Phase I Study of IPH1101 (with Low Dose of IL-2) in Patient with B-NHL

Background: Since the discovery of gd-T lymphocytes in the 80s’, their particular ability to recognize and kill tumours of haematological origin has been extensively studied. The pioneer clinical study using immunotherapy with activated γδ T cells in oncology (with an aminobisphosphonate associated with low dose IL-2 as γδ activator) was conducted in relapsed/refractory low grade B-NHL patients (Wilhelm et al. 2003), demonstrating an interesting correlation between γδ T cell amplification in vivo and clinical response. In order to further exploit the potential of γδ immunotherapy, we have developed the most specific γδ T lymphocyte ligands, referred to as “phosphoantigens”, IPH1101 being the first ever administered to oncology patients. Upon IPH1101 activation, γδ T cells secrete pro-inflammatory cytokines allowing the implementation of an improved adaptive response. When IPH1101 is associated with low doses of IL-2, γδ T cells proliferate and differentiate into highly potent antitumor effectors. Here, we present the safety, pharmacokinetic and pharmacodynamic profiles of IPH1101 associated with low dose IL-2 in relapsed low grade B-NHL patients.

Method: A Phase I, dose-escalation study was conducted in France and Germany in sequential cohorts of patients with low grade B-NHL relapsing after polychemotherapy including rituximab. In this first clinical trial targeting B-NHL, included patients were selected, among other criteria, upon their ability to respond to IPH1101 ex vivo in a standardized culture. The objective was to determine the MTD, pharmacokinetic and pharmacodynamic parameters of IPH1101 administered i.v. on Day 1, in combination with low dose of aldesleukin (1 MIU/m²/day) on Days 1 to 7. The following escalating dose levels of IPH1101 have been established for this study: 100, 300, 600, 900 and 1200 mg/m².

Results: Three patients have been treated at each dose level 100, 300 and 600 and 900 mg/m². In general, IPH1101 with low dose of IL-2 was very well tolerated and neither DLT nor serious or severe adverse events related to the study treatments were reported. Patients presented grade 1 or 2 fever, asthenia, or headache. IL-2 injection site reactions of grade 1 at almost all dose level were also reported. In terms of pharmacokinetics, steady-state concentrations of IPH1101 during the 30-min infusion are reached within 10 minutes. The half-life of IPH1101 is very short, around 2 minutes. The target lymphocyte population amplification was significant, but data from other preclinical and clinical studies indicated that a dose of IL2 of 1 MIU/m² was suboptimal in terms of pharmacodynamic effect. Furthermore, the start of a combination phase I/II study of IPH1101 750 mg/m² with low dose of IL-2 (4 and 8 MIU) in combination with rituximab (375 mg/m²) in patients with follicular lymphoma, led to stop the dose escalation.

Conclusion: This Phase I study of IPH1101 combined with a low dose of IL2 in B-NHL shows a very good safety profile of the first γδ T cell immunotherapeutic agent. IPH1101 was shown to have a very short plasma halflife and to induce moderate pharmacodynamic effect on γδ T cells in vivo, probably due to sub-optimal IL-2 dosing. In order to improve both the pharmacodynamics of γδ T cells and their potential antitumoral effect against B-NHL through ADCC, we have combined IPH1101 with higher doses of IL-2 (4 MIU/m²) and rituximab in a Phase II trial that is currently enrolling in Europe.