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Optimisation d’une stratégie thérapeutique antitumorale conventionnelle par association à une immunothérapie : etude de phase I combinant l’Imatinib à l’Interleukine-2

Abstract : Imatinib mesylate (IM) was the first tyrosine kinase inhibitor to be successfully used in clinical practice and its introduction has revolutionized the management of chronic myeloid leukemia and gastrointestinal stromal tumors. In addition to its direct effects on malignant cells, IM appears to exert immunological off-target effects that contribute to its anticancer effects. Thus, combining IM with immunotherapy might improve patients’ clinical outcome. Indeed, IM combined to Interleukin-2 (IL-2) - a cytokine that enhances natural killer (NK) cells functions - improved antitumor responses in preclinical models. We also observed synergistic effects of cyclophosphamide (CTX) and IM as a result of the inhibition of regulatory T lymphocytes. Based on the promising results of these preclinical studies, we developed a phase 1 clinical trial which combines metronomic CTX, IM and escalating doses of IL-2 in patients affected by refractory solid tumors. The goals of this study were (i) to determine the maximum tolerated dose of IL-2 combined with IM and CTX ; (ii) to study the pharmacokinetics of IM and IL-2 ; (iii) to evaluate clinical efficacy of the combined therapy and (iv) effects of the association on immune parameters. A total of 17 patients were enrolled in the study. The maximum tolerated dose of IL-2 combined with IM, given at a constant dose of 400 mg was determined to be 6 MIU/day. At this dose level, all patients experienced at least one treatment-related adverse event: fevers and chills, transaminase elevation, fatigue and nausea but no dose-limiting toxicities were observed. Pharmacokinetic studies revealed that the co-administration of IL-2 increases the systemic exposure of patients to IM. In contrast, the pharmacokinetics of IL-2 was not modified by IM. The combined therapy markedly reduced the absolute numbers of B lymphocytes, CD4+ T cells and CD8+ T cells in a IL-2 dose-dependant manner. The NK cell compartment was activated, exhibiting a significant upregulation of CD56bright, HLA-DR and TRAIL. Interinstingly, the abundance of HLA-DR+ NK cells after one course of combined therapy positively correlated with both progression free- and overall survival. Thus, it could be of interest to evaluate this immunotherapeutic regimen in a tumor model sensitive to IM and to lysis by NK cells and evaluate whether the adjunction of IL-2 can boost the efficacy of IM. GIST are particularly sensitive to IM, thus we performed a retrospective study of the immune infiltrates and their prognostic value in these tumors. We found that both LT and NK cell infiltrates were independent prognostic factors for progression-free survival. For a phase 2 clinical trial, gastrointestinal stromal tumors appear to be a particularly relevant to evaluate the benefits of the association IM, IL-2 and CTX.
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https://tel.archives-ouvertes.fr/tel-00920831
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Submitted on : Thursday, December 19, 2013 - 11:42:44 AM
Last modification on : Friday, October 23, 2020 - 4:51:25 PM
Long-term archiving on: : Thursday, March 20, 2014 - 4:40:22 AM

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Clara Locher. Optimisation d’une stratégie thérapeutique antitumorale conventionnelle par association à une immunothérapie : etude de phase I combinant l’Imatinib à l’Interleukine-2. Immunologie. Université Paris Sud - Paris XI, 2013. Français. ⟨NNT : 2013PA11T027⟩. ⟨tel-00920831⟩

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