IPH1101, the First Specific γδ T Cell Agonist, Shows Potent Immuno-Biological Efficacy in Low Grade Follicular Lymphoma Patients When Combined with Rituximab: Results From a Phase II Study.

Non-conventional γδ T lymphocytes have strong anti-tumoral activity, particularly against malignant B cells. IPH1101 is an agonist of γδ T cells, which in the presence of low doses of IL-2 potentiates their direct cytotoxic activity. ADCC is a major molecular mechanism underlying rituximab efficacy. Increasing the number and the activation state of killer lymphocytes mediating ADCC is therefore believed to be beneficial for therapeutic potency. Since γδ T cells have been found capable of mediating ADCC, modulating γδ T cells in the context of rituximab is worth being tested in a clinical trial. The main purpose was to assess the clinical efficacy of IPH1101 combined with rituximab in FL patients (see abstract by Laurent et al for clinical data) and the pharmacological activity of IPH1101 in this trial was also closely monitored.

Blood samples were collected weekly in this Phase II study patients who were treated with the combination of rituximab (375 mg/m²), IPH1101 (750 mg/m², 3 times every 3 weeks) and IL-2 (8 MIU daily s.c. for 5 days). Fresh whole blood samples were extensively analysed by flow cytometry for the follow-up of immune cell changes, such as differentiation, activation of proliferation. Plasma samples were collected within hours after each IPH1101 injection to monitor cytokine release. Blood samples were also drawn pre-dose and at Day 8 of each IPH1101 injection to prepare mononuclear cells and assess them for functional activity ex vivo in various standardized assays.

In FL patients treated with rituximab, IPH1101 combined with low dose IL-2 induced robust and sustained γδ T cell differentiation and amplification in blood. In parallel, NK and regulatory T (Treg) cells also proliferated in response to IL-2, though to a much lesser extent. The ratio between effector and suppressor cells remained highly favourable throughout the study. In some patients, γδ T cells showed an increased expression of surface FcRγIIIa, the receptor for rituximab. Pro-inflammatory cytokines were released immediately after each injection, with expected profile and kinetics. Finally, ex vivo functionality assays (direct cytoxicity and CD107a induction) showed an improved overall ADCC-mediated cytotoxic potential of blood cells induced by the treatment.

Altogether, these data demonstrate that effector γδ T cells can be specifically activated and expanded in FL patients receiving standard rituximab therapy through the use of their dedicated agonist IPH1101. The direct immune manipulation of this lymphocyte subset in vivo translates into potentiated anti-lymphoma activity attested by several pharmaco-dynamic parameters.

Lucas:Innate Pharma: Employment. Ingoure:Innate Pharma: Employment. Soule:Innate Pharma: Employment. Faria:Innate Pharma: Employment. Audibert:Innate Pharma: Employment. Blery:Innate Pharma: Employment. Beautier:Innate Pharma: Employment. Romagne:Innate Pharma: Employment. de Micheaux:Innate Pharma: Employment.