Background: The presence of donor Vγ9Vδ2 T-cells after haploidentical hematopoietic stem cell transplant (haplo-HSCT) has been associated with improved disease-free survival. These cells, that kill tumor cells in a non-MHC restricted manner and do not induce graft-versus-host disease (GVHD) can be generated by stimulation with bisphosphonate zoledronic acid (ZA), in combination with interleukin-2 (IL-2). Methods: A prospective monocentric phase 1 dose-escalating study aimed at demonstrating the possibility to generate Vγ9Vδ2 T-cells in vivo after haplo-HSCT with post-transplant cyclophosphamide (PTCY). A 3x3 protocol was designed to determine the maximum tolerated dose (MTD) of early administration of increasing low-doses of IL-2 in combination with a fixed dose of ZA, starting the first Monday after day+15 post-transplant. A single dose of 4 mg IV ZA was administered, followed, by subcutaneous injections of IL-2, 5 days/week, for 4 consecutive weeks. Three IL-2 doses were tested: 2, 4 and 6 million UI/infusion. Main inclusion criteria were patients (pts) between 18-70 years old with a hematological disease eligible for haplo-SCT using a Baltimore-based conditioning, no HLA-matched sibling or unrelated donor, no contra-indication to ZA nor IL-2 and informed consent. MTD was defined by the dose just below that which yielded 2/3 or 2/6 dose limiting toxicities (DLT), including severe or recurrent acute GVHD. Vγ9Vδ2 T-cells monitoring was performed in multiparameter flow cytometry on blood samples collected before conditioning, on the day of the first ZA and IL-2 injection, once a week+-3 for 4 weeks and at day +70 post-graft. The protocol was registered at ClinicalTrials.gov as NCT03862833. Results: Twenty-six pts were included between April 2019 and September 2022 (including 7 controls). Three pts withdraw their consents in the experimental group, and 16 pts were treated with ZA and IL-2 (level 1 n = 7 including 1 not evaluable for DLT, level 2 n = 3, level 3 n = 6). First injections occurred at a median of 20 days after Day 0 (range: 17-21). One, 0 and 1 DLT and 4, 2, 2 acute GVHD (all grade II-III) were documented, and MTD was not reached. Vγ9Vδ2 T cells were clearly detectable in both controls and treated pts before conditioning. The median highest value (0.6x10⁶/L, range: 0.0-3.2) was observed at a median of 12 days (8-12) after first infusion of ZA+IL-2. A significantly higher proportion of Vγ9Vδ2 T cells was observed at days +22 and +29 in treated pts compared to controls. At the date of the submission, 3 relapse/progression occurred in treated pts, and 10 are alive in CR. Median OS is not reached. Conclusions: Early in vivo generation of Vγ9Vδ2 T cells is possible after haplo-SCT with PTCY by using a combination of ZA and repeated IL-2 infusions. The DMT has not been reached. This study lays the groundwork for future phase 2/3 studies. Clinical trial information: NCT03862833.