Copyright
©The Author(s) 2016.
World J Gastroenterol. May 14, 2016; 22(18): 4446-4458
Published online May 14, 2016. doi: 10.3748/wjg.v22.i18.4446
Published online May 14, 2016. doi: 10.3748/wjg.v22.i18.4446
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] |
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] |
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] |
- Citation: Kajihara M, Takakura K, Kanai T, Ito Z, Matsumoto Y, Shimodaira S, Okamoto M, Ohkusa T, Koido S. Advances in inducing adaptive immunity using cell-based cancer vaccines: Clinical applications in pancreatic cancer. World J Gastroenterol 2016; 22(18): 4446-4458
- URL: https://www.wjgnet.com/1007-9327/full/v22/i18/4446.htm
- DOI: https://dx.doi.org/10.3748/wjg.v22.i18.4446