Pretransplant nivolumab further enhanced Treg expansion after posttransplant cyclophosphamide; another aspect for immune tolerance by PTCy after nivolumab

Ikegawa, Shuntaro; Meguri, Yusuke; Mizuhara, Kentaro; Fukumi, Takuya; Kobayashi, Hiroki; Sumii, Yuichi; Kondo, Takumi; Sando, Yasuhisa; Iwamoto, Miki; Asada, Noboru; Ennishi, Daisuke; Nishimori, Hisakazu; Fujii, Keiko; Fujii, Nobuharu; Fujisawa, Yuka; Imai, Tamaki; Maeda, Yoshinobu; Matsuoka, Ken

doi:10.1038/s41375-021-01167-8

Cited by 6 publications

(5 citation statements)

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“… 38 , 39 The PTCy leads to milder GVHD by abrogating the CPI induced immune activation 40 and promoting the vigorous recovery of regulatory T‐cells leading to immune tolerance. 41 In a recently published “real‐world” analysis of cHL patients who underwent allo‐HCT after CPI treatments, those who received Haplo/PTCy had a lower cumulative incidence of relapse (2‐year CIR = 7%) and excellent OS (2‐year OS = 85%). 42 We had only three patients in era2 who received haplo‐HCT, compared to none in era1, a number which we expect will increase in the future.…”

Section: Discussionmentioning

confidence: 99%

“…The utility of haplo‐HCT has increased in the last decade with PTCy (Haplo/PTCy) for GVHD prophylaxis 38,39 . The PTCy leads to milder GVHD by abrogating the CPI induced immune activation 40 and promoting the vigorous recovery of regulatory T‐cells leading to immune tolerance 41 . In a recently published “real‐world” analysis of cHL patients who underwent allo‐HCT after CPI treatments, those who received Haplo/PTCy had a lower cumulative incidence of relapse (2‐year CIR = 7%) and excellent OS (2‐year OS = 85%) 42 .…”

Section: Discussionmentioning

confidence: 99%

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Outcomes associated with allogeneic hematopoietic stem cell transplantation for relapsed and refractory Hodgkin lymphoma in the era of novel agents

et al. 2023

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Background Relapsed or refractory Hodgkin lymphoma (R/R HL) is a challenging disease with limited treatment options beyond brentuximab vedotin and checkpoint inhibitors. Herein we present the time‐trend analysis of R/R HL patients who received allogeneic hematopoietic cell transplantation (allo‐HCT) at our center from 2001–2017. Methods The patients were divided into two distinct treatment cohorts: era1 (2001–2010), and era2 (2011–2017). The primary endpoint was overall survival (OS). Secondary endpoints included progression‐free survival (PFS), non‐relapse mortality (NRM), and cumulative incidence of acute and chronic graft versus host disease (GVHD). Results Among the 51 patients included in the study, 29 were in era1, and 22 were in era2. There was decreased use of myeloablative conditioning in era2 (18% vs. 31%) compared to era1 and 95% of patients in era2 previously received brentuximab Vedotin (BV). Haploidentical donors were seen exclusively in era2 (0% vs. 14%) and more patients received alternative donor transplants (7% vs. 32%) in era2. The 4‐year OS (34% vs. 83%, p < 0.001) and 4‐year PFS (28% vs. 62%, p = 0.001) were significantly inferior in era1 compared to era2. The incidence of 1‐year NRM was lower in era2 compared to era1 (5% vs. 34%, p = 0.06). The cumulative incidence of acute GVHD at day 100 was similar in both eras (p = 0.50), but the incidence of chronic GVHD at 1 year was higher in era2 compared to era1 (55% vs. 21%, p = 0.03). Conclusions Despite the advent of novel therapies, allo‐HCT remains an important therapeutic option for patients with R/R HL.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Outcomes associated with allogeneic hematopoietic stem cell transplantation for relapsed and refractory Hodgkin lymphoma in the era of novel agents

et al. 2023

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“…To further build on this data set, Ikegawa et al., took a closer look into Treg numbers and phenotype in an exploratory study pre- and post-transplant with cyclophosphamide treatment. Their study demonstrated that cyclophosphamide treatment helps with the control of T effector cells and robust recovery of Tregs in the presence of pre-treatment with Nivolumab ( 338 ).…”

Section: Clinical Insights: Learnings From Approved Therapeutics and ...mentioning

confidence: 99%

In or out of control: Modulating regulatory T cell homeostasis and function with immune checkpoint pathways

2022

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Regulatory T cells (Tregs) are the master regulators of immunity and they have been implicated in different disease states such as infection, autoimmunity and cancer. Since their discovery, many studies have focused on understanding Treg development, differentiation, and function. While there are many players in the generation and function of truly suppressive Tregs, the role of checkpoint pathways in these processes have been studied extensively. In this paper, we systematically review the role of different checkpoint pathways in Treg homeostasis and function. We describe how co-stimulatory and co-inhibitory pathways modulate Treg homeostasis and function and highlight data from mouse and human studies. Multiple checkpoint pathways are being targeted in cancer and autoimmunity; therefore, we share insights from the clinic and discuss the effect of experimental and approved therapeutics on Treg biology.

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“…Based on fundamental data from a murine study, we examined clinical samples from patients who underwent HSCT. The clinical sample analyses revealed that PTCy promoted vigorous recovery of Tregs in recipients who underwent HLA-haploidentical transplantation following nivolumab therapy ( 87 ). These results suggest that PD-1 plays a crucial role in Treg homeostasis, especially in the early phase after HSCT.…”

Section: Effects Of Immune-checkpoint Inhibitors On Treg Homeostasismentioning

confidence: 99%

Harnessing Treg Homeostasis to Optimize Posttransplant Immunity: Current Concepts and Future Perspectives

Ikegawa

Matsuoka

2021

Front. Immunol.

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CD4+CD25+Foxp3+ regulatory T cells (Tregs) are functionally distinct subsets of mature T cells with broad suppressive activity and have been shown to play an important role in the establishment of immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT). Tregs exhibit an activated phenotype from the stage of emigration from the thymus and maintain continuous proliferation in the periphery. The distinctive feature in homeostasis enables Tregs to respond sensitively to small environmental changes and exert necessary and sufficient immune suppression; however, on the other hand, it also predisposes Tregs to be susceptible to apoptosis in the inflammatory condition post-transplant. Our studies have attempted to define the intrinsic and extrinsic factors affecting Treg homeostasis from the acute to chronic phases after allogeneic HSCT. We have found that altered cytokine environment in the prolonged post-HSCT lymphopenia or peri-transplant use of immune checkpoint inhibitors could hamper Treg reconstitution, leading to refractory graft-versus-host disease. Using murine models and clinical trials, we have also demonstrated that proper intervention with low-dose interleukin-2 or post-transplant cyclophosphamide could restore Treg homeostasis and further amplify the suppressive function after HSCT. The purpose of this review is to reconsider the distinctive characteristics of post-transplant Treg homeostasis and discuss how to harness Treg homeostasis to optimize posttransplant immunity for developing a safe and efficient therapeutic strategy.

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Pretransplant nivolumab further enhanced Treg expansion after posttransplant cyclophosphamide; another aspect for immune tolerance by PTCy after nivolumab

Cited by 6 publications

References 8 publications

Outcomes associated with allogeneic hematopoietic stem cell transplantation for relapsed and refractory Hodgkin lymphoma in the era of novel agents

Outcomes associated with allogeneic hematopoietic stem cell transplantation for relapsed and refractory Hodgkin lymphoma in the era of novel agents

In or out of control: Modulating regulatory T cell homeostasis and function with immune checkpoint pathways

Harnessing Treg Homeostasis to Optimize Posttransplant Immunity: Current Concepts and Future Perspectives

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