Triple peptide vaccination as consolidation treatment in women affected by ovarian and breast cancer: Clinical and immunological data of a phase I/II clinical trial

Abstract

Vaccination with priming and expansion of tumour reacting T cells is an important therapeutic option to be used in combination with novel checkpoint inhibitors to increase the specificity of the T cell infiltrate and the efficacy of the treatment. In this phase I/II study, 14 high-risk disease-free ovarian (OC) and breast cancer (BC) patients after completion of standard therapies were vaccinated with MUC1, ErbB2 and carcinoembryonic antigen (CEA) HLA-A2+-restricted peptides and Montanide. Patients were subjected to 6 doses of vaccine every two weeks and a recall dose after 3 months. ECOG grade 2 toxicity was observed at the injection site. Eight out of 14 patients showed specific CD8+ T cells to at least one antigen. None of 4 patients vaccinated for compassionate use showed a CD8 activation. An OC patient who suffered from a lymph nodal recurrence, showed specific anti-ErbB2 CD8+ T cells in the bulky aortic lymph nodes suggesting homing of the activated T cells. Results confirm that peptide vaccination strategy is feasible, safe and well tolerated. In particular OC patients appear to show a higher response rate compared to BC patients. Vaccination generates a long-lasting immune response, which is strongly enhanced by recall administrations. The clinical outcome of patients enrolled in the trial appears favourable, having registered no deceased patients with a minimum follow-up of 8 years. These promising data, in line with the results of similar studies, the high compliance of patients observed and the favourable toxicity profile, support future trials of peptide vaccination in clinically disease-free patients who have completed standard treatments.

Figure 1

Vaccination schedule. Patient received 6 consecutive doses of vaccine every two weeks followed by a further recall dose (7th dose) at 3 months from the last dose. Before and after vaccination, and after the recall dose, patients were subjected to DTH.

Figure 2

IFNγ production of specific CD8 T cells from vaccinated patients. ELISPOT analysis of IFNγ released by MUC1 (square), ErbB2 (circle) and CEA (pentagon) specific CD8 T lymphocytes after two weeks of amplification. Data are reported as fold increase obtained dividing the number of IFNγ spots produced before vaccination with those produced after the last dose. The values two fold-increased from baseline (continuous line) are considered positive.

Figure 3

Circulating Treg cell analysis in BC and OC patients. Tregs were analysed by cytofluorimetry for the expression of CD4, CD25 and FOXP3 molecules. Results show CD4⁺CD25⁺FOXP3⁺ cells pre- and post- vaccination. Data are reported as percentage of CD4⁺CD25⁺FOXP3⁺ cells.

Figure 4

Immunomonitoring of OC patients. (A) Number of IFNγ spots released by ErbB2 (circle) and CEA (square) specific CD8 T cells at staging (01/2009), after the first cycle of vaccination (04/2009), at the lymph nodal recurrence (09/2009), after the para-aortic lymphadenectomy (12/2009), after the second cycle of vaccination (04/2010) and at follow-up (03/2013). (B) ErbB2 and CEA pentamer staining performed on purified CD8 T cells obtained from bulky aortic lymph node. (C) Number of IFNγ spots produced by ErbB2 and CEA specific CD8 T cells purified from bulky lymph node.