P53‐specific T cell responses in patients with malignant and benign ovarian tumors: Implications for p53 based immunotherapy

Abstract

Despite intensive treatment, 70% of the ovarian cancer patients will develop recurrent disease, emphasizing the need for new approaches such as immunotherapy. A promising antigenic target for immunotherapy in ovarian cancer is the frequently overexpressed p53 protein. The aim of the study was to evaluate the nature and magnitude of the baseline anti-p53 immune response in ovarian cancer patients. P53-specific T cell responses were detected in both half of the ovarian cancer patients as in the group of control subjects, consisting of women with benign ovarian tumors and healthy controls. Importantly, while in the control group p53-specific immunity was detected among the CD45RA 1 na€ ıve subset of T cells only, the p53-specific T-cell responses in ovarian cancer patients were also present in the CD45RO 1 memory T-cell subset, suggesting that in the cancer patients sufficient amounts of cancer-derived p53 was presented to induce the formation of a p53-specific memory T-cell response. Further characterization of the p53-specific memory T-cell responses revealed that in addition to the type 1 cytokine IFN-c also the type 2 cytokines IL-4 and IL-5, as well as the immunosuppressive cytokine IL-10 were produced. Notably, p53-specific T cells were not only detected in the peripheral blood, but also among tumor infiltrating lymphocytes and in tumor-draining lymph nodes. In conclusion, the existence of a weak mixed T-helper type 1 and 2 p53-specific T-cell repertoire supports the rationale of using p53 long peptides in vaccination strategies aiming at the induction of p53-specific Th1/ CTL immunity. ' 2007 Wiley-Liss, Inc.

Immunization with a P53 synthetic long peptide vaccine induces P53‐specific immune responses in ovarian cancer patients, a phase II trial

“…The IFN-g ELISPOT assay optimized to measure p53-specific T-cell responses was performed according to standard operation procedures as described previously. 15,32,36 Briefly, 1-2 million PBMC were stimulated with the indicated vaccine peptide pools (10 lg/peptide/ml) or MRM (1:50) and cultured in Iscove's medium (Gibco) containing 10% human AB serum (sigma), penicillin, streptomycin and b-mercapto-ethanol for 4 days. Then cells were counted and seeded in quadruplicates in an IFN-g ELISPOT plate at 100,000 cells per well.…”

“…A p53-specific response was defined as 3 Hthymidine incorporation >1000 counts/min and a stimulation index 3 (SI 5 mean of p53-induced proliferation/mean of medium control). 15 A vaccine-induced response was defined as a p53-specific response with proliferation after 4 immunizations/ proliferation before immunization 2.…”

“…26 In view of the fact that p53 is over expressed in many types of tumors, p53-specific CD4 1 T cells may act as ''universal'' T-helper cells for cancer and act analogous to the observed clinical remission and immunological responses to antigens other than NY-ESO-1 after the infusion of NY-ESO-1-specific T-helper cells in a patient with metastatic melanoma. 27 Our analyses of the p53-specific CD4 1 Th-cell repertoire in patients with cancer showed that in general these responses were weak 15,16 and failed to produce any of the Th1 or Th2 key cytokines 17 or were polarized towards a noneffective Th2 response, 15 suggesting that the induction of a strong p53-specific Th1-response through immunization may enhance the efficacy of the anti-tumor response.…”

“…[10][11][12][13][14] Indeed, circulating and tumor-infiltrating p53-specific memory T-cells could be detected and isolated from patients with ovarian cancer but not benign ovarian tumors. 15 In addition, p53-specific memory T cells have been observed in patients with colorectal cancer [15][16][17] and breast cancer, 18 indicating that tumor-derived p53 can effectively be presented to the immune system and activate circulating p53-specific T-lymphocytes. Although accumulating evidence suggests that the p53-specific CD8 1 T-cell repertoire is restricted by self tolerance, 19,20 the CD4 1 T-cell repertoire is not affected.…”

“…In our current study, we used overlapping synthetic long peptides (SLP), constituting the most immunogenic part of the p53 protein, [15][16][17] to enhance the p53-specific immune response in patients with cancer. Because of their length, SLP are predominantly taken up by professional antigen presenting cells (APC) where they are processed for presentation by both MHC class I and II molecules.…”