Phase I study of zoledronic acid combined with escalated doses of interleukine-2 for early in vivo generation of Vγ9Vδ2 T-cells after haploidentical stem cell transplant with posttransplant cyclophosphamide.

Abstract

The presence of donor Vγ9Vδ2 T-cells after haploidentical hematopoietic stem cell transplant (h-HSCT) has been associated with improved disease-free survival. These cells kill tumor cells in a non-MHC restricted manner, do not induce graft-versus-host disease (GVHD), and can be generated by stimulation with zoledronic acid (ZA) in combination with interleukin-2 (IL-2). This monocentric phase I, open-label, dose-escalating study (ClinicalTrials.gov: NCT03862833) aimed at evaluating the safety and possibility to generate Vγ9Vδ2 T-cells early after h-HSCT. It applied a standard 3 + 3 protocol to determine the maximum tolerated dose (MTD) of increasing low-doses of IL-2 (5 days [d] per week, 4 weeks) in combination with a single dose of ZA, starting both the first Monday after d + 15 posttransplant. Vγ9Vδ2 T-cell monitoring was performed by multiparameter flow cytometry on blood samples and compared with a control cohort of h-HSCT recipients. Twenty-six patients were included between April 2019 and September 2022, 16 of whom being ultimately treated and seven being controls who received h-HSCT only. At the three dose levels tested, 1, 0, and 1 dose-limiting toxicities were observed. MTD was not reached. A significantly higher number of Vγ9Vδ2 T-cells was observed during IL-2 treatment compared with controls. In conclusion, early in vivo generation of Vγ9Vδ2 T-cells is feasible after h-HSCT by using a combination of ZA and repeated IL-2 infusions. This study paves the way to a future phase 2 study, with the hope to document lesser posttransplant relapse with this particular adaptive immunotherapy.

• Authors: Maxime Jullien, Thierry Guillaume, Amandine Le Bourgeois, Pierre Peterlin, Alice Garnier, Marion Eveillard, Yannick Le Bris, Simon Bouzy, Benoît Tessoulin, Thomas Gastinne, Viviane Dubruille, Cyrille Touzeau, Béatrice Mahé, Nicolas Blin, Anne Lok, Sophie Vantyghem, Clara Sortais, Chloé Antier, Philippe Moreau, Emmanuel Scotet, Marie C Béné, Patrice Chevallier
• Journal: American journal of hematology (Am J Hematol) Vol. 99 Issue 3 Pg. 350-359 (Mar 2024) ISSN: 1096-8652 [Electronic] United States
• PMID: 38165016 (Publication Type: Clinical Trial, Phase I, Journal Article)
• Copyright: © 2024 Wiley Periodicals LLC.

Chemical References

• Interleukin-2
• Zoledronic Acid
• Cyclophosphamide

Topics

• Humans
• Hematopoietic Stem Cell Transplantation (methods)
• Interleukin-2
• Zoledronic Acid
• T-Lymphocytes (pathology)
• Cyclophosphamide (therapeutic use)
• Graft vs Host Disease (etiology, prevention & control, drug therapy)
• Stem Cell Transplantation