Toward the development of multi-epitope p53 cancer vaccines: An in vitro assessment of CD8+ T cell responses to HLA class I-restricted wild-type sequence p53 peptides

Sakakura, Koichi; Chikamatsu, Kazuaki; Furuya, Nobuhiko; Appella, Ettore; Whiteside, Theresa L.; DeLeo, Albert B.

doi:10.1016/j.clim.2007.05.015

Cited by 24 publications

(13 citation statements)

References 25 publications

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“…Currently a variety of p53-based vaccines have proved effective in animal models and are now undergoing trial in man. Key p53 peptide epitopes have been discovered (Hoffmann et al 2002;Sakakura et al 2007) and the major problem has emerged as one of steering the T-cell response toward effective tumor rejection rather than tolerance. In this context it is provocative to think about how drugs that modulate p53 processing may enhance or inhibit such T-cell responses.…”

Section: P53 Vaccinesmentioning

confidence: 99%

p53-based Cancer Therapy

Lane¹,

Cheok²,

Laı́n³

2010

Cold Spring Harbor Perspectives in Biology

218

187

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Inactivation of p53 functions is an almost universal feature of human cancer cells. This has spurred a tremendous effort to develop p53 based cancer therapies. Gene therapy using wild-type p53, delivered by adenovirus vectors, is now in widespread use in China. Other biologic approaches include the development of oncolytic viruses designed to replicate and kill only p53 defective cells and also the development of siRNA and antisense RNA's that activate p53 by inhibiting the function of the negative regulators Mdm2, MdmX, and HPV E6. The altered processing of p53 that occurs in tumor cells can elicit T-cell and B-cell responses to p53 that could be effective in eliminating cancer cells and p53 based vaccines are now in clinical trial. A number of small molecules that directly or indirectly activate the p53 response have also reached the clinic, of which the most advanced are the p53 mdm2 interaction inhibitors. Increased understanding of the p53 response is also allowing the development of powerful drug combinations that may increase the selectivity and safety of chemotherapy, by selective protection of normal cells and tissues.

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Section: P53 Vaccinesmentioning

confidence: 99%

p53-based Cancer Therapy

Lane¹,

Cheok²,

Laı́n³

2010

Cold Spring Harbor Perspectives in Biology

218

187

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“…Our previous study showed that CD8+ T cell precursors responsive to wt p53 epitopes were detected in the circulation of most subjects with early disease relative to subjects with advanced disease who were largely in the non-responder category [18]. Interestingly, in patients with a tumor burden, our data indicated that patients with early disease showed either Th1-polarized or mixed Th1/Th2 responses, while those with advanced disease had either Th2-polarized or Th1/Th2 responses.…”

Section: Discussionmentioning

confidence: 63%

CD4+ T cell responses to HLA-DP5-restricted wild-type sequence p53 peptides in patients with head and neck cancer

Chikamatsu

Sakakura

Takahashi

et al. 2009

Cancer Immunol Immunother

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Wild-type sequence (wt) p53 peptides are attractive candidates for broadly applicable cancer vaccines. Evidence has been accumulating which indicates that CD4+ Th cells have an important role in generating and maintaining antitumor immune responses. To elucidate the nature of CD4+ Th responses to wt p53 epitopes in patients with squamous cell carcinoma of the head and neck (SCCHN), peripheral blood mononuclear cells (PBMCs) from HLA-DP5+ patients were stimulated with HLA-DP5-restricted wt p53 peptides, p53108–122 or p53153–166, and tested for the release of IFN-γ and IL-5 in ELISPOT assays. Immunohistochemistry for p53 accumulation in tumors, and ELISA for serum antibodies to p53 were also performed. Eleven (57.9%) of 19 HLA-DP5+ patients but none of 5 healthy donors had detectable Th1 and/or Th2 responses to wt p53 peptides by ELISPOT assay. Among these 11 responding patients, 9 (81.8%) and all 11 (100%) patients had a tumor burden and p53 accumulation, respectively. On the other hand, two responding patients were in post-operative condition. Interestingly, among nine patients with a tumor burden, four patients with early disease showed either Th1-polarized or mixed Th1/Th2 responses, while five patients with advanced disease showed either Th2-polarized or mixed Th1/Th2 responses. Our results suggest that wt p53108–122 and p53153–166 peptides stimulate both Th1- and Th2-type CD4+ T cell responses in patients with SCCHN, and anti-p53 Th responses may persist even after surgical resection of the tumor; however, the presence of a tumor and its progression may affect the nature of immune responses to wt p53 peptides.

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“…Ovarian cancer often expresses a mutant form of p53 early in its development making it a potential target for immunotherapy [27]. Early preclinical studies showed that immune responses could be generated to p53 [28]. These data coupled with evidence of possible improved OS in patients who develop antibodies to p53 naturally make it a target of interest [29].…”

Section: Active Immunotherapymentioning

confidence: 99%

Past, Present and Future Targets For Immunotherapy in Ovarian Cancer

et al. 2014

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Ovarian cancer is the leading cause of death from gynecologic malignancy in the US. Treatments have improved with conventional cytotoxic chemotherapy and advanced surgical techniques but disease recurrence is common and fatal in nearly all cases. Current evidence suggests that the immune system and its ability to recognize and eliminate microscopic disease is paramount in preventing recurrence. Ovarian cancer immunotherapy is targeting tumors through active, passive and adoptive approaches. The goal of immunotherapy is to balance the activation of the immune system against cancer while preventing the potential for tremendous toxicity elicited by immune modulation. In this paper we will review the different immunotherapies available for ovarian cancer as well as current ongoing studies and potential future directions.

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Toward the development of multi-epitope p53 cancer vaccines: An in vitro assessment of CD8+ T cell responses to HLA class I-restricted wild-type sequence p53 peptides

Cited by 24 publications

References 25 publications

p53-based Cancer Therapy

p53-based Cancer Therapy

CD4+ T cell responses to HLA-DP5-restricted wild-type sequence p53 peptides in patients with head and neck cancer

Past, Present and Future Targets For Immunotherapy in Ovarian Cancer

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