Dendritic Cell-based Immunotherapy Pulsed with Wilms Tumor 1 Peptide and Mucin 1 as an Adjuvant Therapy for Pancreatic Ductal Adenocarcinoma After Curative Resection: A Phase I/IIa Clinical Trial

Dendritic Cell-based Immunotherapy Pulsed with Wilms Tumor 1 Peptide and Mucin 1 as an Adjuvant Therapy for Pancreatic Ductal Adenocarcinoma After Curative Resection: A Phase I/IIa Clinical Trial

Survival rate

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Summary

The study aims to evaluate the safety, efficacy and feasibility if Wilms tumor gene 1 (WT1) peptide and Mucin 1 (MUC1)-pulsed dendritic cell (DC) (WT1/MUC1-DC) vaccination as an immunotherapy for patients with pancreatic ductal adenocarcinoma (PDA). WT1/MUC1-DC vaccination in the adjuvant setting was safe and well-tolerated in PDA patients after tumor resection.

Patients characteristics

10 patients ages ranged from 56 to 76 years old (median 62.5 years old) histologically diagnosed with pancreatic ductal adenocarcinoma (PDA) and their PS was well maintained. Clinical stage varied from IA to III and curative resection was performed in all cases.
Patients had Eastern Cooperative Oncology Group performance status (PS) of 0-1, had normal organ function, had no chemotherapy-disqualifying sign of infectious disease, had no blood abnormality or bleeding tendency, had no apheresis-disqualifying history of cardiovascular disease or respiratory disorders, and had human leukocyte antigen (HLA) class I genotypes compatible with restriction of the WT1 peptide.

Methodology

Leukapheresis was carried out when patients’ peripheral white blood cell (WBC) count, hemoglobin concentration, and platelet count were above 2000 cells/μl, 9.0 g/dl, and 90,000 cells/μl, respectively. Peripheral blood mononuclear cells (PBMCs) were isolated from leukapheresis products by Ficol-Hypaque gradient density centrifugation. PBMCs were then cultured in tissue-culture plates, and adherent cells were harvested. Adherent cells were cultured in AIM-V medium containing human recombinant granulocyte-macrophage-colony-stimulating factor (GM-CSF) and human recombinant interleukin-4 (IL-4) in order to generate immature DCs.
Five days later, DCs were loaded with HLA-A*24:02-restricted WT1 (235-243: CYTWNQMNL) (mutant WT1 peptide) and HLA-A*02:01/02:06-restricted WT1 peptide (126-134: RMFPNAPYL) (WT1 peptide) according to the compatibility of each patient’s HLA typing. DCs were then stimulated with OK-432, streptococcal preparation, prostaglandin E2 (PGE2), IL-4, and granulocyte-macrophage colony-stimulating factor for 24 hours for maturation.
MUC1 was added to the DC culture media concomitantly with OK-432 and PGE2. The MUC1 long peptide TRPAPGSTAPPAHGVTSAPDTRPAPGSTAP was used for all HLA-A types. DCs were harvested, washed, and dissolved in AIM-V medium containing 10% dimethyl sulfoxide (DMSO) and 10% human albumin and dispensed to cryo-tubes at approximately 1×107 cells per tube. After pre-freezing at –80 ̊C for 4 hours, DCs were cryo-preserved at –150 C̊ in a deep freezer until the day of administration.

Treatment

Cryo-preserved DCs were thawed, washed with physiological saline containing 10% dextran (10 mL) once, and washed with physiological saline (10 ml) twice to get rid of the remaining DMSOand human albumin. WT1/MUC1-DCs were suspended in a total volume of 1 ml of physiological
saline, and approximately 1×107 WT1/MUC1- DCs were injected intradermally (ID) at four positions in the axilla and groin regions on each side (approximately 0.25 ml at each position). They were administered seven times in 2-week intervals. OK-432 was administered subcutaneously (SC) in each axilla (0.5 ml each) in the vicinity of vaccination sites to activate DC functions. Administration was initiated at a dose of 1 Klinische Einheit and increased to 5 KE if no side effects were observed.

Results

AEs were reported in a total of nine (90.0%) patients. The most common AE of any grade was skin reaction (erythema) at the DC vaccine injection site (n=9, 90.0%). Meanwhile, fever (n=6, 60.0%) was observed in six patients, including three patients (30.0%) with Grade 1 fever (>38 C̊ ). Both AEs recurred in most cases and disappeared after a few days. Grade 1 fatigue was observed in six patients (60.0%). Grade 1 leukocytopenia, neutropenia, and anemia were observed in 3, 3, and 1 of the 10 patients, respectively. Overall, no Grade 2 or higher CTCAE v5.0 toxicities were found to be associated with DC vaccination. Therefore, no patient discontinued DC vaccination.
Clinical outcome
Seven of the ten patients relapsed, and the final outcome recorded six deaths because of recurrence and disease progression. The maximum follow-up period was 65 months after completion of vaccine administration. The OS and RFS from the time of surgical resection were 18.5-72.8 months (median 46.4 months) and 12.5-72.8 months (median 17.7 months), respectively. The estimated OS and RFS at 3-years were 77.8% and 35.0%, and those at 5-year were 19.4% and 23.3%, respectively.

Conclusion

In conclusion, the present phase I/IIa study evaluating WT1 peptide and MUC1-pulsed DC vaccination in combination with chemotherapy in patients with resected pancreatic cancer demonstrated the safety and feasibility of this therapy in the adjuvant setting. It was suggested that there appeared to be a survival benefit of add-on DC vaccination in this study compared to that of conventional post-resection adjuvant chemotherapy.

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Scientific article publishing date : 18/07/2019

Immucura identifier : BSC21_057EN

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