Experience in daily practice with ipilimumab for the treatment of patients with metastatic melanoma: an early increase in lymphocyte and eosinophil counts is associated with improved survival

Delyon, Julie; Mateus, C.; Lefeuvre, D.; Lanoy, Émilie; Zitvogel, Laurence; Chaput, Nathalie; Roy, Séverine Le; Eggermont, Alexander; Routier, Émilie; Robert, Caroline

doi:10.1093/annonc/mdt027

Cited by 288 publications

(222 citation statements)

References 21 publications

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“…Combination chemotherapies were shown to reduce peripheral lymphocyte count in cancer patients. These findings suggest that treatment-induced lymphopenia may be associated with an increased tumor response (17). In our study, we demonstrated that patients with PLR >200 and eosinophil count <70x10 3 /mm 3 exhibited better DFS rates.…”

Section: Discussionsupporting

confidence: 57%

Factors affecting disease-free survival in patients with human epidermal growth factor receptor 2-positive breast cancer who receive adjuvant trastuzumab

Gündüz

Göksu

Arslan

et al. 2015

Molecular and Clinical Oncology

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Abstract. Breast cancer is the most frequently diagnosed cancer in women worldwide and the second cause of cancer-related mortality. A total of 20-30% of patients with early-stage breast cancer develop recurrence within the first 5 years following diagnosis. Trastuzumab significantly improves overall survival and disease-free survival (DFS) in women with human epidermal growth factor receptor 2 (HER2)-positive early and locally advanced breast cancer. This study aimed to determine the factors that affect DFS following adjuvant transtuzumab therapy. A total of 62 patients treated with trastuzumab for early and locally advanced breast cancer were included in our study. Data, including pathology, treatment and treatment outcome, rate of recurrence and laboratory tests, were retrospectively collected. There was no significant association between DFS and age, menopausal status, disease stage and hormone receptor status. The median follow-up was 48.4 months. The median DFS of patients treated with adjuvant trastuzumab was 64.1 months. In addition, the median DFS was 44.3 vs. 66.8 months in patients with platelet-lymphocyte ratio (PLR) ≤200 vs. >200, respectively (log-rank test; P=0.001), and 70 vs. 45 months in patients with eosinophil count ≤70 vs. >70x10 3 ̸mm 3 (log-rank test; P=0.001). Our data revealed the prognostic relevance of a decrease in the peripheral blood eosinophil count and PLR value following trastuzumab therapy in breast cancer. PLR and eosinophil count measurements are cost-effective, readily available worldwide, non-invasive and safe. Combined with other markers, such as patient age, tumor stage and tumor histology, may be effectively used for patients with breast cancer.

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Section: Discussionsupporting

confidence: 57%

Factors affecting disease-free survival in patients with human epidermal growth factor receptor 2-positive breast cancer who receive adjuvant trastuzumab

Gündüz

Göksu

Arslan

et al. 2015

Molecular and Clinical Oncology

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“…Indeed, low LDH serum levels were associated with an increased OS [4,5]. In smaller cohorts treated with ipilimumab reported by Wilgenhof et al [57] and Delyon et al [17], the elevated LDH level was also negatively associated with survival. Moreover, a recent report analyzing several prognostic parameters in two European MM cohorts treated with 3 mg/kg of ipilimumab concluded that an LDH level of > 2 folds above the normal range correlated with clinical failure of CTLA4 blockade [58].…”

Section: -Test) (F)mentioning

confidence: 92%

“…In MM patients, ipilimumab treatment increased the absolute lymphocyte count [17] and the frequencies of circulating HLA-DR + or ICOS + T cells [18,19]. An increase in the absolute eosinophil count has also been associated to clinical benefit [17].…”

Section: Introductionmentioning

confidence: 99%

Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25

Hannani¹,

Vétizou²,

Enot³

et al. 2015

Cell Res

144

111

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The cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibody ipilimumab induces immune-mediated longterm control of metastatic melanoma in a fraction of patients. Although ipilimumab undoubtedly exerts its therapeutic effects via immunostimulation, thus far clinically useful, immunologically relevant biomarkers that predict treatment efficiency have been elusive. Here, we show that neutralization of IL-2 or blocking the α and β subunits of the IL-2 receptor (CD25 and CD122, respectively) abolished the antitumor effects and the accompanying improvement of the ratio of intratumoral T effector versus regulatory cells (Tregs), which were otherwise induced by CTLA-4 blockade in preclinical mouse models. CTLA-4 blockade led to the reduction of a suppressive CD4 + T cell subset expressing Lag3, ICOS, IL-10 and Egr2 with a concomitant rise in IL-2-producing effector cells that lost FoxP3 expression and accumulated in regressing tumors. While recombinant IL-2 improved the therapeutic efficacy of CTLA-4 block-

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“…Our data reinforce previous results from clinical trials involving either ipilimumab at a higher dose or another CTLA-4 abrogating antibody, tremelimumab. 21,22,23,38 Prior to treatment, patients' circulating T cells displayed a phenotype compatible with a chronic activation by the tumor, with a lower expression of the costimulatory molecule CD28 and increased percentage of HLA-DR and granzyme B positive CD8 C T cells, when compared to HD. In addition, although not significant, a trend toward higher percentages of TCD8 C T cells expressing CTLA-4 by was also observed, suggesting a post-activation status of T cells.…”

Section: Discussionmentioning

confidence: 99%

“…Increased absolute lymphocyte count (ALC) during the therapy is found to be associated with clinical benefit and overall survival (OS) in uncontrolled studies. 21,22,23,24 In a clinical trial using tremelimumab, another humanized anti-CTLA-4, increased levels of memory and activated T cells were reported in 3 out of 12 patients achieving disease control (DC). 25 Several reports demonstrate immunological changes under ipilimumab therapy, shedding light on in vivo mechanisms of anti-CTLA-4, but their pertinence to predict clinical responses and OS remains to be clarified.…”

Section: Introductionmentioning

confidence: 99%

Ipilimumab reshapes T cell memory subsets in melanoma patients with clinical response

et al. 2016

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Purpose: Therapy targeting CTLA-4 immune checkpoint provides increased survival in patients with advanced melanoma. However, immunotherapy is frequently associated with delayed and heterogeneous clinical responses and it is important to identify prognostic immunological correlates of clinical endpoints. Experimental design: 77 patients with stage III/IV melanoma were treated with ipilimumab alone every 3 weeks, during 9 weeks. Blood samples were collected at the baseline and before each dose for in depth immune monitoring. Results: The median follow-up was 28 mo with a median survival of 7 mo. Survival and clinical benefit were significantly improved when absolute lymphocyte count at the baseline was above 1 £ 10 9 /L. Notably, ipilimumab had a global effect on memory T cells, with an early increase of central and effector subsets in patients with disease control. By contrast, percentages of stem cell memory T cells (TSCM) gradually decreased despite stable absolute counts and sustained proliferation, suggesting a process of differentiation. Higher proportions of eomes C and Ki-67 C T cells were observed, with enhanced skin homing potential and induction of cytotoxic markers. Conclusion: These results suggest that CTLA-4 blockade is able to reshape the memory subset with the potential involvement of Eomes and memory subsets including TSCM.

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Experience in daily practice with ipilimumab for the treatment of patients with metastatic melanoma: an early increase in lymphocyte and eosinophil counts is associated with improved survival

Abstract: Ipilimumab toxic effect is manageable in real life. Biological data such as lymphocyte and eosinophil counts at the time of the second ipilimumab infusion appear to be early markers associated with better OS.

Cited by 288 publications

References 21 publications

Factors affecting disease-free survival in patients with human epidermal growth factor receptor 2-positive breast cancer who receive adjuvant trastuzumab

Factors affecting disease-free survival in patients with human epidermal growth factor receptor 2-positive breast cancer who receive adjuvant trastuzumab

Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25

Ipilimumab reshapes T cell memory subsets in melanoma patients with clinical response

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