A Phase I Trial Using a Multitargeted Recombinant Adenovirus 5 (CEA/MUC1/Brachyury)-Based Immunotherapy Vaccine Regimen in Patients with Advanced Cancer

Margaret E Gatti-Mays, Jason M Redman, Renee N Donahue, Claudia Palena, Ravi A Madan, Fatima Karzai, Marijo Bilusic, Houssein Abdul Sater, Jennifer L Marté, Lisa M Cordes, Sheri McMahon, Seth M Steinberg, Alanvin Orpia, Andrea Burmeister, Jeffrey Schlom, James L Gulley, Julius Strauss, Margaret E Gatti-Mays, Jason M Redman, Renee N Donahue, Claudia Palena, Ravi A Madan, Fatima Karzai, Marijo Bilusic, Houssein Abdul Sater, Jennifer L Marté, Lisa M Cordes, Sheri McMahon, Seth M Steinberg, Alanvin Orpia, Andrea Burmeister, Jeffrey Schlom, James L Gulley, Julius Strauss

Abstract

Lessons learned: Concurrent ETBX-011, ETBX-051, and ETBX-061 can be safely administered to patients with advanced cancer. All patients developed CD4+ and/or CD8+ T-cell responses after vaccination to at least one tumor-associated antigen (TAA) encoded by the vaccine; 5/6 patients (83%) developed MUC1-specific T cells, 4/6 (67%) developed CEA-specific T cells, and 3/6 (50%) developed brachyury-specific T cells. The presence of adenovirus 5-neutralizing antibodies did not prevent the generation of TAA-specific T cells.

Background: A novel adenovirus-based vaccine targeting three human tumor-associated antigens-CEA, MUC1, and brachyury-has demonstrated antitumor cytolytic T-cell responses in preclinical animal models of cancer.

Methods: This open-label, phase I trial evaluated concurrent administration of three therapeutic vaccines (ETBX-011 = CEA, ETBX-061 = MUC1 and ETBX-051 = brachyury). All three vaccines used the same modified adenovirus 5 (Ad5) vector backbone and were administered at a single dose level (DL) of 5 × 1011 viral particles (VP) per vector. The vaccine regimen consisting of all three vaccines was given every 3 weeks for three doses then every 8 weeks for up to 1 year. Clinical and immune responses were evaluated.

Results: Ten patients enrolled on trial (DL1 = 6 with 4 in the DL1 expansion cohort). All treatment-related adverse events were temporary, self-limiting, grade 1/2 and included injection site reactions and flu-like symptoms. Antigen-specific T cells to MUC1, CEA, and/or brachyury were generated in all patients. There was no evidence of antigenic competition. The administration of the vaccine regimen produced stable disease as the best clinical response.

Conclusion: Concurrent ETBX-011, ETBX-051, and ETBX-061 can be safely administered to patients with advanced cancer. Further studies of the vaccine regimen in combination with other agents, including immune checkpoint blockade, are planned.

© AlphaMed Press; the data published online to support this summary are the property of the authors.

References

    1. Gabitzsch ES, Tsang KY, Palena C et al. The generation and analyses of a novel combination of recombinant adenovirus vaccines targeting three tumor antigens as an immunotherapeutic. Oncotarget 2015;6:31344–31359.
    1. Morse MA, Chaudhry A, Gabitzsch ES et al. Novel adenoviral vector induces T‐cell responses despite anti‐adenoviral neutralizing antibodies in colorectal cancer patients. Cancer Immunol Immunother 2013;62:1293–1301.
    1. Balint JP, Gabitzsch ES, Rice A et al. Extended evaluation of a phase 1/2 trial on dosing, safety, immunogenicity, and overall survival after immunizations with an advanced‐generation Ad5 [E1‐, E2b‐]‐CEA(6D) vaccine in late‐stage colorectal cancer. Cancer Immunol Immunother 2015;64:977–987.
    1. Heery CR, Singh BH, Rauckhorst M et al. Phase I trial of a yeast‐based therapeutic cancer vaccine (GI‐6301) targeting the transcription factor brachyury. Cancer Immunol Res 2015;3:1248–1256.
    1. Gabitzsch ES, Xu Y, Balint JP et al. Anti‐tumor immunotherapy despite immunity to adenovirus using a novel adenoviral vector Ad5 [E1‐, E2b‐]‐CEA. Cancer Immunol Immunother 2010;59:1131–1135.
    1. Gabitzsch ES, Xu Y, Balcaitis S et al. An Ad5[E1‐, E2b‐]‐HER2/neu vector induces immune responses and inhibits HER2/neu expressing tumor progression in Ad5 immune mice. Cancer Gene Ther 2011;18:326–335.
    1. Gabitzsch ES, Xu Y, Balint JP et al. Induction and comparison of SIV immunity in Ad5 naïve and Ad5 immune non‐human primates using an Ad5 [E1‐, E2b‐] based vaccine. Vaccine 2011;29:8101–8107.
    1. Gabitzsch ES, Morse MA, Lyerly HK et al. Immunotherapeutic treatment of metastatic colorectal cancer using ETBX‐011. J Clin Oncol 2014;32(suppl 15):3093a.
    1. Massarelli E, William W, Johnson F et al. Combining immune checkpoint blockade and tumor‐specific vaccine for patients with incurable human papillomavirus 16‐related cancer: A phase 2 clinical trial. JAMA Oncol 2019;5:67–73.
    1. Jochems C, Tucker JA, Tsang KY et al. A combination trial of vaccine plus ipilimumab in metastatic castration‐resistant prostate cancer patients: Immune correlates. Cancer Immunol Immunother 2014;63:407–418.
    1. Gatti‐Mays ME, Strauss J, Donahue RN et al. A phase 1 dose escalation trial of BN‐CV301, a recombinant poxviral vaccine targeting MUC1 and CEA with costimulatory molecules. Clin Cancer Res 2019;25:4933–4944.
    1. Gatti‐Mays ME, Redman JM, Collins JM et al. Cancer vaccines: Enhanced immunogenic modulation through therapeutic combinations. Hum Vaccin Immunother 2017;13:2561–2574.
    1. Schlom J, Gulley JL. Vaccines as an integral component of cancer immunotherapy. JAMA 2018;320:2195–2196.
    1. Zaremba S, Barzaga E, Zhu M et al. Identification of an enhancer agonist cytotoxic T lymphocyte peptide from human carcinoembryonic antigen. Cancer Res 1997;57:4570–4577.
    1. Kufe DW. MUC1‐C oncoprotein as a target in breast cancer: Activation of signaling pathways and therapeutic approaches. Oncogene 2013;32:1073–1081.
    1. Tsang KY, Palena C, Gulley J et al. A human cytotoxic T‐lymphocyte epitope and its agonist epitope from the nonvariable number of tandem repeat sequence of MUC‐1. Clin Cancer Res 2004;10:2139–2149.
    1. Jochems C, Tucker JA, Vergati M et al. Identification and characterization of agonist epitopes of the MUC1‐C oncoprotein. Cancer Immunol Immunother 2014;63:161–174.
    1. Fernando RI, Litzinger M, Trono P et al. The T‐box transcription factor brachyury promotes epithelial‐mesenchymal transition in human tumor cells. J Clin Invest 2010;120:533–544.
    1. Hamilton DH, Fernando RI, Schlom J et al. Aberrant expression of the embryonic transcription factor brachyury in human tumors detected with a novel rabbit monoclonal antibody. Oncotarget 2015;6:4853–4862.
    1. Nieto MA, Cano A. The epithelial‐mesenchymal transition under control: Global programs to regulate epithelial plasticity. Semin Cancer Biol 2012;22:361–368.
    1. Tucker JA, Jochems C, Boyerinas B et al. Identification and characterization of a cytotoxic T‐lymphocyte agonist epitope of brachyury, a transcription factor involved in epithelial to mesenchymal transition and metastasis. Cancer Immunol Immunother 2014;63:1307–1317.
    1. Palena C, Polev DE, Tsang KY et al. The human T‐box mesodermal transcription factor brachyury is a candidate target for T‐cell‐mediated cancer immunotherapy. Clin Cancer Res 2007;13:2471–2478.
    1. Zeng Y, Zhang Q, Zhang Y et al. MUC1 predicts colorectal cancer metastasis: A systematic review and meta‐analysis of case controlled studies. PLoS One 2015;10:e0138049.
    1. Kharbanda A, Rajabi H, Jin C et al. Oncogenic MUC1‐C promotes tamoxifen resistance in human breast cancer. Mol Cancer Res 2013;11:714–723.
    1. Huang X, Sun Q, Chen C et al. MUC1 overexpression predicts worse survival in patients with non‐small cell lung cancer: Evidence from an updated meta‐analysis. Oncotarget 2017;8:90315–90326.
    1. Khodarev NN, Pitroda SP, Beckett MA et al. MUC1‐induced transcriptional programs associated with tumorigenesis predict outcome in breast and lung cancer. Cancer Res 2009;69:2833–2837.
    1. Palena C, Roselli M, Litzinger MT et al. Overexpression of the EMT driver brachyury in breast carcinomas: Association with poor prognosis. J Natl Cancer Inst 2014;106.
    1. Maeda T, Hiraki M, Jin C et al. MUC1‐C induces PD‐L1 and immune evasion in triple‐negative breast cancer. Cancer Res 2018;78:205–215.
    1. Bouillez A, Adeegbe D, Jin C et al. MUC1‐C promotes the suppressive immune microenvironment in non‐small cell lung cancer. Oncoimmunology 2017;6:e1338998.
    1. David JM, Hamilton DH, Palena C. MUC1 upregulation promotes immune resistance in tumor cells undergoing brachyury‐mediated epithelial‐mesenchymal transition. Oncoimmunology 2016;5:e1117738.
    1. Bouillez A, Rajabi H, Pitroda S et al. Inhibition of MUC1‐C suppresses MYC expression and attenuates malignant growth in KRAS mutant lung adenocarcinomas. Cancer Res 2016;76:1538–1548.
    1. Rajabi H, Kufe D. MUC1‐C oncoprotein integrates a program of EMT, epigenetic reprogramming and immune evasion in human carcinomas. Biochim Biophys Acta 2017;1868:117–122.
    1. Kharbanda A, Rajabi H, Jin C et al. MUC1‐C confers EMT and KRAS independence in mutant KRAS lung cancer cells. Oncotarget 2014;5:8893–8905.
    1. Wimmers F, Aarntzen EH, Duiveman‐deBoer T et al. Long‐lasting multifunctional CD8. Oncoimmunology 2016;5:e1067745.
    1. Gulley JL, Arlen PM, Tsang KY et al. Pilot study of vaccination with recombinant CEA‐MUC‐1‐TRICOM poxviral‐based vaccines in patients with metastatic carcinoma. Clin Cancer Res 2008;14:3060–3069.
    1. Mohebtash M, Tsang KY, Madan RA et al. A pilot study of MUC‐1/CEA/TRICOM poxviral‐based vaccine in patients with metastatic breast and ovarian cancer. Clin Cancer Res 2011;17:7164–7173.
    1. Hamilton DH, Litzinger MT, Jales A et al. Immunological targeting of tumor cells undergoing an epithelial‐mesenchymal transition via a recombinant brachyury‐yeast vaccine. Oncotarget 2013;4:1777–1790.
    1. Heery CR, Singh BH, Rauckhorst M et al. Phase I trial of a yeast‐based therapeutic cancer vaccine (GI‐6301) targeting the transcription factor brachyury. Cancer Immunol Res 2015;3:1248–1256.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する