Phase I study of a MUC1 vaccine composed of different doses of MUC1 peptide with SB-AS2 adjuvant in resected and locally advanced pancreatic cancer

Abstract

MUC1 is a glycoprotein overexpressed in tumors as a hypoglycosylated form. A vaccine composed of a 100-amino acid peptide corresponding to five 20-amino acid long repeats, and SB-AS2 adjuvant, was tested in a phase I study for safety, toxicity, and ability to elicit or boost MUC1-specific immune responses. Patients with resected or locally advanced pancreatic cancer without prior chemotherapy or radiotherapy were eligible. Escalating doses of the peptide (100, 300, 1,000, and 3,000 mug) were admixed with SB-AS2 and administered intramuscularly every 3 weeks for three doses, in cohorts of four patients. Sixteen patients were enrolled. Common adverse effects were grade 1 flu-like symptoms, tenderness, and erythema at the injection site. Delayed-type hypersensitivity (DTH) sites showed few or no T cells prevaccination (Pre V), but increased T-cell infiltration postvaccination (Post V). There was an increase in the percentage of CD8(+) T cells in the peripheral blood Post V. An increase in total MUC1-specific antibody was seen in some patients, and several patients developed IgG antibody. Two of 15 resected pancreatic cancer patients are alive and disease free at follow-up of 32 and 61 months. MUC1 100mer peptide with SB-AS2 adjuvant is a safe vaccine that induces low but detectable mucin-specific humoral and T-cell responses in some patients. No difference was seen between different peptide doses. Further evaluation is warranted to examine the effect on disease-free survival and overall survival, especially in early disease and in the absence of immunosuppressive standard therapy.

Fig. 1

Increase in the percentage of CD8⁺ T cells and in the ability of all the patient’s T cells to make cytokines when activated following vaccination. Patient’s PBMCs were activated with PMA/ionomycin, and intracellular levels of INF-γ (a) or IL-4 (b) evaluated in CD3⁺ cells by flow cytometry, as described in “Patients and methods.” Samples are from Pre V (Pre-V), 3 weeks after the first injection (V-1), 3 weeks after the second injection (V-2), and 2 weeks after the third injection (V-3).

Fig. 2

T cells infiltrating postvaccination DTH sites. MUC1 peptide and hepatitis B antigen were injected intradermally 14 days after the last injection and injection sites biopsied 48 h later. One third of the biopsy sample was minced and cultured for 2 weeks to allow infiltrating T cells to exit the skin fragments. The cells were analyzed by flow cytometry. The example shown is from the 300-μg dose peptide group.

Fig. 3

CD8⁺ T cells infiltrating the MUC1 DTH site are IFN-γ producers. MUC1 peptide and hepatitis B antigen were injected intradermally 14 days after the last injection, and injection sites biopsied 48 h later. One third of the biopsy sample was minced and cultured for 48 h to allow infiltrating T cells to exit the skin fragments. The cells were analyzed by flow cytometry. The example shown is from the 100-μg dose peptide group.

Fig. 4

Increase following vaccination in the percentage of CD8⁺ T cells that express normal levels of TCR ζ chain (a) and in the percentage of CD8⁺ T cells that produce IFN-γ upon stimulation (b). CD8⁺ T cells from patients’ PBMCs were evaluated for TCR ζ expression without activation. They were activated with PMA/ionomycin to measure intracellular levels of IFN-γ, as described in “Patients and methods.” Samples are from Pre V and the latest Post V time from which cells were available.