Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Proof of principle study of sequential combination atezolizumab and Vigil in relapsed ovarian cancer

Abstract

Vigil® is a personalized vaccine that enhances tumor neoantigen expression. We investigated for the first time safety and efficacy of Vigil in combination with atezolizumab in relapsed ovarian cancer (OC) patients. This is a randomized, Phase 1 study of Vigil, an autologous tumor tissue transfected vaccine encoding for GMCSF and bi-shRNA-furin thereby creating enhanced immune activation and TGFβ expression control. Part 1 is a safety assessment of Vigil (1 × 10e7 cells/mL/21 days) plus atezolizumab (1200 mg/21 days). Part 2 is a randomized study of Vigil first (Vigil-1st) or atezolizumab first (Atezo-1st) for two cycles followed by the combination of both agents. The primary endpoint of the study was the determination of safety. Twenty-four patients were enrolled in the study; three patients to Part 1 and 21 to Part 2. Patients in Part 1 completed combination therapy without dose-limiting toxicity justifying expansion to Part 2. Twenty-one patients were randomized (1:1) to Part 2 to Vigil-1st (n = 11) or Atezo-1st (n = 10). Grade 3/4 treatment-related adverse events of Atezo-1st vs. Vigil-1st were 17.2% vs. 5.1%. Median overall survival (OS) was not reached (NR) (Vigil-1st) vs. 10.8 months (Atezo-1st) (hazard ratio [HR] 0.33). The exploratory subset analysis of BRCAwt suggested improved OS benefit [NR in Vigil-1st vs. 5.2 months in Atezo-1st, HR 0.16, p 0.027]. The Vigil-1st combination therapy with atezolizumab was safe and results in support continued investigation in BRCAwt patients.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Consort diagram.
Fig. 2: Treatment-related adverse events.
Fig. 3: Efficacy analysis from time of study randomization.

References

  1. Infante JR, Braiteh F, Emens L, Balmanoukian AS, Oaknin A, Wang Y, et al. Safety, clinical activity and biomarkers of atezolizumab (atezo) in advanced ovarian cancer (OC). Ann Oncol. 2016;27:871.

    Article  Google Scholar 

  2. Preston CC, Goode EL, Hartmann LC, Kalli KR, Knutson KL. Immunity and immune suppression in human ovarian cancer. Immunotherapy. 2011;3:539–56.

    Article  Google Scholar 

  3. Ino K. Indoleamine 2,3-dioxygenase and immune tolerance in ovarian cancer. Curr Opin Obstet Gynecol. 2011;23:13–8.

    Article  Google Scholar 

  4. Tondini E, Arakelian T, Oosterhuis K, Camps M, van Duikeren S, Han W. et al. A poly-neoantigen DNA vaccine synergizes with PD-1 blockade to induce T cell-mediated tumor control. Oncoimmunology. 2019;8:1652539. https://doi.org/10.1080/2162402X.2019.1652539.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Wada S, Jackson CM, Yoshimura K, Yen H-R, Getnet D, Harris TJ, et al. Sequencing CTLA-4 blockade with cell-based immunotherapy for prostate cancer. J Transl Med. 2013;11:89.

    Article  CAS  Google Scholar 

  6. Verma V, Shrimali RK, Ahmad S, Dai W, Wang H, Lu S, et al. PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1(+)CD38(hi) cells and anti-PD-1 resistance. Nat Immunol. 2019;20:1231–43.

    Article  CAS  Google Scholar 

  7. Oh J, Barve M, Matthews CM, Koon EC, Heffernan TP, Fine B, et al. Phase II study of Vigil(R) DNA engineered immunotherapy as maintenance in advanced stage ovarian cancer. Gynecol Oncol. 2016;143:504–10.

    Article  CAS  Google Scholar 

  8. Barve M, Kuhn J, Lamont J, Beitsch P, Manning L, Pappen B. et al. Follow-up of bi-shRNA furin/GM-CSF Engineered Autologous Tumor Cell (EATC) Immunotherapy Vigil® in patients with advanced melanoma. Biomed Genet Genomics. 2016;1:8186.

    Article  Google Scholar 

  9. Senzer N, Barve M, Nemunaitis J, Kuhn J, Melnyk A, Beitsch P, et al. Long term follow up: Phase I Trial of “bi-shRNA furin/GMCSF DNA/Autologous Tumor Cell” Immunotherapy (FANG™) in advanced cancer. J Vaccines Vaccin. 2013;4:209.

    Google Scholar 

  10. Nemunaitis J, Barve M, Orr D, Kuhn J, Magee M, Lamont J, et al. Summary of bi-shRNA/GM-CSF augmented autologous tumor cell immunotherapy (FANG) in advanced cancer of the liver. Oncology. 2014;87:21–9.

    Article  CAS  Google Scholar 

  11. Barve M, Barve R, Rao D, Rao J, Manning L, Adams N, et al. Case report: vigil therapy in pathology defined high-risk differentiated thyroid cancer compounded by post ablation high-risk factors. J Surg Oncol Clin Res. 2017;1:1005.

    Google Scholar 

  12. Ghisoli M, Barve M, Mennel R, Lenarsky C, Horvath S, Wallraven G, et al. Three-year follow up of GMCSF/bi-shRNA(furin) DNA-transfected autologous tumor immunotherapy (Vigil) in metastatic advanced Ewing’s sarcoma. Mol Ther. 2016;24:1478–83.

    Article  CAS  Google Scholar 

  13. Manning L, Barve M, Wallraven G, Kumar P, Taquet N, Bognar E, et al. Assessment of Low Dose Vigil® Engineered Autologous Tumor Cell (EATC) immunotherapy in patients with advanced solid tumors. Clin Oncol. 2017;2:1254.

    Google Scholar 

  14. Oh J, Barve M, Senzer N, Aaron P, Manning L, Wallraven G, et al. Long-term follow-up of Phase 2A trial results involving advanced ovarian cancer patients treated with Vigil® in frontline maintenance. Gynecol Oncol Rep. 2020;34:100648.

  15. Rocconi RP, Grosen EA, Ghamande SA, Chan JK, Barve MA, Oh J, et al. Gemogenovatucel-T (Vigil) immunotherapy as maintenance in frontline stage III/IV ovarian cancer (VITAL): a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Oncol. 2020;21:1661–72.

    Article  CAS  Google Scholar 

  16. Senzer N, Barve M, Kuhn J, Melnyk A, Beitsch P, Lazar M, et al. Phase I trial of “bi-shRNAi(furin)/GMCSF DNA/autologous tumor cell” vaccine (FANG) in advanced cancer. Mol Ther. 2012;20:679–86.

    Article  CAS  Google Scholar 

  17. Powles T, Duran I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018;391:748–57.

    Article  CAS  Google Scholar 

  18. Fehrenbacher L, von Pawel J, Park K, Rittmeyer A, Gandara DR, Ponce Aix S, et al. Updated efficacy analysis including secondary population results for OAK: a randomized phase III study of atezolizumab versus docetaxel in patients with previously treated advanced non-small cell lung cancer. J Thorac Oncol. 2018;13:1156–70.

    Article  CAS  Google Scholar 

  19. Gadducci A, Cosio S, Conte PF, Genazzani AR. Consolidation and maintenance treatments for patients with advanced epithelial ovarian cancer in complete response after first-line chemotherapy: a review of the literature. Crit Rev Oncol/Hematol. 2005;55:153–66.

    Article  Google Scholar 

  20. Gadducci A, Sartori E, Maggino T, Zola P, Landoni F, Fanucchi A, et al. Analysis of failures after negative second-look in patients with advanced ovarian cancer: an Italian multicenter study. Gynecol Oncol. 1998;68:150–5.

    Article  CAS  Google Scholar 

  21. Markman M, Liu PY, Wilczynski S, Monk B, Copeland LJ, Alvarez RD, et al. Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: a Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol. 2003;21:2460–5.

    Article  CAS  Google Scholar 

  22. Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N. Engl J Med. 2011;365:2473–83.

    Article  CAS  Google Scholar 

  23. Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30:2039–45.

    Article  CAS  Google Scholar 

  24. Coleman RL, Brady MF, Herzog TJ, Sabbatini P, Armstrong DK, Walker JL, et al. Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18:779–91.

    Article  CAS  Google Scholar 

  25. Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol. 2014;32:1302–8.

    Article  CAS  Google Scholar 

  26. Pujade-Laurainea E, Fujiwarab K, Ledermannc JA, Ozad AM, Kristeleitc RS, Ray-Coquarde IL, et al. Avelumab alone or in combination with pegylated liposomal doxorubicin versus pegylated liposomal doxorubicin alone in platinum-resistant or refractory epithelial ovarian cancer: Primary and biomarker analysis of the phase III JAVELIN Ovarian 200 trial. 50th Annual Meeting of the Society of Gynecologic Oncology; March 16–19; Honolulu, HI; 2019.

  27. Henriksen R, Gobl A, Wilander E, Oberg K, Miyazono K, Funa K. Expression and prognostic significance of TGF-beta isotypes, latent TGF-beta 1 binding protein, TGF-beta type I and type II receptors, and endoglin in normal ovary and ovarian neoplasms. Lab Invest. 1995;73:213–20.

    CAS  PubMed  Google Scholar 

  28. Bristow RE, Baldwin RL, Yamada SD, Korc M, Karlan BY. Altered expression of transforming growth factor-beta ligands and receptors in primary and recurrent ovarian carcinoma. Cancer. 1999;85:658–68.

    Article  CAS  Google Scholar 

  29. Li X, Ye F, Chen H, Lu W, Wan X, Xie X. Human ovarian carcinoma cells generate CD4(+)CD25(+) regulatory T cells from peripheral CD4(+)CD25(−) T cells through secreting TGF-beta. Cancer Lett. 2007;253:144–53.

    Article  CAS  Google Scholar 

  30. Polcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, et al. Foxp3(+) cell infiltration and granzyme B(+)/Foxp3(+) cell ratio are associated with outcome in neoadjuvant chemotherapy-treated ovarian carcinoma. Cancer Immunol Immunother. 2010;59:909–19.

  31. Milne K, Kobel M, Kalloger SE, Barnes RO, Gao D, Gilks CB, et al. Systematic analysis of immune infiltrates in high-grade serous ovarian cancer reveals CD20, FoxP3 and TIA-1 as positive prognostic factors. PLoS ONE. 2009;4:e6412.

    Article  Google Scholar 

  32. Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA. 2005;102:18538–43.

    Article  CAS  Google Scholar 

  33. Webb JR, Milne K, Watson P, Deleeuw RJ, Nelson BH. Tumor-infiltrating lymphocytes expressing the tissue resident memory marker CD103 are associated with increased survival in high-grade serous ovarian cancer. Clin Cancer Res. 2014;20:434–44.

    Article  CAS  Google Scholar 

  34. Webb JR, Milne K, Nelson BH. PD-1 and CD103 are widely coexpressed on prognostically favorable intraepithelial CD8 T cells in human ovarian cancer. Cancer Immunol Res. 2015;3:926–35.

    Article  CAS  Google Scholar 

  35. Djenidi F, Adam J, Goubar A, Durgeau A, Meurice G, de Montpreville V, et al. CD8+CD103+ tumor-infiltrating lymphocytes are tumor-specific tissue-resident memory T cells and a prognostic factor for survival in lung cancer patients. J Immunol. 2015;194:3475–86.

    Article  CAS  Google Scholar 

  36. Komdeur FL, Wouters MC, Workel HH, Tijans AM, Terwindt AL, Brunekreeft KL, et al. CD103+ intraepithelial T cells in high-grade serous ovarian cancer are phenotypically diverse TCRαβ+ CD8αβ+ T cells that can be targeted for cancer immunotherapy. Oncotarget. 2016;7:75130–44.

    Article  Google Scholar 

  37. Herron J, Smith N, Stanbery L, Aaron P, Manning L, Bognar E, et al. Vigil: personalized immunotherapy generating systemic cytotoxic T cell response. Cancer Sci Res. 2020;3:1–4.

    Article  Google Scholar 

  38. Tondini E, Arakelian T, Oosterhuis K, Camps M, van Duikeren S, Han W, et al. A poly-neoantigen DNA vaccine synergizes with PD-1 blockade to induce T cell-mediated tumor control. Oncoimmunology. 2018;8:1652539. https://doi.org/10.1080/2162402X.2019.1652539.

    Article  Google Scholar 

  39. Martin CJ, Datta A, Littlefield C, Kalra A, Chapron C, Wawersik S, et al. Selective inhibition of TGFβ1 activation overcomes primary resistance to checkpoint blockade therapy by altering tumor immune landscape. Sci Transl Med. 2020;12:eaay8456.

    Article  CAS  Google Scholar 

  40. O’Donnell JS, Long GV, Scolyer RA, Teng MWL, Smyth MJ. Resistance to PD1/PDL1 checkpoint inhibition. Cancer Treat Rev. 2017;52:71–81.

    Article  Google Scholar 

  41. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348:69–74.

    Article  CAS  Google Scholar 

  42. Ribas A, Shin DS, Zaretsky J, Frederiksen J, Cornish A, Avramis E, et al. PD-1 blockade expands intratumoral memory T cells. Cancer Immunol Res. 2016;4:194–203.

    Article  CAS  Google Scholar 

  43. Farber DL, Yudanin NA, Restifo NP. Human memory T cells: generation, compartmentalization and homeostasis. Nat Rev Immunol. 2014;14:24.

    Article  CAS  Google Scholar 

  44. Harty JT, Badovinac VP. Shaping and reshaping CD8+ T-cell memory. Nat Rev Immunol. 2008;8:107.

    Article  CAS  Google Scholar 

  45. McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351:1463–9.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Brenda Marr for her help in manuscript preparation and submission.

Author information

Authors and Affiliations

Authors

Contributions

All authors made significant contributions to the manuscript and have read and approved the final manuscript.

Corresponding author

Correspondence to John Nemunaitis.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Rocconi, R.P., Stevens, E.E., Bottsford-Miller, J.N. et al. Proof of principle study of sequential combination atezolizumab and Vigil in relapsed ovarian cancer. Cancer Gene Ther 29, 369–382 (2022). https://doi.org/10.1038/s41417-021-00317-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41417-021-00317-5

Search

Quick links