Evaluation of safety and efficacy of p53MVA vaccine combined with pembrolizumab in patients with advanced solid cancers.

Abstract

BACKGROUND:

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.

RESULTS:

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.

CONCLUSION:

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.

• Authors: V Chung, F J Kos, N Hardwick, Y Yuan, J Chao, D Li, J Waisman, M Li, K Zurcher, P Frankel, D J Diamond
• Journal: Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico (Clin Transl Oncol) Vol. 21 Issue 3 Pg. 363-372 (Mar 2019) ISSN: 1699-3055 [Electronic] Italy
• PMID: 30094792 (Publication Type: Clinical Trial, Phase I, Journal Article)

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents, Immunological
• Cancer Vaccines
• MVAp53 vaccine
• TP53 protein, human
• Tumor Suppressor Protein p53
• pembrolizumab

Topics

• Adult
• Aged
• Antibodies, Monoclonal, Humanized (therapeutic use)
• Antineoplastic Agents, Immunological (therapeutic use)
• CD8-Positive T-Lymphocytes (immunology)
• Cancer Vaccines (immunology, therapeutic use)
• Combined Modality Therapy (methods)
• Female
• Genetic Vectors
• Humans
• Male
• Middle Aged
• Neoplasms (immunology, therapy)
• Tumor Suppressor Protein p53 (administration & dosage, immunology)