Abstract
Background: IPH1101, a chemically-synthesized, structural analogue of γδ T lymphocyte natural phosphoantigens, combined with low doses of IL-2 induces a highly selective proliferation of γδ T cells, non conventional lymphocytes bearing potent effector and regulatory immune functions. Today, IPH1101 is tested in Phase II clinical trials in different indications and settings (alone or in combination), as the first specific γδ T cell-mediated immunotherapy. Whereas γδT cells from healthy donors always proliferate in response to IPH1101 + IL-2, cells from cancer patients often present moderate to very strong impaired proliferative capacity. The reasons for this defect are still unclear, but might result from a suppressive effect induced by the tumour itself. Thus, defective γδ T cell responses might be partly disease-dependent. In some cases, the decreased ability to respond to IPH1101 might also correlate with the stage of the disease or the nature of previous or ongoing treatments. In order to explore in which cancer indications or clinical settings γδ T cell pharmacology is impaired or fully maintained, we have set up a quantitative standardized in vitro “IPH1101 sensitivity test” that requires only a small sample of patient’s PBMC. The objective of this ongoing ex-vivo observational study is to identify types of cancers and settings for which γδ T cell immunotherapy using IPH1101 treatment may be beneficial. Here are reported results from 3 hematological indications: multiple myeloma (MM), follicular lymphoma (FL) and chronic myeloid leukaemia (CML) receiving long term imatinib treatment.
Method: Patients with MM, FL and CML have been enrolled at 2 French sites. A small sample of blood (20 mL) is sufficient to prepare PBMCs and culture them in the presence of IPH1101 and IL-2. Results on the extent of in vitro amplification of cells by IPH1101 are available within 8 days and are expressed as
% of γδ T cells in the culture and total amplification rate of γδ T cells.
Results: Nineteen patients with MM, 31 with FL and 19 with CML receiving imatinib were evaluable in this study. One patient by indication was found strictly not sensitive to IPH1101 stimulation ex vivo, meaning that their γδT cells showed no signs of proliferation in culture. Samples from patients with MM and, to a lesser extent, FL showed a clear impairment of their proliferative response as compared to samples from healthy individuals, with 32% and 10% of MM and FL samples, respectively, demonstrating an impaired response. Finally, in imatinib-treated CML patients, 94% PBMC samples had γδ T cells with full proliferative capacity in response to IPH1101.
Conclusion: Ex vivo, γδ T cells from multiple myeloma and follicular lymphoma patients show a low proportion of moderate to strong impairment of their proliferative capacity in response to their specific stimulus IPH1101. For future γδ T cell based immunotherapy trials in these indications, it might be beneficial to consider selecting patients based on such a criteria. In CML patients undergoing long-term treatment with imatinib, γδ T cells have maintained full ability to respond to their specific stimulus (despite the well-known immunosuppressive effects of imatinib). Thus, these results confirm the biological feasibility of combining imatinib and IPH1101 in a clinical trial in CML.
Activation-induced Modification in the CD3 Complex of the γδ T Cell Receptor
