Immunological and biological changes during ipilimumab treatment and their potential correlation with clinical response and survival in patients with advanced melanoma

Simeone, Ester; Gentilcore, Giusy; Giannarelli, Diana; Grimaldi, Antonio; Caracò, Corrado; Curvietto, Marcello; Esposito, Assunta; Paone, Miriam; Palla, Marco; Cavalcanti, Ernesta; Sandomenico, Fabio; Petrillo, Antonella; Botti, Gerardo; Fulciniti, Franco; Palmieri, Giuseppe; Queirolo, Paola; Marchetti, Paolo; Ferraresi, Virginia; Rinaldi, Gaetana; Pistillo, Maria Pia; Ciliberto, Gennaro; Mozzillo, Nicola; Ascierto, Paolo A.

doi:10.1007/s00262-014-1545-8

Cited by 232 publications

(188 citation statements)

References 30 publications

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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%

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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“…[32][33][34] Moreover, the frequency of these cells in the circulation at baseline of cancer patients has been shown to act as a possible predictor of clinical outcome for IPI regimens. 32,35,36 Unfortunately, the limited availability of PBMCs from these patients prevented to evaluate the frequency of circulating Tregs and MDSCs in these MM patients; this analysis will be objective of future studies.…”

Section: Discussionmentioning

confidence: 99%

Immunological markers and clinical outcome of advanced melanoma patients receiving ipilimumab plus fotemustine in the NIBIT-M1 study

Maccalli

Giannarelli²,

Capocefalo³

et al. 2015

OncoImmunology

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Moreover, either the absence or the presence of soluble NKG2D ligands (ULBP-1 or ¡2) at baseline in the serum of MM patients enabled to discriminate subjects with long-term survival (median overall survival, (OS) D 33.6 mo for ULBP-1 and ¡2) from poor survivors (OS D 9.8 or 6.6 mo, respectively). Conversely, no significant association between the levels of soluble MICA, MICB and ULBP-3 and the clinical outcome of patients was observed. An inverse correlation between circulating levels of these molecules at baseline and frequency of either CD3 C CD4 C CD45RO C BTLA C or Th17 or CD3 C CD4 C 4-1BB C T cells occurred in patients with a favorable clinical outcome. The simultaneous monitoring of different immune parameters, though validation in a large cohort of patients is needed, allowed to identify an association between phenotypic and soluble markers representing a possible predictive immunological signature for the clinical activity of IPI plus FTM.

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“…3,6,8,16,17 In a study of 95 patients treated with ipilimumab, Simeone et al reported that decreased levels of lactate dehydrogenase (LDH), c-reactive protein (CRP), and circulating regulatory T cells (Treg) were all significantly associated with clinical response to ipilimumab and improved survival. 3,24 Large multicenter studies will be required to validate these tests, and others, so that care for patients with advanced melanoma can be tailored appropriately.…”

Section: 22mentioning

confidence: 99%

Ipilimumab and craniotomy in patients with melanoma and brain metastases: a case series

Jones¹,

Cahill²,

Brastianos

et al. 2015

FOC

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OBJECT In patients with large or symptomatic brain lesions from metastatic melanoma, the value of resection of metastases to facilitate administration of systemic ipilimumab therapy has not yet been described. The authors undertook this study to investigate whether craniotomy creates the opportunity for patients to receive and benefit from ipilimumab who would otherwise succumb to brain metastasis prior to the onset of regression. METHODS All patients with metastatic melanoma who received ipilimumab and underwent craniotomy for metastasis resection between 2008 and 2014 at the Massachusetts General Hospital were identified through retrospective chart review. The final analysis included cases involving patients who underwent craniotomy within 3 months prior to initiation of therapy or up to 6 months after cessation of ipilimumab administration. RESULTS Twelve patients met the inclusion criteria based on timing of therapy (median age 59.2). The median number of metastases at the time of craniotomy was 2. The median number of ipilimumab doses received was 4. Eleven of 12 courses of ipilimumab were stopped for disease progression, and 1 was stopped for treatment-induced colitis. Eight of 12 patients had improvement in their performance status following craniotomy. Of the 6 patients requiring corticosteroids prior to craniotomy, 3 tolerated corticosteroid dose reduction after surgery. Ten of 12 patients had died by the time of data collection, with 1 patient lost to follow-up. The median survival after the start of ipilimumab treatment was 7 months. CONCLUSIONS In this series, patients who underwent resection of brain metastases in temporal proximity to receiving ipilimumab had qualitatively improved performance status following surgery in most cases. Surgery facilitated corticosteroid reduction in select patients. Larger analyses are required to better understand possible synergies between craniotomy for melanoma metastases and ipilimumab treatment.

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Immunological and biological changes during ipilimumab treatment and their potential correlation with clinical response and survival in patients with advanced melanoma

Cited by 232 publications

References 30 publications

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

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

Immunological markers and clinical outcome of advanced melanoma patients receiving ipilimumab plus fotemustine in the NIBIT-M1 study

Ipilimumab and craniotomy in patients with melanoma and brain metastases: a case series

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