Understanding the immune response and the current landscape of immunotherapy in pancreatic cancer

Table 1 Clinical trials on pancreatic ductal adenocarcinoma using immunotherapy

National clinical trial number	Sample	Phase	Settings	Drug	Results
NCT00112580	82	II	Advanced; Metastatic; Any line	Ipilimumab	No improvement in survival rate
NCT02527434	64	II	Advanced; Metastatic; ≥ Second line	Tremelimumab	OS 4 m (95%CI: 2.83-5.42)
NCT02558894	65	II	Metastatic; ≥ Second line	Tremelimumab + Durvalumab vs Durvalumab alone	OS 3.1 m (95%CI: 2.2-6.1) Combination therapy; OS 3.6 m (95%CI: 2.7-6.1) Durvalumab alone
NCT00112580	27	II	Advanced; Metastatic; ≥ Second line	Ipilimumab	No improvement in survival rate
NCT03379259	14	I	Advanced (PDAC and other tumors); ≥ Second line	Anti-PD-L1 (BMS-936559)	No improvement in survival rate
NCT01928394	1131	I/II	Advanced (PDAC and other tumors) Any line	Nivolumab ± Ipilimumab	Ongoing
NCT03829501	412	I/II	Advanced (PDAC and other tumors); ≥ Second line	Atezolizumab	Ongoing
NCT03080974	10	I	Advanced (stage III) Any line	Nivolumab +Irreversible electroporation	PFS 6.3 m (95%CI: 3.5-10.0); OS 18 m (95%CI: 9.2-26.8)

OS: Overall survival; PDAC: Pancreatic ductal adenocarcinoma; PFS: Progression-free survival.

Table 2 Clinical trials on pancreatic ductal adenocarcinoma combining immunotherapy and chemotherapy

National clinical trial number	Sample	Phase	Settings	Drug	Results
NCT01473940	21	I	Advanced; Metastatic; Any line	Ipilimumab; Gemcitabine	OS 8,5 m (95%CI: 2.2-10.3)
NCT00556023	34	I	Metastatic Chemotherapy naïve	Tremelimumab Gemcitabine	OS 7.4 m (95%CI: 5.8-9.4)
NCT02331251	81	I/II	Metastatic (PDAC and other tumors) Chemotherapy naïve	Pembrolizumab; Nab-Paclitaxel Gemcitabine	OS 15 m (95%CI: 6.8-22.6)
Beatty et al, Clin Cancer Res 2013; 19: 6286–6295	22	I	Advanced; First line	CD40 agonist (CP-870893); Gemcitabine	PFS 5.2 m (95%CI: 1.9-7.4); OS 8.4 m (95%CI: 5.3-11.8); 1-y OS 28.6%
NCT01413022	47	I	Borderline; Locally advanced Chemotherapy naïve	CCR2 inhibitor (PF-04136309); FOLFIRINOX	Combination arm: 49% OR Chemotherapy arm: 0% OR
NCT02268825	39	I	Advanced; Metastatic (gastrointestinal malignancies) ; Any line	Pembrolizumab mFOLFOX	No results posted
NCT02309177	138	I	Advanced; Metastatic (PDAC and other tumors); Any treatment naive	Nivolumab; Nab-Paclitaxel Gemcitabine	No results posted
NCT02077881	98	I/II	Metastatic; First line	IDO inhibitor (indoximod); Nab-Paclitaxel; Gemcitabine	No results posted
NCT04045730	17	I/II	Metastatic First line	Gemcitabine; Nab-Pacliatxel; Pembrolizumab	PFS 9.1 m (95%CI: 4.9-13.3); OS 15 m (95%CI: 6.8-23)
NCT03214250	30	I	Metastatic; First line	Gemcitabine; Nab-Paclitaxel; Nivolumab; CD40 (agonistic monoclonal antibody) APX005M (sotigalimab)	Ongoing
NCT02826486	80	II	Metastatic; Any line	BL-8040; Pembrolizumab; Pegylated liposomal Irinotecan + 5FU	Disease Control Rate 34.5%; OS: 3.3 m Patients receiving study drugs as second-line therapy: 7.5 m

OS: Overall survival; PDAC: Pancreatic ductal adenocarcinoma; PFS: Progression-free survival; OR: Objective response.

Table 3 Clinical trials on pancreatic ductal adenocarcinoma using vaccines

National clinical trial number	Sample	Phase	Settings	Drug	Results
UMIN000004919	31	I/II	Metastatic ≥ Second line	KIF20A-66	KIF20A-66 vaccine: OS 4.7 m ± 0.8; Best supportive care: OS 2.7 m ± 1.1
UMIN000000905	6	I	Advanced (gastrointestinal and endocrine malignancies) ; Any line	SVN-2B; IFA; INFa	> 50% of the patients had positive clinical and immunological responses
NCT00569387	73	II	Adjuvant treatment	Algenpantucel-L	12-m OS: 86%
Kaufman et al, J Transl Med 2007; 5: 60	10	I	Advanced; Metastatic; Any line	MUC1; HLA-A2; ICAM-1; LFA-3; CM-CSF	antiCEA/MUC-1 positive: OS 15.1 m; antiCEA/MUC-1 negative: OS 3.9 m
Lepisto et al, Cancer Ther 2008; 6: 955–964	12	I/II	Adjuvant treatment	MUC1 peptide-loaded DC vaccine	Four of twelve patients are still alive without disease recurrence
NCT01410968	12	I	Advanced; Metastatic; Any line	w/Poly-ICLC peptide-pulsed DC-CIK	OS 7.7 m
Gjertsen et al, Int J Cancer 2001; 92: 441–50	48	I/II	Surgically resected; Advanced; Any line	K-Ras vaccine GM-CSF	Resected: OS 25.6 m (95%CI: 10-39); Unresectable: OS 10.2 m (95%CI: 3-28)
Abou-Alfa et al, Am J Clin Oncol 2011; 34: 321–5	24	I	Adjuvant (KRAS mutant)	Ras-peptide GM-CSF	OS 20.3 (95%CI: 11.6-45.3)
Bernhardt et al, Br J Cancer 2006; 95: 1474–1482	48	I/II	Advanced Treatment naive	GV1001; GM-CSF	Responders: OS 7.2 m (95%CI: 4.8-10.7); Non-responders: OS 2.9 m (95%CI: 1.7-6.30)
Shima et al, Cancer Sci 2019; 110: 2378-2385	83	II	Unresectable ≥ Second line	Survivin 2B peptide (SVN-2B); Interferon-β	SVN-2B + IFNβ: OS 312 d (95%CI: 43-460); IFNβ: OS 39 d (95%CI: 13-153)

CIK: cytokine-induced killer ; DC: dendritic cells; GM-CSF: granulocyte-macrophage colony-stimulating factor; IFN: interferon; m: months; OS: overall survival; PDAC: pancreatic ductal adenocarcinoma; PFS: progression-free survival.

Table 4 Clinical trials on pancreatic ductal adenocarcinoma combining vaccines and chemotherapy

National clinical trial number	Sample	Phase	Settings	Drug	Results
Jaffee et al, J Clin Oncol 2001; 19: 145–56	14	I	Adjuvant (stage I/II/III)	CVAX, Chemorradiation	Effective anti-tumor immunty
NCT00084383	60	II	Adjuvant (stage I/II)	GVAX; 5FU; Chemorradiation	Combination: OS 24.8 m (95%CI: 21.2-31.6); 5FU/Chemorradiation: OS 20.3 m (95%CI: 18-23.9)
NCT01417000	93	IIa	Metastatic ≥ Second line	GVAX/Cy CRS-207	Combination: OS 6.28 m (95%CI: 4.47-9.40); GVAX/Cy: OS 4.07 m (95%CI: 3.32-5.42)
NCT02004262	303	IIb	Metastatic ≥ Second line	GVAX/Cy CRS-207 Chemotherapy	Combination: OS 3.7 m (95%CI: 2.9-5.3); CRS-207 alone: OS 5.4 m (95%CI: 4.2-6.4); Chemotherapy: OS 4.6 m (95%CI: 4.2-5.7)
UMIN000008082	60	II	Advanced First line	KIF20A; VEGFR1/2; Gemcitabine	OS 9 m HLA matched; OS 10 m HLA unmatched
NCT01072981	722	III	Adjuvant treatment	Algenpantucel-L; Gemcitabine-5FU	1-y DFS 86% algenpantucel-L vs 63% Gemcitabine-5FU; 1-y OS 65% algenpantucel-L vs 45% Gencitabine-5FU
NCT01836432	302	III	Borderline resectable; Locally advanced usresectable; First line	Algenpantucel-L; FOLFIRINOX; Gemcitabine; Nab-Paclitaxel; Capecitabine; 5FU	No results posted
NCT01781520	47	I/II	Unresectable locally advancedMetastatic Chemotherapy naïve	DC-CIK Chemotherapy S-1	DC-CIK+Chemotherapy S-1: OS 7 m; DC-CIK alone: OS 4.2 m; Chemotherapy S-1 alone: OS 4.7 m; Supportive care only: OS 1.73 m
Muscarella et al, J Clin Oncol 2012; 30: e14501-e.	176	II	Resected (KRAS mutant) adjuvant	GI-4000 Gemcitabine	GI-4000+Gemcitabine OS 19.8 m; Placebo-gemcitabine: OS 14.8 m
Middleton et al, Lancet Oncol 2014; 15: 829–840	1062	III	AdvancedMetastatic Chemotherapy naïve	GV1001 Gemcitabine Capecitabine	Treated group: OS 6.9 m (95%CI: 6.4-7.6); Chemotherapy alone: OS 7.9 m (95% 7.1-8.8)
Yanagisawa et al, Anticancer Res 2018; 38: 2217-2225	8	I	Adjuvant (I, II, III)	WT1-DC VaccineS-1 Chemotherapy Gemcitabine	No results posted
Suzuki et al, Cancer Sci 2017; 108: 73-80	66	II	Advanced First line	Antiangiogenic cancer vaccines targeting VEGFR1 and VEGFR2 in addition to the KIF20A peptide; Gemcitabine	PFS HLA matched: 4.7 m; PFS HLA unmatched: 5.2 m

OS: overall survival; PDAC: pancreatic ductal adenocarcinoma: PFS: progression-free survival; Cy: Cyclophosphamide; VEGFR: vascular endothelial growth factor receptor.

Table 5 Clinical trials on pancreatic ductal adenocarcinoma combining vaccines and immunotherapy

National clinical trial number	Sample	Phase	Settings	Drug	Results
NCT00836407	30	I	Metastatic ≥ Second line	Ipilimumab GVAX	Combination: OS 5.7 m (95%CI: 4.3-14.7); Ipilimumab: OS 3.6 m (95%CI: 2.5-9.2)
NCT02243371	93	II	Metastatic ≥ Second line	Nivolumab Cy; GVAX; CRS-207	No results posted
NCT02451982	62	I/II	Neoadjuvant Adjuvant	Nivolumab Cy GVAX Urelumab	No results posted
NCT04627246	3	I/II	Adjuvant	DC vaccine loaded with personalized peptides (PEP-DC); Nivolumab SOC	No results posted
NCT02432963	11	I	Advanced (solid malignancies) ≥ Second line	Pembrolizumab p53MVA	Clinical responses in three out of eleven patients

OS: overall survival; Cy: Cyclophosphamide; SOC: Standard of Care Chemotherapy; p53MVA: Modified Vaccinia Virus Ankara Vaccine Expressing p53.

Table 6 Clinical trials on pancreatic ductal adenocarcinoma using adoptive cell transfer

National clinical trial number	Sample	Phase	Settings	Drug	Results
NCT00570713	155	II	Unresectable First-line	MORb-009 Gemcitabine	Combination: OS 6.5 m (95%CI: 4.5-8.10); Placebo plus Gemcitabine: OS 6.9 m (95%CI: 5.4-8.8)
NCT01935843	10	I/II	Advanced (PDAC and other tumors Her2-positive) ≥ Second line	Her2-specific CAR-T cells	OS 4.8 m (95%CI: 1.5-8.3)
NCT01781520	47	I/II	Advanced; Any line	DC-CIK Chemoterapy S-1	DC-CIK + Chemotherapy S-1: OS 7 m DC-CIK alone: OS 4.2 m; Chemotherapy S-1 alone: OS 4.7 m; Supportive care only: OS 1.73 m
Aoki et al, Cytotherapy 2017; 19: 473-485	48	I	Adjuvant	Gemcitabine; Autologous γδ; T-cell transfer	PFS 26 m (no statistical diference); OS No statistical difference
NCT01959672	11	I/II	Neoadjuvant	Gemcitabine; Leucovorin-Fluorouracil; Oregovomab; Nelfinavir + SBRT	Prematurely closed; PFS 8.6 m; OS 13 m (95%CI: 7-22)
NCT00720785	40	I	Metastatic (PDAC and other tumors) ≥ Second line	Irreversible electroporation (IRE); Allogeneic natural killer cell therapy	No results posted
NCT04212026	67	I	Metastatic ≥ Second line	Irreversible electroporation; Allogeneic natural killer cell therapy	Stage III PFS 9,1 m (IRE-NK) vs 7.9 m (IRE); Stage III OS 13.6 m (IRE-NK) vs 12.2 m (IRE); Stage IV OS 10.2 m (IRE-NK) vs 9.1 m (IRE)
NCT01583686	6	I	Metastatic ≥ Second line	Mesothelin-CART	2 patients stabilized diseasePFS patient 1: 3.8 mPFS patient 2: 5.4 m

CAR: chimeric antigen receptor; DC-CIK: dendritic cell-activated cytokine-induced killer cell; IRE: irreversible electroporation; OS: overall survival; NK: natural killer; PFS: progression-free survival; SBRT: stereotactic body radiation therapy.