Cancer Immunology, Immunotherapy

, Volume 57, Issue 11, pp 1599–1609

Phase-I study of Innacell γδ™, an autologous cell-therapy product highly enriched in γ9δ2 T lymphocytes, in combination with IL-2, in patients with metastatic renal cell carcinoma

  • Jaafar Bennouna
  • Emmanuelle Bompas
  • Eve Marie Neidhardt
  • Frédéric Rolland
  • Irène Philip
  • Céline Galéa
  • Samuel Salot
  • Soraya Saiagh
  • Marie Audrain
  • Marie Rimbert
  • Sylvie Lafaye-de Micheaux
  • Jérôme Tiollier
  • Sylvie Négrier
Original Article

Abstract

Purpose

γ9δ2 T lymphocytes have been shown to be directly cytotoxic against renal carcinoma cells. Lymphocytes T γδ can be selectively expanded in vivo with BrHPP (IPH1101, Phosphostim) and interleukin 2 (IL-2). A phase I Study was conducted in patients with metastatic renal cell carcinoma (mRCC) to determine the maximum-tolerated dose and safety of Innacell γδ™, an autologous cell-therapy product based on γ9δ2 T lymphocytes, in patients with mRCC.

Experimental design

A 1-h intravenous infusion of γ9δ2 T lymphocytes was administered alone during treatment cycle 1 and combined with a low dose of subcutaneous interleukin-2 (IL-2, 2 MIU/m2 from Day 1 to Day 7) in the two subsequent cycles (at 3-week intervals). The dose of γ9δ2 T lymphocytes was escalated from 1 up to 8 × 109 cells.

Results

Ten patients underwent a total of 27 treatment cycles. Immunomonitoring data demonstrate that γ9δ2 T lymphocytes are initially cleared from the blood to reappear at the end of IL-2 administration. Dose-limiting toxicity occurred in one patient at the dose of 8 × 109 cells (disseminated intravascular coagulation). Other treatment-related adverse events (AEs) included mainly gastrointestinal disorders and flu-like symptoms (fatigue, pyrexia, rigors). Hypotension and tachycardia also occurred, especially with co-administered IL-2. Six patients showed stabilized disease. Time to progression was 25.7 weeks.

Conclusion

The data collected in ten patients with mRCC indicate that repeated infusions of Innacell γδ™ at different dose levels (up to 8 × 109 total cells), either alone or with IL-2 is well tolerated. These results are in favor of the therapeutic value of cell therapy with Innacell γδ™ for the treatment of cancers.

Keywords

Metastatic renal cell carcinoma γ9δ2 T lymphocytes Interleukin-2 Clinical efficacy Safety and tolerability 

References

  1. 1.
    Atkins M, Regan M, McDermott D, Mier J, Stanbridge E, Youmans A, Febbo P, Upton M, Lechpammer M, Signoretti S (2005) Carbonic anhydrase IX expression predicts outcome of interleukin-2 therapy for renal cancer. Clin Cancer Res 11:3714–21PubMedCrossRefGoogle Scholar
  2. 2.
    Bukowski RM (2001) Cytokine therapy for metastatic renal cell carcinoma. Semin Urol Oncol 19:148–54PubMedGoogle Scholar
  3. 3.
    Common Toxicity Criteria (CTC) (1999) Cancer Therapy Evaluation Program. Common Toxicity Criteria, version 2.0. DCTD, NCI, NIH, DHHSGoogle Scholar
  4. 4.
    Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM; TARGET Study Group (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134PubMedCrossRefGoogle Scholar
  5. 5.
    Espinosa E, Belmant C, Pont F, Luciani B, Poupot R, Romagné F, Brailly H, Bonneville M, Fournié JJ (2001) Chemical synthesis and biological activity of bromohydrin pyrophosphate, a potent stimulator of human γδ T cells. J Biol Chem 276:18337–18344PubMedCrossRefGoogle Scholar
  6. 6.
    Kato Y, Tanaka Y, Miyagawa F, Yamashita S, Minato N (2001) Targeting of tumor cells for human γδ T cells by nonpeptide antigens. J Immunol 167:5092–5098PubMedGoogle Scholar
  7. 7.
    Kobayashi H, Tanaka Y, Yagi J, Toma H, Uchiyama T (2001) Gamma/delta T cells provide innate immunity against renal cell carcinoma. Cancer Immunol Immunother 50:115–124PubMedCrossRefGoogle Scholar
  8. 8.
    Kobayashi H, Tanaka Y, Yagi J, Osaka Y, Nakazawa H, Uchiyama T, Minato N, Toma H (2006) Safety profile and anti-tumor effects of adoptive immunotherapy using gamma-delta T cells against advanced renal cell carcinoma: a pilot study. Cancer Immunol Immunother 56:469–476PubMedCrossRefGoogle Scholar
  9. 9.
    Medical Research Council Renal Cancer Collaborators (1999) Interferon-α and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Lancet 353:14–17CrossRefGoogle Scholar
  10. 10.
    Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J (1999) Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 17:2530–2540PubMedGoogle Scholar
  11. 11.
    Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124PubMedCrossRefGoogle Scholar
  12. 12.
    Negrier S, Escudier B, Lasset C, Douillard JY, Savary J, Chevreau C, Ravaud A, Mercatello A, Peny J, Mousseau M, Philip T, Tursz T (1998) Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. N Engl J Med 338:1272–1278PubMedCrossRefGoogle Scholar
  13. 13.
    Poccia F, Boullier S, Lecoeur H, Cochet M, Poquet Y, Colizzi V, Fournie JJ, Gougeon ML (1996) Peripheral V gamma 9/V delta 2 T cell deletion and anergy to nonpeptidic mycobacterial antigens in asymptomatic HIV-1-infected persons. J Immunol 157:449–461PubMedGoogle Scholar
  14. 14.
    Pyrhönen S, Ellmén J, Vuorinen J, Gershanovich M, Tominaga T, Kaufmann M, Hayes DF (1999) Prospective randomized trial of interferonalfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer. J Clin Oncol 17:2859–2867PubMedGoogle Scholar
  15. 15.
    Reddy GK, Bukowski RM (2006) Sorafenib: recent update on activity as a single agent and in combination with interferon-alpha2 in patients with advanced-stage renal cell carcinoma. Clin Genitourin Cancer 4:246–248PubMedCrossRefGoogle Scholar
  16. 16.
    Salot S, Laplace C, Saïagh S, Bercegeay S, Tenaud I, Cassidanius A, Romagne F, Dreno B, Tiollier J (2007) Large scale expansion of g9d2 T lymphocytes: Innacell gd™ cell therapy product. J Immunol Methods 326:63–75PubMedCrossRefGoogle Scholar
  17. 17.
    Sicard H, Al Saati T, Delsol G, Fournie JJ (2001) Synthetic phosphoantigens enhance human Vγ9Vδ2 T lymphocytes killing of non-Hodgkin’s B lymphoma. Mol Med 7:711–22PubMedGoogle Scholar
  18. 18.
    Sicard H, Ingoure S, Luciani B, Serraz C, Fournié JJ, Bonneville M, Tiollier J, Romagné F (2005) In vivo immunomanipulation of Vγ9Vδ2 T cells with a synthetic phosphoantigen in a preclinical nonhuman primate model. J Immunol 175:5471–80PubMedGoogle Scholar
  19. 19.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216PubMedCrossRefGoogle Scholar
  20. 20.
    Viey E, Fromont G, Escudier B, Morel Y, Da Rocha S, Chouaib S, Caignard A (2005) Phosphostim-activated γδ T cells kill autologous metastatic renal cell carcinoma. J Immunol 174:1338–1347PubMedGoogle Scholar
  21. 21.
    Viey E, Laplace C., Escudier B (2005) Peripheral γδ T lymphocytes as an innovative tool in immunotherapy for metastatic renal cell carcinoma. Expert Rev Anticancer Ther 5:973–86 PubMedCrossRefGoogle Scholar
  22. 22.
    Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA (2003) A randomised trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cell cancer. N Engl J Med 349:427-434PubMedCrossRefGoogle Scholar
  23. 23.
    Yee C, Thompson JA, Roche P, Byrd D, Lee P, Piepkorn M, Kenyon K, Davis M, Riddell S, Greenberg P (2000) Melanocyte destruction after antigen-specific immunotherapy of Melanoma: direct evidence of T cell-mediated vitiligo. J Exp Med 192:1637–1643PubMedCrossRefGoogle Scholar
  24. 24.
    Zheng BJ, Ng SP, Chua DT, Sham JS, Kwong DL, Lam CK, Ng MH (2002) Peripheral gamma delta T-cell deficit in nasopharyngeal carcinoma. Int J Cancer 99:213–217PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Jaafar Bennouna
    • 1
    • 5
  • Emmanuelle Bompas
    • 1
  • Eve Marie Neidhardt
    • 2
  • Frédéric Rolland
    • 1
  • Irène Philip
    • 2
  • Céline Galéa
    • 4
  • Samuel Salot
    • 4
  • Soraya Saiagh
    • 3
  • Marie Audrain
    • 3
  • Marie Rimbert
    • 3
  • Sylvie Lafaye-de Micheaux
    • 4
  • Jérôme Tiollier
    • 4
  • Sylvie Négrier
    • 2
  1. 1.Department of Medical OncologyCentre René GauducheauNantes-Saint-HerblainFrance
  2. 2.Department of Medical OncologyCentre Léon BérardLyonFrance
  3. 3.UTCG and Immunomonitoring LaboratoryHôtel-Dieu HospitalNantesFrance
  4. 4.Innate Pharma SASMarseilleFrance
  5. 5.Centre René GauducheauNantes-Saint-HerblainFrance

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