Conclusions: This new study confirms that clinical efficacy of ISA101 vaccination is related to the strength of vaccine-induced HPV16-specific T-cell immunity and is an effective therapy for HPV16... Show moreConclusions: This new study confirms that clinical efficacy of ISA101 vaccination is related to the strength of vaccine-induced HPV16-specific T-cell immunity and is an effective therapy for HPV16-induced high-grade VIN/VaIN. (C) 2016 AACR. Show less
Approximately 50% of human malignancies carry p53 mutations, which makes it a potential antigenic target for cancer immunotherapy. Adoptive transfer with p53-specific cytotoxic T-lymphocytes (CTL)... Show moreApproximately 50% of human malignancies carry p53 mutations, which makes it a potential antigenic target for cancer immunotherapy. Adoptive transfer with p53-specific cytotoxic T-lymphocytes (CTL) and CD4(+) T-helper cells eradicates p53-overexpressing tumors in mice. Furthermore, p53 antibodies and p53-specific CTLs can be detected in cancer patients, indicating that p53 is immunogenic. Based on these results, clinical trials were initiated. In this paper, we review immunological and clinical responses observed in cancer patients vaccinated with p53 targeting vaccines. In most trials, p53-specific vaccine-induced immunological responses were observed. Unfortunately, no clinical responses with significant reduction of tumor-burden have occurred. We will elaborate on possible explanations for this lack of clinical effectiveness. In the second part of this paper, we summarize several immunopotentiating combination strategies suitable for clinical use. In our opinion, future p53-vaccine studies should focus on addition of these immunopotentiating regimens to achieve clinically effective therapeutic vaccination strategies for cancer patients. Show less
Immune response characterization at the primary tumor site enables the design of therapeutic vaccination strategies with higher efficacy in epithelial ovarian cancer (EOC). In this study, we... Show moreImmune response characterization at the primary tumor site enables the design of therapeutic vaccination strategies with higher efficacy in epithelial ovarian cancer (EOC). In this study, we related Wilms tumor protein 1 (WT1) overexpression, a well-established immunotherapeutic target, to clinicopathological characteristics, immunological parameters, and survival in primary EOC. WT1 overexpression was evaluated in primary EOC tissue of 270 patients by immunohistochemistry on tissue microarrays (TMAs). Clinicopathological characteristics, follow-up, and data on infiltration of CD8(+) cytotoxic T lymphocytes (CTLs), FoxP3(+) regulatory T lymphocytes (Tregs), major histocompatibility complex (MHC) class I, and II molecule expression, were derived from a previously published dataset. WT1 overexpression was defined as positive immunostaining for WT1. WT1 overexpression, present in 56.3% of EOC, was associated with infiltration of Tregs [ odds ratio (OR), 2.7; 95% confidence interval (95% CI), 1.6-4.7; P < 0.001] and up-regulation of MHC class II (OR, 2.2; 95% CI, 1.2-4.1; P = 0.014). Advanced stage (OR, 4.0; 95% CI, 1.9-8.6; P < 0.001) and serous histology (OR, 6.7; 95% CI, 3.2-13.6; P < 0.001) were independent predictors of WT1 overexpressing EOC. High number of CTL was an independent prognostic factor for progression-free survival (hazard ratio, 0.5; 95% CI, 0.3-0.8; P = 0.006) in WT1 overexpressing EOC. As WT1 overexpressing EOC is associated with CTL and Treg infiltration next to MHC class II up-regulation, future clinical trials should evaluate the combination of therapeutic WT1 vaccines with strategies depleting Tregs and/or up-regulating MHC class I, in an attempt to enhance clinical efficacy in EOC patients. Show less
