This study aims to determine the clinical efficacy of immunotherapy using both dendritic cells pulsed with MUC1 peptide (MUC1-DC) and, cytotoxic T lymphocyte (CTL) sensitized with a pancreatic cancer. The results suggest that adoptive immunotherapy with MUC1-DC and MUC1-CTL may be feasible and effective for pancreatic cancer.
20 patients with unresectable or recurrent pancreatic cancer histologically confirmed as invasive ductal carcinoma. Eleven of the 20 patients showed liver metastasis and 5 showed peritoneal dissemination. One patient showed lung metastasis, but no liver metastasis or peritoneal dissemination. Fifteen of the 20 patients were stage IV and 5 were stage III according to the TNM staging of the UICC, and all showed histologically confirmed invasive ductal carcinoma of the pancreas. Sixteen of the twenty patients did not receive chemotherapy. Four patients had received gemcitabine prior to the present AIT.
Separation of adherent and non-adherent cells
Peripheral blood mononuclear cells were harvested with the COBE Spectra Apheresis System every 2 to 4 weeks. PBMCs from 2,500 ml of blood were enriched by density gradient centrifugation with Ficoll-Paque. The PBMCs were incubated for 45 min in a 5% CO2 atmosphere at 37°C in serum-free AIM-V medium. Plastic-adherent cells were used for generation of DCs,
while non-adherent cells were used for generation of CTLs.
Generation of MUC1-CTLs
The PBMCs harvested from each patient were incubated for 45 min in a plastic plate. Non-adherent cells were cultured in AIM-V with the MUC1-expressing pancreatic cancer cell line YPK-1
inactivated with 0.2 mg/mL mitomycin C. After 3 days of culture, the cells were cultured with 10 Japan Reference Units (JRU)/mL recombinant human interleukin (rhIL)-2 in a 5% CO2 atmosphere at 37°C for 7 days. These cells were termed MUC1-CTLs. On day 10, MUC1-CTLs were washed 3 times with saline, suspended in 100 mL saline and administered intravenously as maximum available cell products.
Patients were treated from 2 to 15 times with both cell types. Total numbers of MUC1-DCs and
7889 MUC1- CTLs administered were 1.1×10 to 3.1×10 and 5.0×10 to 6.8×10 , respectively.
Efficacy
One of the 20 patients (patient 2), who had multiple lung metastases after curative surgery, had a complete response. After AIT, multiple lung nodules disappeared completely.
Five of twenty patients had stable disease. The duration of stable disease is range from 6 to 24 months as time to progression (TTP). Patient 1, who had unresectable pancreatic cancer with multiple liver metastases, had stable disease for at least 6 months. After AIT, there was no progression of the primary pancreatic cancer. One hepatic metastasis decreased in size, although another increased.
The survival times of the 20 pancreatic cancer patients who underwent AIT with MUC1-CTLs and MUC1-DCs ranged from 2 to 75 months, with a mean survival time of 9.8 months. One-, two-, and three-year survival rates after AIT were 20.0%, 10.0%, and 5.0%, respectively.
Toxicity
No grade II-IV toxicity according to CTCAE was observed in any patient after injection of MUC1-DC and MUC1-CTL. Only one patient developed transient systemic itching.
Adoptive immunotherapy with MUC1- DC and MUC1-CTL may be feasible and effective for pancreatic cancer.
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