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p53MVA Therapy in Patients with Refractory Gastrointestinal Malignancies Elevates p53-Specific CD8+ T-cell Responses
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Abstract
Purpose: To conduct a phase I trial of a modified vaccinia Ankara (MVA) vaccine delivering wild-type human p53 (p53MVA) in patients with refractory gastrointestinal cancers. Experimental Design: Three patients were vaccinated with 1.0 × 108 plaque-forming unit (pfu) p53MVA followed by nine patients at 5.6 × 108 pfu. Toxicity was classified using the NCI Common Toxicity Criteria and clinical responses were assessed by CT scan. Peripheral blood samples were collected pre- and post-immunization for immunophenotyping, monitoring of p53MVA-induced immune response, and examination of PD1 checkpoint inhibition in vitro. Results: p53MVA immunization was well tolerated at both doses, with no adverse events above grade 2. CD4+ and CD8+ T cells showing enhanced recognition of a p53 overlapping peptide library were detectable after the first immunization, particularly in the CD8+ T-cell compartment (P = 0.03). However, in most patients, this did not expand further with the second and third immunization. The frequency of PD1+ T cells detectable in patients' peripheral blood mononuclear cells (PBMC) was significantly higher than in healthy controls. Furthermore, the frequency of PD1+ CD8+ T cells showed an inverse correlation with the peak CD8+ p53 response (P = 0.02) and antibody blockade of PD1 in vitro increased the p53 immune responses detected after the second or third immunizations. Induction of strong T-cell and antibody responses to the MVA backbone were also apparent. Conclusion: p53MVA was well tolerated and induced robust CD8+ T-cell responses. Combination of p53MVA with immune checkpoint inhibition could help sustain immune responses and lead to enhanced clinical benefit. Clin Cancer Res; 20(17); 4459–70. ©2014 AACR.
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“Later in 2014 and 2018, Hardwick’s group conducted two early-phase clinical trials involving a modified vaccinia virus ankara vaccine encoding wtp53 (MVAp53 (253)). The studies showed that MVAp53 could induce CD8+ and CD4+ T cell responses in patients with refractory gastrointestinal cancer and ovarian cancer, respectively.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [593]
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396
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Metadata
- Authors
- Hardwick, N. R., Carroll, M., Kaltcheva, T., Qian, D., Lim, D., Leong, L., Chu, P., Kim, J., Chao, J., Fakih, M., Yen, Y., Espenschied, J., Ellenhorn, J. D. I., Diamond, D. J., & Chung, V.
- Affiliations
- City Of Hope National Medical Center (US)
- Cedars-Sinai Medical Center (US)
- Corresponding author
- Diamond, Don J.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2014-09-01
- Volume
- 20
- Issue
- 17
- Pages
- 4459-4470
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC4155000
- OpenAlex
- W2045927502
- Cited by
- 45
- References
- 50
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 5 · 2023: 8 · 2022: 4 · 2021: 4 · 2020: 2 · 2018: 4 · 2017: 6 · 2016: 1 · 2015: 2 · 2014: 1
- FWCI
- 1.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r29ca070819-04)
- National Cancer Institute (R29 CA 70819, CA033572, R21CA114889, P30CA033572)
- National Center for Research Resources (M01RR000043)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- modified vaccinia Ankara, CD8+ T cell responses, PD-1 checkpoint, immune checkpoint blockade, vaccine immunogenicity, vaccine toxicity
- MeSH terms
- Aged, Female, Gastrointestinal Neoplasms, Humans, Male, Middle Aged, Mutation, CD4-Positive T-Lymphocytes, Tumor Suppressor Protein p53, CD8-Positive T-Lymphocytes, Cancer Vaccines
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