Evaluation of safety and efficacy of p53MVA vaccine combined with pembrolizumab in patients with advanced solid cancers
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Vaccination of cancer patients with p53-expressing modified vaccinia Ankara virus (p53MVA) has shown in our previous studies to activate p53-reactive T cells in peripheral blood but without immediate clinical benefit. We hypothesized that the immunological responses to p53MVA vaccine may require additional immune checkpoint blockade to achieve clinically beneficial levels. We therefore conducted a phase I trial evaluating the combination of p53MVA and pembrolizumab (anti-PD-1) in patients with advanced solid tumors.
Patients and methods
Eleven patients with advanced breast, pancreatic, hepatocellular, or head and neck cancer received up to 3 triweekly vaccines in combination with pembrolizumab given concurrently and thereafter, alone at 3-week intervals until disease progression. The patients were assessed for toxicity and clinical response. Correlative studies analyzed p53-reactive T cells and profile of immune function gene expression.
We observed clinical responses in 3/11 patients who remained with stable disease for 30, 32, and 49 weeks. Two of these patients showed increased frequencies and persistence of p53-reactive CD8+ T cells and elevation of expression of multiple immune response genes. Borderline or undetectable p53-specific T cell responses in 7/11 patients were related to no immediate clinical benefit. The first study patient had a grade 5 fatal myocarditis. After the study was amended for enhanced cardiac monitoring, no additional cardiac toxicities were noted.
We have shown that the combination of p53MVA vaccine with pembrolizumab is feasible, safe, and may offer clinical benefit in select group of patients that should be identified through further studies.
KeywordsImmunotherapy Vaccine MVA p53 PD-1 Pembrolizumab
We thank the following City of Hope staff members and departments: The Investigational Drug Service, Center for Biomedicine and Genetics, The Office of IND Development and Regulatory Affairs, and Molecular Pathology Core. We are grateful to the staff of the Molecular Pathology Core and Clinical Molecular Diagnostic Laboratory for performing NanoString nCounter assay. We thank Bernard Moss (National Institutes of Health) for allowing access to 1974-MVA and the NIAID for agreeing to its transfer by MTA for clinical use. The RAID program of the NCI is acknowledged for partial support of the original derivation of the p53MVA vaccine.
This work was supported by funds from the Hope Portfolio Fund, R21CA114889, NCI-SAIC 25XS061, FAMRI 042275, 2 K12 CA001727 and the Phase One Foundation. Research reported in this publication included work performed in the Molecular Pathology Core supported by the National Cancer Institute of the National Institutes of Health under award number P30CA033572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
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