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First-in-human phase 1 dose-escalating trial of G305 in patients with advanced solid tumors expressing NY-ESO-1

Abstract

Human tumor cells express antigens that serve as targets for the host cellular immune system. This phase 1 dose-escalating study was conducted to assess safety and tolerability of G305, a recombinant NY-ESO-1 protein vaccine mixed with glucopyranosyl lipid A (GLA), a synthetic TLR4 agonist adjuvant, in a stable emulsion (SE). Twelve patients with solid tumors expressing NY-ESO-1 were treated using a 3 + 3 design. The NY-ESO-1 dose was fixed at 250 µg, while GLA-SE was increased from 2 to 10 µg. Safety, immunogenicity, and clinical responses were assessed prior to, during, and at the end of therapy. G305 was safe and immunogenic at all doses. All related AEs were Grade 1 or 2, with injection site soreness as the most commonly reported event (100%). Overall, 75% of patients developed antibody response to NY-ESO-1, including six patients with increased antibody titer ( ≥ 4-fold rise) and three patients with seroconversion from negative (titer < 100) to positive (titer ≥ 100). CD4 T-cell responses were observed in 44.4% of patients; 33.3% were new responses and 1 was boosted ( ≥ 2-fold rise). Following treatment, 8 of 12 patients had stable disease for 3 months or more; at the end of 1 year, three patients had stable disease and nine patients were alive. G305 is a potent immunotherapeutic agent that can stimulate NY-ESO-1-specific antibody and T-cell responses. The vaccine was safe at all doses of GLA-SE (2–10 µg) and showed potential clinical benefit in this population of patients.

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Abbreviations

AE:

Adverse event

AESI:

Adverse event of special interest

ALP:

Alkaline phosphatase

BCG:

Bacillus Calmette–Guerin

CpG:

Cytosine phosphate–guanine

CT:

Computed tomography

CTCAE:

Common Terminology Criteria for Adverse Events

DLT:

Dose-limiting toxicity

ECOG:

Eastern Cooperative Oncology Group

ELISA:

Enzyme-linked immunosorbent assay

ELISPOT:

Enzyme-linked immunospot assay

GLA:

Glucopyranosyl lipid A

GLA-SE:

Glucopyranosyl lipid A in stable emulsion

GM-CSF:

Granulocyte–macrophage colony-stimulating factor

GMT:

Geometric mean titers

HLA:

Human leukocyte antigen

ICS:

Intracellular cytokine staining

IHC:

Immunohistochemistry

IM:

Intramuscularly

IRB:

Institutional Review Board

LDH:

Lactate dehydrogenase

MedDRA:

Medical Dictionary for Regulatory Activities

MTD:

Maximum tolerated dose

MyD88:

Myeloid differentiation primary response 88

NCI:

National Cancer Institute USA

NF-kB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NLRP3:

NACHT, LRR and PYD domains-containing protein 3

NSCLC:

Non-small cell lung cancer

NY-ESO-1:

New York esophageal squamous cell carcinoma 1

PBMC:

Peripheral blood mononuclear cells

Poly-ICLC:

Polyinosinic-polycytidylic acid–poly-l-lysine carboxymethylcellulose

RECIST:

Response Evaluation Criteria in Solid Tumors

SAE:

Serious adverse events

SD:

Standard deviation

SE:

Stable emulsion

SEB:

Staphylococcus aureus enterotoxin type B

SMC:

Safety Monitoring Committee

TAA:

Tumor-associated antigens

TEAE:

Treatment emergent adverse events

TLR:

Toll-like receptor

TRIF:

TIR-domain-containing adapter-inducing interferon-β

ULN:

Upper limit of normal

References

  1. 1.

    Mahipal A, Odunsi K, Gnjatic S, Kim-Schulze S, Kenney RT, Ejadi S (2015) A first-in-human phase 1 dose-escalating trial of G305 in patients with solid tumors expressing NY-ESO-1. J Clin Oncol 33:3073. https://doi.org/10.1200/jco.2015.33.15_suppl.3073

    Article  Google Scholar 

  2. 2.

    Mellman I, Coukos G, Dranoff G (2011) Cancer immunotherapy comes of age. Nature 480:480–489. https://doi.org/10.1038/nature10673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Melief CJ, van Hall T, Arens R, Ossendorp F, van der Burg SH (2015) Therapeutic cancer vaccines. J Clin Investig 125:3401–3412. https://doi.org/10.1172/JCI80009

    Article  PubMed  Google Scholar 

  4. 4.

    Gnjatic S, Nishikawa H, Jungbluth AA, Gure AO, Ritter G, Jager E, Knuth A, Chen YT, Old LJ (2006) NY-ESO-1: review of an immunogenic tumor antigen. Adv Cancer Res 95:1–30. https://doi.org/10.1016/S0065-230X(06)95001-5

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    Thomas R, Al-Khadairi G, Roelands J, Hendrickx W, Dermime S, Bedognetti D, Decock J (2018) NY-ESO-1 based immunotherapy of cancer: current perspectives. Front Immunol 9:947. https://doi.org/10.3389/fimmu.2018.00947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Park TS, Groh EM, Patel K, Kerkar SP, Lee CC, Rosenberg SA (2016) Expression of MAGE-A and NY-ESO-1 in primary and metastatic cancers. J Immunother 39:1–7. https://doi.org/10.1097/CJI.0000000000000101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Gjerstorff MF, Andersen MH, Ditzel HJ (2015) Oncogenic cancer/testis antigens: prime candidates for immunotherapy. Oncotarget 6:15772–15787. https://doi.org/10.18632/oncotarget.4694

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Sabado RL, Pavlick A, Gnjatic S et al (2015) Resiquimod as an immunologic adjuvant for NY-ESO-1 protein vaccination in patients with high-risk melanoma. Cancer Immunol Res 3:278–287. https://doi.org/10.1158/2326-6066.CIR-14-0202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Odunsi K, Matsuzaki J, Karbach J et al (2012) Efficacy of vaccination with recombinant vaccinia and fowlpox vectors expressing NY-ESO-1 antigen in ovarian cancer and melanoma patients. Proc Natl Acad Sci USA 109:5797–5802. https://doi.org/10.1073/pnas.1117208109

    Article  PubMed  Google Scholar 

  10. 10.

    Fonteneau JF, Brilot F, Munz C, Gannage M (2016) The tumor antigen NY-ESO-1 mediates direct recognition of melanoma cells by CD4+ T cells after intercellular antigen transfer. J Immunol 196:64–71. https://doi.org/10.4049/jimmunol.1402664

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Jager E, Chen YT, Drijfhout JW et al (1998) Simultaneous humoral and cellular immune response against cancer-testis antigen NY-ESO-1: definition of human histocompatibility leukocyte antigen (HLA)-A2-binding peptide epitopes. J Exp Med 187:265–270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Jager E, Nagata Y, Gnjatic S et al (2000) Monitoring CD8 T cell responses to NY-ESO-1: correlation of humoral and cellular immune responses. Proc Natl Acad Sci USA 97:4760–4765

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    Yuan J, Adamow M, Ginsberg BA et al (2011) Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab. Proc Natl Acad Sci USA 108:16723–16728. https://doi.org/10.1073/pnas.1110814108

    Article  PubMed  Google Scholar 

  14. 14.

    Sharma P, Bajorin DF, Jungbluth AA, Herr H, Old LJ, Gnjatic S (2008) Immune responses detected in urothelial carcinoma patients after vaccination with NY-ESO-1 protein plus BCG and GM-CSF. J Immunother 31:849–857. https://doi.org/10.1097/CJI.0b013e3181891574

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Coler RN, Bertholet S, Moutaftsi M et al (2011) Development and characterization of synthetic glucopyranosyl lipid adjuvant system as a vaccine adjuvant. PLoS ONE 6:e16333. https://doi.org/10.1371/journal.pone.0016333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Lambert SL, Yang CF, Liu Z, Sweetwood R, Zhao J, Cheng L, Jin H, Woo J (2012) Molecular and cellular response profiles induced by the TLR4 agonist-based adjuvant glucopyranosyl lipid A. PLoS ONE 7:e51618. https://doi.org/10.1371/journal.pone.0051618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Orr MT, Duthie MS, Windish HP et al (2013) MyD88 and TRIF synergistic interaction is required for TH1-cell polarization with a synthetic TLR4 agonist adjuvant. Eur J Immunol 43:2398–2408. https://doi.org/10.1002/eji.201243124

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    Desbien AL, Reed SJ, Bailor HR et al (2015) Squalene emulsion potentiates the adjuvant activity of the TLR4 agonist, GLA, via inflammatory caspases, IL-18, and IFN-gamma. Eur J Immunol 45:407–417. https://doi.org/10.1002/eji.201444543

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Seydoux E, Liang H, Dubois Cauwelaert N, Archer M, Rintala ND, Kramer R, Carter D, Fox CB, Orr MT (2018) Effective combination adjuvants engage both TLR and inflammasome pathways to promote potent adaptive immune responses. J Immunol 201:98–112. https://doi.org/10.4049/jimmunol.1701604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Duthie MS, Coler RN, Laurance JD et al (2014) Protection against Mycobacterium leprae infection by the ID83/GLA-SE and ID93/GLA-SE vaccines developed for tuberculosis. Infect Immun 82:3979–3985. https://doi.org/10.1128/IAI.02145-14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Lambert SL, Aslam S, Stillman E et al (2015) A novel respiratory syncytial virus (RSV) F subunit vaccine adjuvanted with GLA-SE elicits robust protective TH1-type humoral and cellular immunity in rodent models. PLoS ONE 10:e0119509. https://doi.org/10.1371/journal.pone.0119509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Clegg CH, Roque R, Van Hoeven N, Perrone L, Baldwin SL, Rininger JA, Bowen RA, Reed SG (2012) Adjuvant solution for pandemic influenza vaccine production. Proc Natl Acad Sci USA 109:17585–17590. https://doi.org/10.1073/pnas.1207308109

    Article  PubMed  Google Scholar 

  23. 23.

    Baldwin SL, Bertholet S, Reese VA, Ching LK, Reed SG, Coler RN (2012) The importance of adjuvant formulation in the development of a tuberculosis vaccine. J Immunol 188:2189–2197. https://doi.org/10.4049/jimmunol.1102696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Johnson RF, Kurup D, Hagen KR et al (2016) An inactivated rabies virus-based Ebola vaccine, FILORAB1, adjuvanted with glucopyranosyl lipid A in stable emulsion confers complete protection in nonhuman primate challenge models. J Infect Dis 214:S342–S354. https://doi.org/10.1093/infdis/jiw231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Pillet S, Aubin E, Trepanier S, Poulin JF, Yassine-Diab B, Ter Meulen J, Ward BJ, Landry N (2018) Humoral and cell-mediated immune responses to H5N1 plant-made virus-like particle vaccine are differentially impacted by alum and GLA-SE adjuvants in a phase 2 clinical trial. NPJ Vaccines 3:3. https://doi.org/10.1038/s41541-017-0043-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Falloon J, Yu J, Esser MT, Villafana T, Yu L, Dubovsky F, Takas T, Levin MJ, Falsey AR (2017) An adjuvanted, postfusion F protein-based vaccine did not prevent respiratory syncytial virus illness in older adults. J Infect Dis 216:1362–1370. https://doi.org/10.1093/infdis/jix503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Treanor JJ, Essink B, Hull S, Reed S, Izikson R, Patriarca P, Goldenthal KL, Kohberger R, Dunkle LM (2013) Evaluation of safety and immunogenicity of recombinant influenza hemagglutinin (H5/Indonesia/05/2005) formulated with and without a stable oil-in-water emulsion containing glucopyranosyl-lipid A (SE+GLA) adjuvant. Vaccine 31:5760–5765. https://doi.org/10.1016/j.vaccine.2013.08.064

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Odegard JM, Flynn PA, Campbell DJ, Robbins SH, Dong L, Wang K, Ter Meulen J, Cohen JI, Koelle DM (2016) A novel HSV-2 subunit vaccine induces GLA-dependent CD4 and CD8 T cell responses and protective immunity in mice and guinea pigs. Vaccine 34:101–109. https://doi.org/10.1016/j.vaccine.2015.10.137

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    Valmori D, Souleimanian NE, Tosello V et al (2007) Vaccination with NY-ESO-1 protein and CpG in Montanide induces integrated antibody/Th1 responses and CD8 T cells through cross-priming. Proc Natl Acad Sci USA 104:8947–8952. https://doi.org/10.1073/pnas.0703395104

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Klein O, Davis ID, McArthur GA et al (2015) Low-dose cyclophosphamide enhances antigen-specific CD4(+) T cell responses to NY-ESO-1/ISCOMATRIX vaccine in patients with advanced melanoma. Cancer Immunol Immunother 64:507–518. https://doi.org/10.1007/s00262-015-1656-x

    Article  CAS  PubMed  Google Scholar 

  31. 31.

    Chen JL, Dawoodji A, Tarlton A et al (2015) NY-ESO-1 specific antibody and cellular responses in melanoma patients primed with NY-ESO-1 protein in ISCOMATRIX and boosted with recombinant NY-ESO-1 fowlpox virus. Int J Cancer 136:E590–601. https://doi.org/10.1002/ijc.29118

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Sabbatini P, Tsuji T, Ferran L et al (2012) Phase I trial of overlapping long peptides from a tumor self-antigen and poly-ICLC shows rapid induction of integrated immune response in ovarian cancer patients. Clin Cancer Res 18:6497–6508. https://doi.org/10.1158/1078-0432.CCR-12-2189

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Wada H, Isobe M, Kakimi K et al (2014) Vaccination with NY-ESO-1 overlapping peptides mixed with Picibanil OK-432 and montanide ISA-51 in patients with cancers expressing the NY-ESO-1 antigen. J Immunother 37:84–92. https://doi.org/10.1097/CJI.0000000000000017

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    Robbins PF, Morgan RA, Feldman SA et al (2011) Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol 29:917–924. https://doi.org/10.1200/JCO.2010.32.2537

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Melero I, Gaudernack G, Gerritsen W et al (2014) Therapeutic vaccines for cancer: an overview of clinical trials. Nat Rev Clin Oncol 11:509–524. https://doi.org/10.1038/nrclinonc.2014.111

    Article  CAS  PubMed  Google Scholar 

  36. 36.

    Cheever MA, Allison JP, Ferris AS et al (2009) The prioritization of cancer antigens: a national cancer institute pilot project for the acceleration of translational research. Clin Cancer Res 15:5323–5337. https://doi.org/10.1158/1078-0432.CCR-09-0737

    Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Tagliamonte M, Petrizzo A, Tornesello ML, Buonaguro FM, Buonaguro L (2014) Antigen-specific vaccines for cancer treatment. Hum Vaccin Immunother 10:3332–3346. https://doi.org/10.4161/21645515.2014.973317

    Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Gouttefangeas C, Rammensee HG (2018) Personalized cancer vaccines: adjuvants are important, too. Cancer Immunol Immunother 67:1911–1918. https://doi.org/10.1007/s00262-018-2158-4

    Article  CAS  PubMed  Google Scholar 

  39. 39.

    Provine NM, Larocca RA, Aid M et al (2016) Immediate dysfunction of vaccine-elicited CD8+ T cells primed in the absence of CD4+ T cells. J Immunol 197:1809–1822. https://doi.org/10.4049/jimmunol.1600591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Pollack SM (2018) The potential of the CMB305 vaccine regimen to target NY-ESO-1 and improve outcomes for synovial sarcoma and myxoid/round cell liposarcoma patients. Expert Rev Vaccines 17:107–114. https://doi.org/10.1080/14760584.2018.1419068

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

The authors thank the patients and staff at each clinical site, Kevin Tuballes for technical help as part of the Human Immune Monitoring Center at Mount Sinai, and Karen Rappaport for assistance with drafting the manuscript as part of the team at Immune Design.

Funding

This research was funded by Immune Design Corp.

Author information

Affiliations

Authors

Contributions

Trial conception and design: AM, SE, RK, KO. Acquisition of data: AM, SE, SG, SK-S, HL, RK, KO. Analysis and interpretation of data: AM, SE, SG, HL, JM, RK, KO. Writing, review, and/or revision of the manuscript: AM, RK, JM. Study supervision: AM, SE, RK, KO.

Corresponding author

Correspondence to Jan H. ter Meulen.

Ethics declarations

Conflict of interest

Hailing Lu, Richard Kenney, and Jan ter Meulen are full-time employees and shareholders of Immune Design Corp. Sacha Gnjatic has received research support from Immune Design Corp. The authors declare that there are no other conflicts of interest.

Ethical approval and ethical standards

This trial is registered in the USA under the ClinicalTrials.gov identifier (NCT number): NCT02015416. Institutional Review Boards (IRBs) reviewed and approved the protocol, all protocol amendments, informed consent documents, and written study materials before their use.

Institutional approvals

Roswell Park Cancer Institute (sponsor protocol #IDC-G305-2013-001 and RPCI protocol # PH 244813); Scottsdale Healthcare (WIRB Protocol Number: 20131768; WIRB Study Number: 1142287); Karmanos Cancer Institute (WIRB Protocol Number: 20131768; WIRB Study Number: 1143287); H. Lee Moffitt Cancer Ctr & Research Inst, Inc. (sponsor protocol #IDC-G305-2013-001–MCC 17622). The Karmanos Cancer Institute did not identify suitable patients to enroll on the trial.

Human/animal rights statement

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

All patients provided informed consent prior to study enrollment at the screening visit. Patients also agreed on the use of patient data for research and publication.

Additional information

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Note on previous publication: Preliminary data of this study was presented at the 2015 American Society of Clinical Oncology (ASCO) meeting, Chicago, IL, USA, Abstract # 152974 [1].

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Mahipal, A., Ejadi, S., Gnjatic, S. et al. First-in-human phase 1 dose-escalating trial of G305 in patients with advanced solid tumors expressing NY-ESO-1. Cancer Immunol Immunother 68, 1211–1222 (2019). https://doi.org/10.1007/s00262-019-02331-x

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Keywords

  • NY-ESO-1
  • Solid tumors
  • Vaccine
  • Glucopyranosyl lipid A
  • Clinical trial