 inhibitor, PD-L1 inhibitor, iPSC-NK cell, Cytotoxic drugs	MSI High/advanced pancreatic cancer	Phase I, NCT03841110	Recruiting	Recruiting	Therapeutics 2019^Citation156
LY3300054/Ramucirumab/Abemaciclib/Merestinib/LY3321367	PD-1 inhibitor, VEGFR2 antagonist, CDK inhibitor, HGFR inhibitor, anti-TIM3	MSI High/pancreatic cancer	Phase I, NCT02791334	Recruiting	Recruiting	Lilly and Company 2016^Citation157
TIL Fludarabine/CY	Adoptive cell transfer Cytotoxic drugs	MSI High/advanced, recurrent, or metastatic pancreatic cancer	Phase II, NCT03935893	Recruiting	Recruiting	Kammula 2019^Citation158

Abbreviations: MSI, microsatellite instability; Hh-pathway, hedgehog signaling pathway; IAP, inhibitor of apoptosis proteins; VEGFR2, vascular endothelial growth factor receptor 2; CDK, cyclin-dependent kinase; HGFR, hepatocyte growth factor receptor; TIM3, T-cell immunoglobulin and mucin domain-3; TIL, tumor infiltrating lymphocytes; CY, Cyclophosphamide; iPSC-NK, induced pluripotent stem cells-derived Natural Killer cell.

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