Abstract
Purpose
Peptide antigens have been administered by different approaches as cancer vaccine therapy, including direct injection or pulsed onto dendritic cells; however, the optimal delivery method is still debatable. In this study, we describe the immune response elicited by two vaccine approaches using the wild-type (wt) p53 vaccine.
Experimental design
Twenty-one HLA-A2.1 patients with stage III, IV, or recurrent ovarian cancer overexpressing the p53 protein with no evidence of disease were treated in two cohorts. Arm A received SC wt p53:264-272 peptide admixed with Montanide and GM-CSF. Arm B received wt p53:264-272 peptide-pulsed dendritic cells IV. Interleukin-2 (IL-2) was administered to both cohorts in alternative cycles.
Results
Nine of 13 patients (69%) in arm A and 5 of 6 patients (83%) in arm B developed an immunologic response as determined by ELISPOT and tetramer assays. The vaccine caused no serious systemic side effects. IL-2 administration resulted in grade 3 and 4 toxicities in both arms and directly induced the expansion of T regulatory cells. The median overall survival was 40.8 and 29.6 months for arm A and B, respectively; the median progression-free survival was 4.2 and. 8.7 months, respectively.
Conclusion
We found that using either vaccination approach generates comparable specific immune responses against the p53 peptide with minimal toxicity. Accordingly, our findings suggest that the use of less demanding SC approach may be as effective. Furthermore, the use of low-dose SC IL-2 as an adjuvant might have interfered with the immune response. Therefore, it may not be needed in future trials.
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Acknowledgments
Supported in part by the intramural research program of the National Institute of Health (NIH), National Cancer Institute, Center for Cancer Research and by of the NCI/NIH grants P01 CA109688 (TLW) and R01 DE13918 (TLW) as well as National Institute grants to the Gynecologic Oncology Group Administrative Office (CA27469) and the Gynecologic Oncology Group Statistical Office (CA37517). Dr. M. Szajnik is a postdoctoral fellow supported by the NHLBI contract HB-37-165 (TLW). The following member institutions participated in this study: Tacoma General Hospital; MD Anderson Cancer Center; Columbus Cancer Council and the Cleveland Clinic Foundation.
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262_2011_1100_MOESM1_ESM.pdf
Immune Response Measured in the Peripheral Blood Obtained from Patient# 10A. The immune response of patient #10A using IFN-γ ELISPOT; reciprocal frequencies of wt p53 tetramer+ T cells; differentiation status of tetramer+ CD8+ T cells; percentage of activated CD4+ T cells and Treg in the peripheral circulation; percentage of Tr1 cells (CD132+TGF-β1+) in the peripheral circulation; and percentage of IL-10+ T cells measured ± stimulation signal. The samples were taken after each vaccine as indicated on the X axis with an arrow pointing to the IL-2 cycle. (PDF 137 kb)
262_2011_1100_MOESM2_ESM.pdf
Immune Response Measured in the Peripheral Blood Obtained from Patient# 6B. The immune response of patients #6B using IFN-γ ELISPOT; reciprocal frequencies of wt p53 tetramer+ T cells; differentiation status of tetramer+ CD8+ T cells; percentage of activated CD4+ T cells and Treg in the peripheral circulation; percentage of Tr1 cells (CD132+TGF-β1+) in the peripheral circulation; and percentage of IL-10+ T cells measured ± stimulation signal. The samples were taken after each vaccine as indicated on the X axis with an arrow pointing to the IL-2 cycle. (PDF 58 kb)
262_2011_1100_MOESM3_ESM.pdf
Levels of CA125 in Patients’ Sera Prior to and After Vaccination on Each Arm. The post-vaccination CA125 values are taken after the last vaccine that each patient received. CA125 levels are shown in U/mL. (PDF 5 kb)
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Rahma, O.E., Ashtar, E., Czystowska, M. et al. A gynecologic oncology group phase II trial of two p53 peptide vaccine approaches: subcutaneous injection and intravenous pulsed dendritic cells in high recurrence risk ovarian cancer patients. Cancer Immunol Immunother 61, 373–384 (2012). https://doi.org/10.1007/s00262-011-1100-9
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DOI: https://doi.org/10.1007/s00262-011-1100-9