Advances in inducing adaptive immunity using cell-based cancer vaccines: Clinical applications in pancreatic cancer

Table 1 Cell-based cancer vaccines

Cell	Antigen source	Ref.
Dendritic cells	Whole tumor cell lysates	[33]
	MHC class I restricted antigenic peptides	[33,56,60,61]
	MHC class I and II restricted antigenic peptides	[31,57,62]
	Dying or dead tumor cells	[34]
	mRNA encoding tumor associated antigens	[35,36]
	cDNA	[37]
	Exosomes	[38]
	Fusions generated with whole tumor cells	[39-43]
Immunogenic whole tumor cells	A GM-CSF-secreting, irradiated, allogeneic PDA cell line	[76-82]
Cancer stem cells	Cancer stem-like cell-associated antigens	[107-109]

GM-CSF: Granulocyte macrophage colony-stimulating factor; PDA: Pancreatic ductal adenocarcinoma; MHC: Major histocompatibility complex.

Table 2 Clinical trials of dendritic cell-based cancer vaccines in pancreatic cancer patients

Cell-based cancer vaccines	Targets	Vaccines	Phase	Patients	Results	Ref.
Dendritic cells (DCs)	MUC1	DCs loaded with MUC1 peptide	Phase I/II	12 pancreatic or biliary cancer patients following surgical resection	These patients have been followed for more than 4 yr after vaccination, and 4 of them were alive without recurrence.	[46]
			Phase I	16 patients with pancreatic cancer	2 of 15 patients with resected PDA were alive and disease free at 32 and 61 mo.	[47]
			Phase I	7 patients with pancreatic cancer	These patients showed MUC1-specific immune responses; however, there was no significant clinical benefit.	[48]
		DCs transfected with MUC1 cDNA	Phase I/II	10 patients with pancreatic cancer	MUC1 specific immune responses were observed in 4 of 10 patients.	[49]
	WT1	DCs loaded with MHC class I restricted WT1 peptides	Retrospective analysis	49 patients with pancreatic cancer refractory to standard treatment	The median survival time from vaccines was 360 d. Erythema reaction at the vaccination site was a prognostic factor for a significant survival benefit.	[56]
		DCs loaded with MHC class I restricted WT1 peptides	Retrospective analysis	255 patients with pancreatic cancer refractory to standard treatment	The median survival time from diagnosis was 16.5 mo. Erythema reaction at the vaccination site was a prognostic factor for a significant survival benefit.	[60]
		DCs loaded with MHC class I restricted WT1 peptides	Phase I	10 patients with pancreatic cancer	The therapy was feasible, tolerable and effective in PDA patients without liver metastases.	[61]
		DCs loaded with MHC class I and class II restricted WT1 peptides	Phase I	7 patients with pancreatic cancer	WT1 peptide-specific delayed-type hypersensitivity (DTH) was detected in 4 of 7 patients with PDA vaccinated with DC/WT1-I/II and in 0 of 3 patients with PDA vaccinated with DC/WT1-I or DC/WT1-II. All 3 PDA patients with strong WT1-specific DTH reactions had a median OS of 717 d. A patient with multiple liver metastases has remained alive for over 1000 d and received more than 71 vaccinations.	[31,62,63]
	hTERT	DCs transfected with hTERT mRNA	Phase I	A patient who could not receive chemotherapy due to sever neutropenia	Vaccination was associated with induction of strong immune responses to multiple hTERT epitopes. The patient had been vaccinated with DC/hTERT mRNA alone for 3 yr and resulted in no evidence of active disease.	[66]
	CEA	DCs loaded with CEA mRNA	Phase I	3 patients with resected pancreatic cancer following neoadjuvant vaccine therapy	All 3 PDA patients showed injection site reactivity and remained alive without recurrence at more than 2.5 yr from the original diagnosis	[68]
	DCs transfected with an adenovirus encoding IL-12		Phase I	3 patients with pancreatic cancer	Intratumoral DC injections were guided by ultrasound. Vaccines induced a significantly increased infiltration of CD8+ T cells in some patients. A partial response was observed in 1 of 3 patients.	[73]
	penicillin-killed and lyophilized preparations of a low virulence strain (Su) of Streptococcus pyogenes (OK-432)-activated DCs and CD3-stimulated LAK cells		Phase I	5 patients with pancreatic cancer	Intratumoral injection of OK432-activated DCs, followed by intravenous infusion of CD3-stimulated LAK cells. One patient had a partial response and 2 had stable disease for over 6 mo. The median OS was 478 d.	[75]
Peripheral blood mononuclear cells (PBMCs)	K-ras	irradiated PBMCs were used as antigen-presenting cells and loaded with K-ras peptide	Phase I	9 patients with pancreatic cancer	Only one patient showed a positive cellular immune response. The worse prognosis of PDA patients on this immunization protocol using PBMCs as APCs may be associated with impaired induction of an antitumor immune responses.	[71]

MHC: Major histocompatibility complex; PDA: Pancreatic ductal adenocarcinoma; APC: Antigen-presenting cells; IL-12: Interleukin-12; WT1: Wilms’ tumor gene 1; MUC1: Mucin 1; hTERT: Human telomerase reverse transcriptase; CEA: Carcinoembryonic antigen.

Table 3 Clinical trials of whole tumor cell-based cancer vaccines in pancreatic cancer patients

Cell-based cancer vaccines	Vaccine	Phase	Patients	Results	Ref.
Whole tumor cell	GM-CSF-secreting allogeneic pancreatic cancer cell lines (GVAX) and chemoradiotherapy	Phase II	14 patients with resected pancreatic cancer	3 patients were disease free at least 25 mo after diagnosis	[76]
	GVAX (arm A)/GM-CSF vaccine and cyclophosphamide (arm B)	Phase II	50 patients with pancreatic cancer (2 arm)	Median OS: 2.3 mo in arm A, 4.3 mo in arm B	[77]
	GVAX and chemoradiotherapy	Phase II	60 patients with resected pancreatic cancer	Induction of mesothelin-specific CD8+ T cells correlated with disease-free survival. Median OS: 24.8 mo	[78]
	Ipilimumab (anti-CTLA-4 monoclonal antibody) alone (arm 1), Ipilimumab and GVAX (arm 2)	Phase II	30 patients with pancreatic cancer (2 arm: 1:1)	Three of 15 patients had evidence of prolonged disease stabilization (31, 71, and 81 wk) and 7 patients experienced CA19-9 declines (arm 1). In 2 of these patients, disease stabilization occurred after an initial period of progression. The median OS was 5.7 mo and 1 yr OS was 27%. Among patients with OS > 4.3 mo, there was an increase in the peak mesothelin-specific T cells and enhancement of the T-cell repertoire.	[79]
	GVAX	Phase II	39 patients with pancreatic cancer	GVAX treatment was associated with the formation of vaccine-induced intratumoral tertiary lymphoid aggregates in 33 of 39 patients. Enhanced CD8+ CTL responses against multiple mesothelin-specific epitopes that have been correlated with survival benefits were also found.	[80]
	GVAX with low-dose cyclophosphamide (Cy) followed by CRS-207 (live-attenuated Listeria monocytogenes-expressing mesothelin) (arm A), GVAX + Cy (arm B)	Phase II	90 patients with pancreatic cancer	Enhanced mesothelin-specific CD8+ CTL responses were associated with longer OS. Median OS was 9.7 mo (arm A, n = 61).	[81]
	Algenpantucel-L (2 pancreatic cancer cell lines that have been modified to express alpha-gal)	Phase II	62 patients with resected pancreatic cancer	The 12-mo disease-free survival was 62%, and the 12-mo overall survival was 86%; the phase III study is ongoing.	[82]