A Brief Communication on Circulating PD-1-positive T-Regulatory Lymphocytes in Melanoma Patients Undergoing Adjuvant Immunotherapy With Nivolumab

Gambichler, Thilo; Schröter, Ulrike; Höxtermann, Stefan; Susok, Laura; Stockfleth, Eggert; Becker, Jürgen C.

doi:10.1097/cji.0000000000000277

Cited by 11 publications

(13 citation statements)

References 11 publications

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“…We can only speculate that the assessment of a larger study sample would have resulted in other findings, possibly identifying a high baseline frequency of PD‐1 + Tregs as a significant predictor for more favourable outcome. Notably, we recently also studied the early effect of adjuvant nivolumab on circulating Treg subpopulations in patients with stage III melanoma . In line with the present study, circulating PD‐1 + Tregs significantly decreased after the first cycle of immunotherapy and maintained that decrease during a 3‐month course of treatment.…”

Section: Discussionsupporting

confidence: 89%

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Decline of programmed death‐1‐positive circulating T regulatory cells predicts more favourable clinical outcome of patients with melanoma under immune checkpoint blockade

et al. 2019

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Background The role of T regulatory lymphocytes (Tregs) and their immunosuppressive mechanisms in the context of programmed death (PD)-1 blockade is not completely understood. Objectives To assess the impact of PD-1-blocking antibody treatment on Treg subpopulations in the blood. Methods We studied circulating Treg subpopulations in patients with melanoma under nivolumab or pembrolizumab treatment using flow cytometry and correlated these findings with clinical outcomes. Results These analyses revealed that the frequency of CD4 + CD25 ++ CD127 À PD-1 + lymphocytes (PD-1 + Tregs) significantly decreased after the first cycle of immunotherapy (23% vs. 8Á6%, P = 0Á043). Compared with patients who did not show a significant decline of PD-1 + Tregs after the first treatment, those who did had better clinical outcomes with respect to progression-free survival (PFS, P = 0Á022) and melanoma-specific death (MSD, P = 0Á0038). Multivariate analysis confirmed that a significant decline of PD-1 + Tregs in peripheral blood after the first treatment cycle is a significant predictor of more favourable PFS and MSD (P = 0Á04 and 0Á017, respectively). Interestingly, the occurrence of immune-related adverse events was also an independent predictor for decreased risk of MSD (P = 0Á047; odds ratio 0Á064, 95% confidence interval 0Á0042-0Á97). Conclusions We provide preliminary evidence that circulating PD-1 + Tregs rapidly decline after the initiation of treatment with PD-1-blocking antibodies, which is associated with reduced risk of melanoma progression and MSD. Patients showing no decrease of these PD-1 + Tregs in peripheral blood are characterized by an impaired response to immune checkpoint blockade and worse outcome.What's already known about this topic?• Programmed death (PD)-1-blocking antibodies are highly effective in melanoma treatment.• However, more than half of patients do not benefit from this therapy and to date it is difficult to predict which patients will respond to it.What does this study add?• PD-1-blocking antibody therapy rapidly results in a decline of circulating PD-1 + T regulatory cells (Tregs).

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Section: Discussionsupporting

confidence: 89%

“…By contrast, CTLA‐4 + Tregs significantly increased after the first nivolumab dose compared with CTLA‐4 + Tregs before the second treatment. Blood levels of PD‐1 + Tregs and CTLA‐4 + Tregs remained more or less decreased or increased during a 3‐month course of therapy with nivolumab, respectively …”

Section: Discussionmentioning

confidence: 96%

Decline of programmed death‐1‐positive circulating T regulatory cells predicts more favourable clinical outcome of patients with melanoma under immune checkpoint blockade

et al. 2019

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“…This case provided us with an insight that compared with the intravenous pembrolizumab monotherapy, CATAP therapy might be able to tilt the body's immune balance toward enhanced anticancer immune response. This effect might also be reflected by the results on increased NK cells and decreased Tregs in peripheral blood after single cycle of treatment in the combined stage, as both increased NK cells [25,26] and decreased Tregs [27,28] had been reported to correlate with favorable response of immunotherapy in melanoma. 1 3 Although no significant correlations between clinical factors and treatment response were identified, all responders had intrahepatic tumors with maximal diameter less than 5 cm, indicating intrahepatic tumor size could be a potential predictor of response for CATAP therapy.…”

Section: Discussionmentioning

confidence: 94%

Cryoablation combined with transarterial infusion of pembrolizumab (CATAP) for liver metastases of melanoma: an ambispective, proof-of-concept cohort study

Shen

Chen

et al. 2020

Cancer Immunol Immunother

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Background The presence of liver metastasis correlates with poor therapeutic response of PD-1 blockade therapy in melanoma. A novel treatment protocol by combining cryoablation with transarterial infusion of pembrolizumab (CATAP) was proposed, and its feasibility and safety was assessed among this group of patients. Methods This registered ambispective cohort study enrolled fifteen melanoma patients with multiple hepatic metastases who received planned two-stage CATAP therapy: in the combined stage, subtotal cryoablation on day 1, in which one to two intrahepatic lesions were ablated completely with other lesions left untreated, sequentially combined transarterial infusion of pembrolizumab on day 3, every three weeks, for at least one cycle; in the infusion stage, arterial infusion of pembrolizumab was recommended at three-week interval until disease progression. The primary endpoint was objective response rate by RECIST (version 1.1); secondary end points included progression-free survival (PFS) and safety; exploratory endpoints were changes of cytokines and immune cell compositions in peripheral blood samples. Results Of the 15 patients enrolled, no grade 3-4 adverse events or major complications were observed. One patient (6.7%) achieved complete response, and 3 (20.0%) achieved partial response. The overall response rates of CATAP for the entire cohort and patients with cutaneous melanoma were 26.7% (95% confidence interval (CI) 4.3-49.0%) and 33.3% (95% CI 2.5-64.1%), respectively. Clinical response was observed in a proportion of patients (2/6; 33.3%) who failed first-line intravenous pembrolizumab treatment. The median overall PFS time and hepatic PFS time were 4.0 (95% CI 2.5-5.5) and 5.73 (95% CI 1.1-10.4) months, respectively. A significant increase in CD3-CD16 + CD56 + cells (natural killer cells; P = 0.0124) and a marginally significant decrease in CD4 + CD25 + cells (regulatory T cells; P = 0.0546) were observed three weeks after the first cycle of treatment in the combined stage. Conclusions The CATAP therapy demonstrated positive clinical activity and a favorable safety profile for melanoma patients with liver metastasis.

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“…For example, decreased circulating PD1 + Tregs could offer a predictive marker for favorable clinical outcomes from anti-PD1 Abs in advanced melanoma [50]. Moreover, in another report, nivolumab monotherapy in an adjuvant setting decreased circulating PD1 + Tregs in stage III melanoma patients [51].…”

Section: Tregs and Icis: Anti-pd1 Abs And Anti-ctla4 Absmentioning

confidence: 97%

“…Moreover, eTregs produce inhibitory cytokines (TGF-b, IL-10, IL-35) to promote B lymphocyte-induced maturation protein (BLIMP1)-dependent exhaustion of CD8 + TILs in the tumor microenvironments of B16 melanoma and the BrafPten melanoma model [49]. In addition to being a therapeutic target, PD1 + Tregs are also a useful diagnostic target for anti-PD1 Ab monotherapy [50][51][52]. For example, decreased circulating PD1 + Tregs could offer a predictive marker for favorable clinical outcomes from anti-PD1 Abs in advanced melanoma [50].…”

Section: Tregs and Icis: Anti-pd1 Abs And Anti-ctla4 Absmentioning

confidence: 99%

Significance of Immunosuppressive Cells as a Target for Immunotherapies in Melanoma and Non-Melanoma Skin Cancers

Fujimura

Aiba

2020

Biomolecules

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Tumor-associated macrophages (TAMs) have been detected in most skin cancers. TAMs produce various chemokines and angiogenic factors that promote tumor development, along with other immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and tumor-associated neutrophils. TAMs generated from monocytes develop into functional, fully activated macrophages, and TAMs obtain various immunosuppressive functions to maintain the tumor microenvironment. Since TAMs express PD1 to maintain the immunosuppressive M2 phenotype by PD1/PD-L1 signaling from tumor cells, and the blockade of PD1/PD-L1 signaling by anti-PD1 antibodies (Abs) activate and re-polarize TAMs into immunoreactive M1 phenotypes, TAMs represent a potential target for anti-PD1 Abs. The main population of TAMs comprises CD163+ M2 macrophages, and CD163+ TAMs release soluble (s)CD163 and several proinflammatory chemokines (CXCL5, CXCL10, CCL19, etc.) as a result of TAM activation to induce an immunosuppressive tumor microenvironment together with other immunosuppressive cells. Since direct blockade of PD1/PD-L1 signaling between tumor cells and tumor-infiltrating T cells (both effector T cells and Tregs) is mandatory for inducing an anti-immune response by anti-PD1 Abs, anti-PD1 Abs need to reach the tumor microenvironment to induce anti-immune responses in the tumor-bearing host. Taken together, TAM-related factors could offer a biomarker for anti-PD1 Ab-based immunotherapy. Understanding the crosstalk between TAMs and immunosuppressive cells is important for optimizing PD1 Ab-based immunotherapy.

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A Brief Communication on Circulating PD-1-positive T-Regulatory Lymphocytes in Melanoma Patients Undergoing Adjuvant Immunotherapy With Nivolumab

Cited by 11 publications

References 11 publications

Decline of programmed death‐1‐positive circulating T regulatory cells predicts more favourable clinical outcome of patients with melanoma under immune checkpoint blockade

Decline of programmed death‐1‐positive circulating T regulatory cells predicts more favourable clinical outcome of patients with melanoma under immune checkpoint blockade

Cryoablation combined with transarterial infusion of pembrolizumab (CATAP) for liver metastases of melanoma: an ambispective, proof-of-concept cohort study

Significance of Immunosuppressive Cells as a Target for Immunotherapies in Melanoma and Non-Melanoma Skin Cancers

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