Skip to main content
SpringerLink
Log in

Phase I study of bromohydrin pyrophosphate (BrHPP, IPH 1101), a Vγ9Vδ2 T lymphocyte agonist in patients with solid tumors

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Purpose

Vγ9Vδ2 (γδ) T lymphocytes, a critical peripheral blood lymphocyte subset, are directly cytotoxic against many solid and hematologic tumor types. Vγ9Vδ2 T lymphocytes can be selectively expanded in vivo with BrHPP (IPH1101) and IL-2. The present phase I trial was conducted with the aim of determining the maximum-tolerated dose (MTD) and safety of IPH1101 combined with a low dose of IL-2 in patients with solid tumors.

Experimental design

A 1-h intravenous infusion of IPH11 was administered alone at cycle 1, combined with a low dose of SC IL-2 (1 MIU/M2 d1 to d7) in the subsequent cycles (day 1 every 3 weeks). The dose of IPH1101 was escalated from 200 to 1,800 mg/m2.

Results

As much as 28 patients with solid tumors underwent a total of 109 treatment cycles. Pharmacodynamics data demonstrate that γδ T lymphocyte amplification in humans requires the co-administration of IL-2 and is dependent on IPH 1101 dose. Dose-limiting toxicity occurred in two patients at a dose of 1,800 mg/m2: one grade 3 fever (1 patient) and one grade 3 hypotension (1 patient) suggesting cytokine release syndrome immediately following the first infusion. At lower doses the treatment was well tolerated; the most frequent adverse events were mild fever, chills and abdominal pain, without exacerbation in the IL-2 combined cycles.

Conclusion

IPH1101 in combination with SC low-dose IL-2 is safe, well tolerated and induces a potent γδ T lymphocyte expansion in patients. Its clinical activity will be evaluated in phase II clinical trials.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Choudhary A, Davodeau F, Moreau A, Peyrat MA, Bonneville M, Jotereau F (1995) Selective lysis of autologous tumor cells by recurrent gamma delta tumor-infiltrating lymphocytes from renal carcinoma. J Immunol 154:3932–3940

    CAS  PubMed  Google Scholar 

  2. Viey E, Fromont G, Escudier B et al (2005) IPH1101-activated gamma delta T cells kill autologous metastatic renal cell carcinoma. J Immunol 174:1338–1347

    CAS  PubMed  Google Scholar 

  3. Bachelez H, Flageul B, Degos L, Boumsell L, Bensussan A (1992) TCR gamma delta bearing T lymphocytes infiltrating human primary cutaneous melanomas. J Invest Dermatol 98:369–374

    Article  CAS  PubMed  Google Scholar 

  4. Bouet-Toussaint F, Cabillic F, Toutirais O, Le Gallo M, Thomas de la Pintière C, Daniel P, Genetet N, Meunier B, Dupont-Bierre E, Boudjema K, Catros V (2008) Vgamma9Vdelta2 T cell-mediated recognition of human solid tumors Potential for immunotherapy of hepatocellular and colorectal carcinomas. Cancer Immunol Immunother 57:531–539

    Article  CAS  PubMed  Google Scholar 

  5. Wrobel P, Shojaei H, Schittek B, Gieseler F, Wollenberg B, Kalthoff H, Kabelitz D, Wesch D (2007) Lysis of a broad range of epithelial tumour cells by human gamma delta T cells: involvement of NKG2D ligands and T-cell receptor-versus NKG2D-dependent recognition. Scand J Immunol 66:320–328

    Article  CAS  PubMed  Google Scholar 

  6. Corvaisier M, Moreau-Aubry A, Diez E, Bennouna J, Mosnier JF, Scotet E, Bonneville M, Jotereau F (2005) V gamma 9V delta 2 T cell response to colon carcinoma cells. J Immunol 175:5481–5488

    CAS  PubMed  Google Scholar 

  7. Murayama M, Tanaka Y, Yagi J, Uchiyama T, Ogawa K (2008) Antitumor activity and some immunological properties of gammadelta T-cells from patients with gastrointestinal carcinomas. Anticancer Res 28:2921–2931

    CAS  PubMed  Google Scholar 

  8. Bryant NL, Suarez-Cuervo C, Gillespie GY, Markert JM, Nabors LB, Meleth S, Lopez RD, Lamb LS Jr (2009) Characterization and immunotherapeutic potential of gammadelta T-cells in patients with glioblastoma. Neuro Oncol 11:3557–3567

    Article  Google Scholar 

  9. Todaro M, D’Asaro M, Caccamo N, Iovino F, Francipane MG, Meraviglia S, Orlando V, La Mendola C, Gulotta G, Salerno A, Dieli F, Stassi G (2009) Efficient killing of human colon cancer stem cells by gammadelta T lymphocytes. J Immunol 182:7287–7296

    Article  CAS  PubMed  Google Scholar 

  10. Chen J, Niu H, He W, Ba D (2001) Antitumor activity of expanded human tumor-infiltrating gammadelta T lymphocytes. Int Arch Allergy Immunol 125:256–263

    Article  CAS  PubMed  Google Scholar 

  11. Kang N, Zhou J, Zhang T, Wang L, Lu F, Cui Y, Cui L, He W (2009) Adoptive immunotherapy of lung cancer with immobilized anti-TCR gammadelta antibody-expanded human gammadelta T-cells in peripheral blood. Cancer Biol Ther 8:1540–1549

    Article  CAS  PubMed  Google Scholar 

  12. Viey E, Lucas C, Romagne F, Escudier B, Chouaib S, Caignard A (2008) Chemokine receptors expression and migration potential of tumor-infiltrating and peripheral-expanded Vgamma9Vdelta2 T cells from renal cell carcinoma patients. J Immunother 31:313–323

    Article  CAS  PubMed  Google Scholar 

  13. 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 gamma delta T cells. J Biol Chem 276:18337–18344

    Article  CAS  PubMed  Google Scholar 

  14. Wilhelm M, Kunzmann V, Eckstein S, Reimer P, Weissinger F, Ruediger T, Tony HP (2003) Gammadelta T cells for immune therapy of patients with lymphoid malignancies. Blood 102:200–206

    Article  CAS  PubMed  Google Scholar 

  15. Dieli F, Vermijlen D, Fulfaro F, Caccamo N, Meraviglia S, Cicero G, Roberts A, Buccheri S, D’Asaro M, Gebbia N, Salerno A, Eberl M, Hayday AC (2007) Targeting human gammadelta T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer. Cancer Res 67:7450–7457

    Article  CAS  PubMed  Google Scholar 

  16. Sicard H, Ingoure S, Luciani B, Serraz C, Fournié JJ, Bonneville M, Tiollier J, Romagné F (2005) In vivo immunomanipulation of V gamma 9V delta 2 T cells with a synthetic phosphoantigen in a preclinical nonhuman primate model. J Immunol 175:5471–5480

    CAS  PubMed  Google Scholar 

  17. Bennouna J, Bompas E, Neidhardt EM, Rolland F, Philip I, Galéa C, Salot S, Saiagh S, Audrain M, Rimbert M, Lafaye-de Micheaux S, Tiollier J, Négrier S (2008) Phase-I study of Innacell gammadelta, an autologous cell-therapy product highly enriched in gamma9delta2 T lymphocytes, in combination with IL-2, in patients with metastatic renal cell carcinoma. Cancer Immunol Immunother 57:1599–1609

    Article  CAS  PubMed  Google Scholar 

  18. Casetti R, Perretta G, Taglioni A, Mattei M, Colizzi V, Dieli F, D’Offizi G, Malkovsky M, Poccia F (2005) Drug-induced expansion and differentiation of V gamma 9V delta 2 T cells in vivo: the role of exogenous IL-2. J Immunol 175:1593–1598

    CAS  PubMed  Google Scholar 

  19. Laurent G, Lafaye de Micheaux S, Solal-Celigny P, Soubeyran P, Delwail V, Ghesquieres H, Thieblemont C, Jourdan E, Beautier L, Audibert F, Squiban P, Sicard H, Rossi JF (2009) Phase I/II study of IPH1101, γδ T cell agonist, combined with rituximab, in low grade follicular lymphoma patients. Blood 114:658–659

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Centre René Gauducheau, 44805, Nantes-Saint-Herblain, France

    Jaafar Bennouna, Hélène Senellart, Sandrine Hiret & Frédéric Rolland

  2. Clinical Investigation Center-INSERM, Saint-Louis Hospital, Paris, France

    Vincent Levy, Heriberto Bruzzoni-Giovanelli & Fabien Calvo

  3. Innate Pharma SAS, Marseille, France

    Hélène Sicard, Céline Galéa & Jérome Tiollier

  4. UTCG and Immunomonitoring Laboratory, Hôtel Dieu Hospital, Nantes, France

    Marie Audrain & Marie Rimbert

Authors
  1. Jaafar Bennouna
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vincent Levy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hélène Sicard
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hélène Senellart
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marie Audrain
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sandrine Hiret
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Frédéric Rolland
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Heriberto Bruzzoni-Giovanelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marie Rimbert
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Céline Galéa
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jérome Tiollier
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Fabien Calvo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jaafar Bennouna.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bennouna, J., Levy, V., Sicard, H. et al. Phase I study of bromohydrin pyrophosphate (BrHPP, IPH 1101), a Vγ9Vδ2 T lymphocyte agonist in patients with solid tumors. Cancer Immunol Immunother 59, 1521–1530 (2010). https://doi.org/10.1007/s00262-010-0879-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-010-0879-0

Keywords

Search

Navigation