ELYPSE-7: a randomized placebo-controlled phase IIa trial with CYT107 exploring the restoration of CD4+ lymphocyte count in lymphopenic metastatic breast cancer patients

Trédan, Olivier; Ménétrier‐Caux, Christine; Ray‐Coquard, Isabelle; Garin, Gwenaëlle; Cropet, Claire; Verronèse, Estelle; Bachelot, Thomas; Rebattu, P.; Heudel, Pierre; Cassier, Philippe; Chabaud, Sylvie; Croughs, Thérèse; Dupont, Patricia; Cadore, Anne-claire; Clapisson, Gilles; Delgado, Ana Sofia; Bardin-Dit-Courageot, Christine; Rigal, Chantal; N'Kodia, Axelle; Gilles-Afchain, L.; Morre, Michel; Pérol, David; Blay, Jean‐Yves; Caux, Christophe

doi:10.1093/annonc/mdv173

Cited by 58 publications

(33 citation statements)

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“…The clinical significance of lymphopenia after surgery is highlighted by its negative correlation with the probability of long-term survival. The development of strategies based on immunonutrition [43], recombinant IL-7 [44], to expand CD4 T cells and the preliminary results of novel immunotherapies [45], offer new therapeutic endpoints to be assessed in pancreatic cancer patients.…”

Section: Discussionmentioning

confidence: 99%

Additive value of pre-operative and one-month post-operative lymphocyte count for death-risk stratification in patients with resectable pancreatic cancer: a multicentric study

et al. 2016

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BackgroundPancreatic adenocarcinoma (PDAC) incidence is increasing worldwide. Several studies have shown that lymphopenia was correlated with a poor prognosis but the potential interest to measure lymphopenia in the pre and post-operative setting as well as its added value among conventional prognostic factors was never investigated.MethodsData from two independent cohorts in whom patients underwent resection for pancreatic carcinoma were retrospectively recorded. We examined the association between perioperative findings, pre and post-operative lymphocyte counts and overall survival (OS) in univariate and multivariate analyses. Performance assessment and internal validation of the final model were evaluated with Harrell’s C-index, calibration plot and bootstrap sample procedures.ResultsThree hundred ninety patients were included in the analysis between 2000 and 2011. Pre and post-operative lymphocyte counts were independent prognostic factors associated with OS in multivariate analysis (p = 0.0128 and p = 0.0764, respectively). The addition of lymphocyte count variable to the conventional parameters identified in multivariate analysis (metastatic lymph node ratio, veinous emboli and adjuvant chemotherapy) significantly improved the model discrimination capacity (bootstrap mean difference = 0.04; 95 % CI, 0.01–0.06). The use of a threshold and combining the categorical (≥1000; <1000) information in pre and post lymphocyte counts permitted the identification of 4 subgroups of patients with different prognosis (p < 0.0001). Finally, the description of patients in long-term remission showed that only 3 of 65 (4.6 %) patients with post-operative lymphocyte count under 1000/mm3 were alive 4 years after surgery contrary to 54 of 236 (22.8 %) patients with a post-operative lymphocyte count above 1000/mm3.ConclusionPre and post-operative lymphopenia are independent prognostic factors for OS and they have an additive value regarding conventional prognostic factors for death-risk stratification and to predict long-term survival. Lymphopenia should be included as stratification factors in future clinical trial assessing overall survival in pancreatic cancer patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2860-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Additive value of pre-operative and one-month post-operative lymphocyte count for death-risk stratification in patients with resectable pancreatic cancer: a multicentric study

et al. 2016

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“…Recombinant IL-7 has been extensively studied for its potential to enhance immune recovery in different clinical setting of accelerated thymic involution ( 23 ). IL-7 has been shown to promote immune reconstitution both from thymus-independent homeostatic expansion of peripheral T cells and thymopoiesis in different clinical settings including idiopathic CD4 lymphopenia, septic shock, and cancer ( 24 – 28 ). Nevertheless, to date, no study assessed the potential efficacy of rhIL-7 in the ESRD-associated immune defect.…”

Section: Discussionmentioning

confidence: 99%

Pre-transplant Thymic Function Predicts Is Associated With Patient Death After Kidney Transplantation

et al. 2020

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Accelerated thymic involution is a main feature of end-stage renal disease (ESRD)-associated immune senescence. Recent evidences suggest that ESRD-associated immune senescence is associated with adverse outcomes in dialysis patients. However, no study focused on the association between pre-transplant thymic function and patient survival after transplantation. We conducted a prospective, multicenter study to assess whether pre-transplant thymic function measured by recent thymic emigrants (RTE) may predict death after first kidney transplantation. Results were tested in a validation cohort. Nine hundred and sixty-seven incident kidney transplant recipients were included in the prospective study. Mean follow up was 5.1 + 2.9 years. Eighty two patients (8.5%) died during follow up. Lower RTE levels were associated with a higher risk of death (2.53; 95%CI, 1.54–4.39 for each decrease of 1 log in RTE; p < 0.001). Cancer-related death was particularly increased in patients with low RTE levels (4.23; 95%CI, 1.43–12.13; p = 0.007). One hundred and thirty-six patients having received a first kidney transplantation were included in the validation cohort. Lower TREC levels were associated with higher risk of death (1.90; 95%CI, 1.11–3.51 for each decrease of 1 log in RTE; p = 0.025). RTE were not associated with death-censored graft loss. Pre-transplant thymic function is strongly associated with death after transplantation. Attempt to reverse ESRD-related thymic loss may prevent premature death.

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“…A Phase I study in patients with solid tumors has been completed and proved tolerance and rIL-7 potency resulting in rejuvenated circulating T-cell profile with increase in overall naive T cells but a decreased T reg number making this effect opposite from the one observed in treatments employing IL-2 ( 198 ). In lymphopenic metastatic breast cancer patients during Phase II trial it increased CD4+ and other T-cell subset counts without altering their function ( 194 , 195 ). Combining rIL-7 with vaccine therapy was used in two completed phase I clinical trials in patients with melanoma and pediatric solid tumors ( 182 , 193 ).…”

Section: Modulators Of Il-7 Signalingmentioning

confidence: 99%

Modulation of Signaling Mediated by TSLP and IL-7 in Inflammation, Autoimmune Diseases, and Cancer

Marković

Savvides

2020

Front. Immunol.

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Thymic Stromal Lymphopoietin (TSLP) and Interleukin-7 (IL-7) are widely studied cytokines within distinct branches of immunology. On one hand, TSLP is crucially important for mediating type 2 immunity at barrier surfaces and has been linked to widespread allergic and inflammatory diseases of the airways, skin, and gut. On the other hand, IL-7 operates at the foundations of T-cell and innate lymphoid cell (ILC) development and homeostasis and has been associated with cancer. Yet, TSLP and IL-7 are united by key commonalities in their structure and the structural basis of the receptor assemblies they mediate to initiate cellular signaling, in particular their cross-utilization of IL-7Rα. As therapeutic targeting of TSLP and IL-7 via diverse approaches is reaching advanced stages and in light of the plethora of mechanistic and structural data on receptor signaling mediated by the two cytokines, the time is ripe to provide integrated views of such knowledge. Here, we first discuss the major pathophysiological roles of TSLP and IL-7 in autoimmune diseases, inflammation and cancer. Subsequently, we curate structural and mechanistic knowledge about receptor assemblies mediated by the two cytokines. Finally, we review therapeutic avenues targeting TSLP and IL-7 signaling. We envision that such integrated view of the mechanism, structure, and modulation of signaling assemblies mediated by TSLP and IL-7 will enhance and fine-tune the development of more effective and selective approaches to further interrogate the role of TSLP and IL-7 in physiology and disease.

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ELYPSE-7: a randomized placebo-controlled phase IIa trial with CYT107 exploring the restoration of CD4+ lymphocyte count in lymphopenic metastatic breast cancer patients

Cited by 58 publications

References 38 publications

Additive value of pre-operative and one-month post-operative lymphocyte count for death-risk stratification in patients with resectable pancreatic cancer: a multicentric study

Additive value of pre-operative and one-month post-operative lymphocyte count for death-risk stratification in patients with resectable pancreatic cancer: a multicentric study

Pre-transplant Thymic Function Predicts Is Associated With Patient Death After Kidney Transplantation

Modulation of Signaling Mediated by TSLP and IL-7 in Inflammation, Autoimmune Diseases, and Cancer

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