Enhancing Lysis of B Cell Lymphoma by Innovative γδ T Cell Immunotherapies Using Agonist IPH1101 (Phosphostim, BrHPP).
Authors: Rossi Jean-Francois , Gertner Julie , Sicard Helene , PhD Guy Laurent , de Micheaux Sylvie Lafaye , Tiollier Jerome , Fournie Jean-Jacques , Squiban Patrick , PhD Volker Kunzmann 
Published: October 2019

Abstract
Since the early 90’s, it was observed that blood γδ T cells could kill a broad variety of tumor cells, including malignant B-cells, in vitro as well as in human PBMC-reconstituted NOD-SCID mice.
Today, with specific antigens activating γδ T cells like IPH1101 (Phosphostim, BrHPP), these effector cells can be strongly amplified in vivo and their cytotoxic activity toward B-Non Hodgkin’s Lymphoma (B-NHL) enhanced.
Furthermore, γδ T cells are potential effectors of ADCC which is one of the major mechanisms underlying rituximab efficacy for the depletion of B-NHL: we demonstrated in short-term standard cytotoxicity assays that there is a strong synergy between IPH1101-activated γδ cells and rituximab for the killing of B-NHL lines of various histologies (mantle cell, follicular and Burkitt’s lymphomas). Impressive results were obtained with follicular lymphoma (FL) cells (RL and Karpas-422) for which the addition of rituximab in the co-culture containing stimulated γδ T cells and FL cells resulted in target cell lysis as high as 70% at E:T ratio of 30:1 whereas stimulated γδ T cells alone induced less than 30% lysis in the same conditions.
We are currently running a cognitive biological study using blood samples from FL and multiple myeloma patients: PBMC purified from these patients are cultured in a standardized assay in the presence of IPH1101 and IL-2 in order to evaluate the proportion of patients whose γδ cells can efficiently respond to IPH1101-treatment.
A Phase I, dose-escalation study is currently being conducted in France and Germany in sequential cohorts of patients with B-NHL relapsing after polychemotherapy with rituximab. In this first clinical trial, included patients are selected, among other criteria, upon their ability to respond to IPH1101 in vitro in this standardized culture.
The objective is 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 5. Low doses IL-2 (1/10th of the therapeutic dose) are required to sustain γδ proliferation in response to IPH1101. The following escalating dose levels of IPH1101 have been established for this study: 100, 300, 600, 900 and 1200 mg/m2.
To date 7 patients have been treated at dose levels 100, 300 and 600 mg/m2 without any signs of toxicity and with significant target γδ lymphocyte population amplification. Updated results will be presented at the time of the conference.
A phase II study of IPH1101 associated with low dose of IL-2 in combination with rituximab in FL patients progressing after one or more rituximab-containing lines of treatment is proposed. Its objective will be to assess the clinical efficacy of the combination and investigate the relationship between biological activity and clinical efficacy of the combination. This strategy is strongly sustained by convincing scientific data and stands for a very innovative combination of immunotherapies.