Clinical and Translational Oncology

, Volume 21, Issue 3, pp 363–372 | Cite as

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

  • V. Chung
  • F. J. Kos
  • N. Hardwick
  • Y. Yuan
  • J. Chao
  • D. Li
  • J. Waisman
  • M. Li
  • K. Zurcher
  • P. Frankel
  • D. J. DiamondEmail author
Research Article



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.


Immunotherapy 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.

Ethical approval

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

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Pardoll D, Drake C. Immunotherapy earns its spot in the ranks of cancer therapy. J Exp Med. 2012;209:201–9. Scholar
  2. 2.
    Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168:707–23. Scholar
  3. 3.
    Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359:1350–5. Scholar
  4. 4.
    Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol. 2010;2:a001008. Scholar
  5. 5.
    Bueter M, Gasser M, Lebedeva T, Benichou G, Waaga-Gasser AM. Influence of p53 on anti-tumor immunity (review). Int J Oncol. 2006;28:519–25.Google Scholar
  6. 6.
    Song GY, Gibson G, Haq W, Huang EC, Srivasta T, Hollstein M, Daftarian P, Wang Z, Diamond D, Ellenhorn JD. An MVA vaccine overcomes tolerance to human p53 in mice and humans. Cancer Immunol Immunother. 2007;56:1193–205. Scholar
  7. 7.
    Song GY, Srivastava T, Ishizaki H, Lacey SF, Diamond DJ, Ellenhorn JD. Recombinant modified vaccinia virus ankara (MVA) expressing wild-type human p53 induces specific antitumor CTL expansion. Cancer Investig. 2011;29:501–10. Scholar
  8. 8.
    Liu X, Peralta EA, Ellenhorn JD, Diamond DJ. Targeting of human p53-overexpressing tumor cells by an HLA A*0201-restricted murine T-cell receptor expressed in Jurkat T cells. Cancer Res. 2000;60:693–701.Google Scholar
  9. 9.
    Oseroff C, Kos F, Bui HH, Peters B, Pasquetto V, Glenn J, Palmore T, Sidney J, Tscharke DC, Bennink JR, Soutwood S, Grey HM, Yewdell JW, Sette A. HLA class I-restricted responses to vaccinia recognize a broad array of proteins mainly involved in virulence and viral gene regulation. Proc Natl Acad Sci USA. 2005;102:13980–5. Scholar
  10. 10.
    Espenschied J, Lamont J, Longmate J, Pendas S, Wang Z, Diamond DJ, Ellenhorn JD. CTLA-4 blockade enhances the therapeutic effect of an attenuated poxvirus vaccine targeting p53 in an established murine tumor model. J Immunol. 2003;170:3401–7.CrossRefGoogle Scholar
  11. 11.
    Daftarian P, Song GY, Ali S, Faynsod M, Longmate J, Diamond DJ, Ellenhorn JD. Two distinct pathways of immuno-modulation improve potency of p53 immunization in rejecting established tumors. Cancer Res. 2004;64:5407–14. Scholar
  12. 12.
    Hardwick NR, Carroll M, Kaltcheva T, Qian D, Lim D, Leon L, Chu P, Kim J, Chao J, Fakih M, Yen Y, Espenschied J, Ellenhorn JD, Diamond DJ, Chung V. p53MVA therapy in patients with refractory gastrointestinal malignancies elevates p53-specific CD8+ T-cell responses. Clin Cancer Res. 2014;20:4459–70. Scholar
  13. 13.
    Khoja L, Butler MO, Kang SP, Ebbinghaus S, Joshua AM. Pembrolizumab. J Immunother Cancer. 2015;3:36. Scholar
  14. 14.
    Hardwick N, Chung V, Cristea M, Ellenhorn JD, Diamond DJ. Overcoming immunosuppression to enhance a p53MVA vaccine. OncoImmunology. 2014;3:e958949. Scholar
  15. 15.
    Yuan Y, Kos FJ, He TF, Yin HH, Li M, Hardwick N, Zurcher K, Schmolze D, Lee P, Pillai RK, Chung V, Diamond DJ. Complete regression of cutaneous metastases with systemic immune response in a patient with triple negative breast cancer receiving p53MVA vaccine with pembrolizumab. OncoImmunology. 2017;6:e1363138. Scholar
  16. 16.
    Laubli H, Balmelli C, Bossard M, Pfister O, Glatz K, Zippelius A. Acute heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic melanoma. J Immunother Cancer. 2015;3:11. Scholar
  17. 17.
    Wolfl M, Kuball J, Ho WY, Nguyen H, Manley TJ, Bleakly M, Greenberg PD. Activation-induced expression of CD137 permits detection, isolation, and expansion of the full repertoire of CD8+ T cells responding to antigen without requiring knowledge of epitope specificities. Blood. 2007;110:201–10. Scholar
  18. 18.
    Wolfl M, Kuball J, Eyrich M, Schlegel PG, Greenberg PD. Use of CD137 to study the full repertoire of CD8+ T cells without the need to know epitope specificities. Cytometry A. 2008;73:1043–9. Scholar
  19. 19.
    Ye Q, Song DG, Poussin M, Yamamoto T, Best A, Li C, Coukos G, Powell DJ Jr. CD137 accurately identifies and enriches for naturally occurring tumor-reactive T cells in tumor. Clin Cancer Res. 2014;20:44–55. Scholar
  20. 20.
    Hardwick NR, Frankel P, Ruel C, Kilpatrick J, Tsai W, Kos F, Kaltcheva TL, Leong L, Morgan R, Chung V, Tinsley R, Eng M, Wilczynski SP, Ellenhorn JDI, Diamond DJ, Cristea M. p53-reactive T cells are associated with clinical benefit in patients with platinum-resistant epithelial ovarian cancer after treatment with a p53 vaccine and gemcitabine chemotherapy. Clin Cancer Res. 2018;24:1315–25. Scholar
  21. 21.
    McBride JA, Striker R. Imbalance in the game of T cells: What can the CD4/CD8 T-cell ratio tell us about HIV and health? PLoS Pathog. 2017;13:e1006624. Scholar
  22. 22.
    Hadrup SR, Strindhall J, Kollgaard T, Seremet T, Johansson B, Pawelec G, Thor Straten P, Wikby A. Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly. J Immunol. 2006;176:2645–53.CrossRefGoogle Scholar
  23. 23.
    Subudhi SK, Aparicio A, Gao J, Zurita AJ, Araujo JC, Logothetis CJ, Tathi SA, Korivi BR, Slack RS, Vence I, Emerson RO, Yusko E, Vignali M, Robins HS, Sun J, Allison JP, Sharma P. Clonal expansion of CD8 T cells in the systemic circulation precedes development of ipilimumab-induced toxicities. Proc Natl Acad Sci USA. 2016;113:11919–24. Scholar
  24. 24.
    Weber JS, Postow M, Lao CD, Schadendorf D. Management of adverse events following treatment with anti-programmed death-1 agents. Oncologist. 2016;21:1230–40. Scholar
  25. 25.
    Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23. Scholar
  26. 26.
    Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54. Scholar
  27. 27.
    Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65. Scholar
  28. 28.
    Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34. Scholar
  29. 29.
    Pauken KE, Sammons MA, Odorizzi PM, et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science. 2016;354:1160–5. Scholar
  30. 30.
    Hodi FS, Hwu WJ, Kefford R, et al. Evaluation of immune-related response criteria and RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab. J Clin Oncol. 2016;34:1510–7. Scholar
  31. 31.
    Long GV, Weber JS, Larkin J, et al. Nivolumab for patients with advanced melanoma treated beyond progression: analysis of 2 phase 3 clinical trials. JAMA Oncol. 2017;3:1511–9. Scholar
  32. 32.
    Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17:1497–508. Scholar
  33. 33.
    Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med. 2018;378:1976–86. Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2018

Authors and Affiliations

  1. 1.Department of Medical OncologyCity of Hope National Medical CenterDuarteUSA
  2. 2.Department of Immuno-OncologyBeckman Research Institute of the City of HopeDuarteUSA
  3. 3.Clinical Trials OfficeCity of Hope National Medical CenterDuarteUSA
  4. 4.Department of Clinical ResearchCity of Hope National Medical CenterDuarteUSA
  5. 5.Division of BiostatisticsCity of Hope National Medical CenterDuarteUSA

Personalised recommendations