Clinical and Immunological Effects of p53-Targeting Vaccines

Abstract

Immunotherapy, including immune checkpoint blockade and chimeric antigen receptor T cells, is one of the most promising approaches to treat cancer. Vaccines have been effective in preventing cancers like liver cancer and cervical cancer with a viral etiology. Instead of preventing disease, therapeutic cancer vaccines mobilize the immune system to attack existing cancer. p53 is dysregulated in the majority of human cancers and is a highly promising target for cancer vaccines. Over twenty clinical trials have targeted p53 in malignant diseases using vaccines. In this work, we review the progress of vaccinations with p53 or its peptides as the antigens and summarize the clinical and immunological effects of p53-targeting vaccines from clinical trials. The delivery platforms include p53 peptides, viral vectors, and dendritic cells pulsed with short peptides or transduced by p53-encoding viruses. These studies shed light on the feasibility, safety, and clinical benefit of p53 vaccination in select groups of patients, implicating that p53-targeting vaccines warrant further investigations in experimental animals and human studies.

Targeting Mutant p53 for Cancer Treatment: Moving Closer to Clinical Use?

“…As TP53 is mutated in a large proportion of human cancers, it would be expected to act as a neoantigen and promote an immune response, thereby opening up the potential of exploiting it as an anti-cancer vaccine. Evidence from mice models and patients with cancer showed that administration of certain p53 neo-epitopes containing hot-spot mutations did indeed provoke the generation of specific T cell (CD8+ and CD4+ cells) responses against p53 peptides containing the hot-spot mutations [ 93 , 94 ]. Thus, cytotoxic T lymphocytes recognizing the p53 25–35 , p53 110–124 , p53 149–157 and p53 264–272 have been observed in experimental systems [ 93 , 94 ].…”

“…Evidence from mice models and patients with cancer showed that administration of certain p53 neo-epitopes containing hot-spot mutations did indeed provoke the generation of specific T cell (CD8+ and CD4+ cells) responses against p53 peptides containing the hot-spot mutations [ 93 , 94 ]. Thus, cytotoxic T lymphocytes recognizing the p53 25–35 , p53 110–124 , p53 149–157 and p53 264–272 have been observed in experimental systems [ 93 , 94 ]. These findings led to the development of several different vaccines for enhancing T cell responses against tumors possessing mutant p53 [ 93 , 94 ].…”

“…Thus, cytotoxic T lymphocytes recognizing the p53 25–35 , p53 110–124 , p53 149–157 and p53 264–272 have been observed in experimental systems [ 93 , 94 ]. These findings led to the development of several different vaccines for enhancing T cell responses against tumors possessing mutant p53 [ 93 , 94 ]. Since these vaccines were generally well tolerated when administered to mice models, they were tested in multiple phase I/II clinical trials across different cancer types [ 93 ].…”

Current State of Cell Therapies for Breast Cancer

“…Tumor suppressor gene TP53 is the most frequently mutated gene in approximately 30% of all BC patients 99 . Dendritic cell vaccination approach targeting p53 protein can be an effective therapeutic strategy to trigger immune response against p53 (p53 mutant) overexpressing BC 100 . A phase I/II clinical trial has been recently completed in testing the efficacy and adverse effects of adenovirus p53–infected DC vaccine in stage III BC patients receiving neoadjuvant or adjuvant chemotherapy and adjuvant radiation therapy (NCT00082641).…”

“… 99 Dendritic cell vaccination approach targeting p53 protein can be an effective therapeutic strategy to trigger immune response against p53 (p53 mutant) overexpressing BC. 100 A phase I/II clinical trial has been recently completed in testing the efficacy and adverse effects of adenovirus p53–infected DC vaccine in stage III BC patients receiving neoadjuvant or adjuvant chemotherapy and adjuvant radiation therapy (NCT00082641). A combination treatment approach of adenovirus p53–transduced DC vaccine with 1-methyl- d -tryptophan was investigated in MBC patients and observed enhanced antitumor response (NCT01042535).…”