Recombinant Modified Vaccinia Virus Ankara (MVA) Expressing Wild-Type Human p53 Induces Specific Antitumor CTL Expansion

Song, Guang-Yun; Srivastava, Tumul; Ishizaki, Hidenobu; Lacey, Simon F.; Diamond, Don J.; Ellenhorn, Joshua D. I.

doi:10.3109/07357907.2011.606248

Cited by 12 publications

(7 citation statements)

References 43 publications

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“…Hupki mice immunized with p53MVA showed regression of established 4TI syngeneic breast tumors with murine p53 knockout and engineered human p53 expression, and generation of systemic anti-tumor immunity (15). Finally, studies with PBMC collected from cancer patients with solid tumors showed that specific recall immune responses to p53 could be stimulated in vitro with p53MVA (16). …”

Section: Introductionmentioning

confidence: 99%

p53MVA Therapy in Patients with Refractory Gastrointestinal Malignancies Elevates p53-Specific CD8+ T-cell Responses

Hardwick

Carroll

Kaltcheva

et al. 2014

Clinical Cancer Research

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PURPOSE: To conduct a Phase I trial of a Modified Vaccinia Ankara vaccine delivering wild type human p53 (p53MVA) in patients with refractory gastrointestinal cancers. EXPERIMENTAL DESIGN: Three patients were vaccinated with 1.0 × 108 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 PD-1 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 PD-1+ T cells detectable in patients PBMC was significantly higher than in healthy controls. Furthermore, the frequency of PD-1+ CD8+ T cells showed an inverse correlation with the peak CD8+ p53 response (p=0.02) and antibody blockade of PD-1 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.

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Section: Introductionmentioning

confidence: 99%

p53MVA Therapy in Patients with Refractory Gastrointestinal Malignancies Elevates p53-Specific CD8+ T-cell Responses

Hardwick

Carroll

Kaltcheva

et al. 2014

Clinical Cancer Research

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“…Recent clinical trials with wtMVA as well as recombinant MVA vaccine candidates confirmed the safety of MVA in humans . In line with this, recombinant MVA vaccines have been shown to induce protective immunity in tumor therapy and various infectious diseases .…”

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confidence: 74%

Vaccination with recombinant modified vaccinia virus Ankara prevents the onset of intestinal allergy in mice

Bohnen

Wangorsch

Schülke

et al. 2013

Allergy

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Background Modified vaccinia virus Ankara (MVA)‐encoding antigens are considered as safe vaccine candidates for various infectious diseases in humans. Here, we investigated the immune‐modulating properties of MVA‐encoding ovalbumin (MVA‐OVA) on the allergen‐specific immune response. Methods The immune‐modulating properties of MVA‐OVA were investigated using GM‐CSF‐differentiated BMDCs from C57BL/6 mice. OVA expression upon MVA‐OVA infection of BMDCs was monitored. Activation and maturation markers on viable MVA‐OVA‐infected mDCs were analyzed by flow cytometry. Secretion of INF‐γ, IL‐2, and IL‐10 was determined in a co‐culture of BMDCs infected with wtMVA or MVA‐OVA and OVA‐specific OT‐I CD8+ and OT‐II CD4+ T cells. BALB/c mice were vaccinated with wtMVA, MVA‐OVA, or PBS, sensitized to OVA/alum and challenged with a diet containing chicken egg white. OVA‐specific IgE, IgG1, and IgG2a and cytokine secretion from mesenteric lymph node (MLN) cells were analyzed. Body weight, body temperature, food uptake, intestinal inflammation, and health condition of mice were monitored. Results Infection with wtMVA and MVA‐OVA induced comparable activation of mDCs. MVA‐OVA‐infected BMDCs expressed OVA and induced enhanced IFN‐γ and IL‐2 secretion from OVA‐specific CD8+ T cells in comparison with OVA, wtMVA, or OVA plus wtMVA. Prophylactic vaccination with MVA‐OVA significantly repressed OVA‐specific IgE, whereas OVA‐specific IgG2a was induced. MVA‐OVA vaccination suppressed TH2 cytokine production in MLN cells and prevented the onset of allergic symptoms and inflammation in a mouse model of OVA‐induced intestinal allergy. Conclusion Modified vaccinia virus Ankara‐ovalbumin (MVA‐OVA) vaccination induces a strong OVA‐specific TH1‐ immune response, likely mediated by the induction of IFN‐γ and IgG2a. Finally, MVA‐based vaccines need to be evaluated for their therapeutic potential in established allergy models.

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“…However, clinical benefit could not be demonstrated. Another vaccine, the recombinant modified vaccinia virus Ankara (MVA) expressing wild-type human p53 (MVAp53), was found to induce p53-specific IFN-γ production, degranulation, cell proliferation, and lysis of p53-overexpressed tumor cells [18]. A phase II trial of two different p53 peptide vaccines showed specific immune responses with minimal toxicity in patients with ovarian cancer.…”

Section: Potential Treatments For Tp53 Altered Tumorsmentioning

confidence: 99%

Next Generation Sequencing (NGS) in Relapsed/Refractory HPV Negative Head and Neck Squamous Cell Carcinoma (HNSCC) Reveals Diverse Genomic Alterations and Potential Targets of Therapy

Esmat

Hilly

Mizrachi

et al. 2019

BJSTR

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Background: Managing relapsing metastatic, head and neck squamous cell carcinoma (HNSCC) is challenging. The genomic landscape of HNSCC has been recently described by numerous studies; however clinical utility studies are absent. Methods:We describe next generation sequencing (NGS) results and clinical outcomes of eight patients with advanced recurrent HPV-negative HNSCC. NGS platform (FoundationOneTM) included the coding sequence of 236 cancer-related genes and 47 introns.Results: All eight cases harbored ≥1 Genomic alterations (GA) accumulating to a total of 31 GA (average 3.9/tumor): the most common GA were; 10 in TP53 (6 tumors) and 5 in CDKN2A. Three GA were associated with FDA-approved drugs for HNSCC (EGFR amplification; Cetuximab), or other tumors (mTOR inhibitors -FBXW7-R465C; BRAF inhibitors -BRAF-K601E). Clinical trials associated with specific gene alterations were found to be applicable in all cases.Conclusions: NGS in HNSCC is clinically feasible, revealing actionable GA in a high percentage of patients. Larger studies with access to early-phase clinical trials should improve outcome.

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Recombinant Modified Vaccinia Virus Ankara (MVA) Expressing Wild-Type Human p53 Induces Specific Antitumor CTL Expansion

Cited by 12 publications

References 43 publications

p53MVA Therapy in Patients with Refractory Gastrointestinal Malignancies Elevates p53-Specific CD8+ T-cell Responses

p53MVA Therapy in Patients with Refractory Gastrointestinal Malignancies Elevates p53-Specific CD8+ T-cell Responses

Vaccination with recombinant modified vaccinia virus Ankara prevents the onset of intestinal allergy in mice

Next Generation Sequencing (NGS) in Relapsed/Refractory HPV Negative Head and Neck Squamous Cell Carcinoma (HNSCC) Reveals Diverse Genomic Alterations and Potential Targets of Therapy

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