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

Abstract

The prognosis of ovarian cancer, the primary cause of death from gynecological malignancies, has only modestly improved over the last decades. Immunotherapy is one of the new treatment modalities explored for this disease. To investigate safety, tolerability, immunogenicity and obtain an impression of clinical activity of a p53 synthetic long peptide (p53‐SLP) vaccine, twenty patients with recurrent elevation of CA‐125 were included, eighteen of whom were immunized 4 times with 10 overlapping p53‐SLP in Montanide ISA51. The first 5 patients were extensively monitored for toxicity, but showed no ≥ grade 3 toxicity, thus accrual was continued. Overall, toxicity was limited to grade 1 and 2, mostly locoregional, inflammatory reactions. IFN‐γ producing p53‐specific T‐cell responses were induced in all patients who received all 4 immunizations as measured by IFN‐γ ELISPOT. An IFN‐γ secretion assay showed that vaccine‐induced p53‐specific T‐cells were CD4+, produced both Th1 and Th2 cytokines as analyzed by cytokine bead array. Notably, Th2 cytokines dominated the p53‐specific response. P53‐specific T‐cells were present in a biopsy of the last immunization site of at least 9/17 (53%) patients, reflecting the migratory capacity of p53‐specific T‐cells. As best clinical response, stable disease evaluated by CA‐125 levels and CT‐scans, was observed in 2/20 (10%) patients, but no relationship was found with vaccine‐induced immunity. This study shows that the p53‐SLP vaccine is safe, well tolerated and induces p53‐specific T‐cell responses in ovarian cancer patients. Upcoming trials will focus on improving T helper‐1 polarization and clinical efficacy. © 2009 UICC

Systemic and local human papillomavirus 16‐specific T‐cell immunity in patients with head and neck cancer

“…We have previously shown that it is possible to isolate p53-specific CD4þ T cells from the TIL of patients with ovarian cancer. 23 Furthermore both p53-specific CD4þ and CD8þ T cells can be isolated from the vaccine site in our studies on p53 vaccination. 22 Although the existence of HPV16-specific regulatory T cells is reported, there is no evidence for the existence of p53-specific regulatory T cells.…”

“…[18][19][20] Similar vaccine approaches are tested for the treatment of p53-overexpressing cancers. [21][22][23] There is a strong notion that the presence and type of preexisting circulating and local tumor-specific immunity influences the clinical outcome as well as that of immunotherapeutic approaches. 6,18 Thus, to optimize immune resistance to HNSCC, a better understanding of the character and specificity of tumor-infiltrating-lymphocytes (TIL) in HNSCC is needed.…”

Immunotherapy in ovarian cancer

“…32 The vaccine was generally well-tolerated and was successful in inducing p53-specific, Th2-dominant T cell responses in patients who received all four vaccinations. However, clinical response did not correlate with vaccine-mediated immunity.…”

Cancer vaccine therapy based on peptides

“…Long peptides do not bind to HLA directly and only professional APCs, such as DCs, can take it up [76] . However, it was reported that some long peptides might induce peptide-specific regulatory T cells (Tregs) and Th2 cells to limit the clinical efficacy of long peptides [77,78] . On the other hand, in DC vaccine therapy, peptides are pulsed on mature DCs ex vivo and they cannot be loaded on unprofessional APCs.…”