Dynamical Systems Modeling of Early-Term Immune Reconstitution with Different Antithymocyte Globulin Administration Schedules in Allogeneic Stem Cell Transplantation

Zelikson, Viktoriya; Simmons, Gary; Raman, Natasha; Krieger, Elizabeth; Rebiero, Anatevka; Hawks, Kelly G.; Aziz, May; Roberts, Catherine; Chesney, Alden; Reed, Jason; Gress, Ronald E.; Toor, Amir A.

doi:10.1016/j.jtct.2021.10.012

Cited by 7 publications

(10 citation statements)

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“…9 Previous work has demonstrated that immune reconstitution following HCT has characteristics of a dynamical system; systems that may be modelled with mathematical precision. [10][11][12] In these studies, lymphocyte and T-cell recovery post-transplant was modelled utilising equations of growth, where cell proliferation occurs as a logistic function of time. This entails, a period of slow initial growth, followed by an exponential proliferation of the immune cell populations with a final steady state being reached with stable counts in the absence of events, such as infections, GVHD or chemotherapy, which would trigger either renewed growth or decline in cell counts.…”

Section: Introductionmentioning

confidence: 99%

“…The central role of immune recovery, particularly that of T‐cells, in transplant immunobiology has been established through observations such as, relapse prevention in patients with GVHD, 7 relapse treatment with donor lymphocyte infusions 8 and establishment of engraftment with nonmyeloablative conditioning 9 . Previous work has demonstrated that immune reconstitution following HCT has characteristics of a dynamical system; systems that may be modelled with mathematical precision 10–12 . In these studies, lymphocyte and T‐cell recovery post‐transplant was modelled utilising equations of growth, where cell proliferation occurs as a logistic function of time.…”

Section: Introductionmentioning

confidence: 99%

“…However, ATG administration delays T‐cell recovery, especially CD4 + helper T‐cell reconstitution 23–25 and may impact relapse and viral infection risk. The timing of administration of ATG for in vivo T‐cell depletion alters the dynamics of T‐cell recovery post‐transplant and allows superior T‐cell recovery if given early in the conditioning regimen 11,26 . Furthermore, given the dynamical systems nature of immune recovery, T‐cell reconstitution may be further enhanced by adjustment in the early post‐transplant immune milieu, such as intensity of immune suppression and myeloid populations recovering post‐transplant.…”

Section: Introductionmentioning

confidence: 99%

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Allogeneic haematopoietic cell transplants as dynamical systems: influence of early‐term immune milieu on long‐term T‐cell recovery

et al. 2023

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Objectives Immune recovery following haematopoietic cell transplantation (HCT) functions as a dynamical system. Reducing the duration of intense immune suppression and augmenting antigen presentation has the potential to optimise T‐cell reconstitution, potentially influencing long‐term outcomes. Methods Based on donor‐derived T‐cell recovery, 26 patients were adaptively randomised between mycophenolate mofetil (MMF) administered for 30‐day post‐transplant with filgrastim for cytokine support (MMF30 arm, N = 11), or MMF given for 15 days with sargramostim (MMF15 arm, N = 15). All patients underwent in vivo T‐cell depletion with 5.1 mg kg−1 antithymocyte globulin (administered over 3 days, Day −9 through to Day −7) and received reduced intensity 450 cGy total body irradiation (3 fractions on Day −1 and Day 0). Patients underwent HLA‐matched related and unrelated donor haematopoietic cell transplantation (HCT). Results Clinical outcomes were equivalent between the two groups. The MMF15 arm demonstrated superior T‐cell, as well as T‐cell subset recovery and a trend towards superior T‐cell receptor (TCR) diversity in the first month with this difference persisting through the first year. T‐cell repertoire recovery was more rapid and sustained, as well as more diverse in the MMF15 arm. Conclusion The long‐term superior immune recovery in the MMF15 arm, administered GMCSF, is consistent with a disproportionate impact of early interventions in HCT. Modifying the ‘immune‐milieu’ following allogeneic HCT is feasible and may influence long‐term T‐cell recovery.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Allogeneic haematopoietic cell transplants as dynamical systems: influence of early‐term immune milieu on long‐term T‐cell recovery

et al. 2023

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“…Previous work has demonstrated that immune reconstitution following HCT has many characteristics of a dynamical system; systems which may be modelled with mathematical precision. 7 8 As an example, T cell recovery post-transplant may be modelled utilizing equations of growth, where cell proliferation occurs as a logistic function of time. Furthermore, in an antigen affinity driven logistic expansion model of individual T cell clonal growth, Power law distribution of the T cell clonal frequencies is observed.…”

Section: Introductionmentioning

confidence: 99%

“…The timing of administration of ATG for in vivo T cell depletion alters the dynamics of T cell recovery post-transplant and allows superior T cell recovery if given early in the conditioning regimen. 8 20 Further, given the dynamical systems nature of immune recovery, the T cell reconstitution may be further enhanced by adjustment in post-transplant immune suppression.…”

Section: Introductionmentioning

confidence: 99%

Allogeneic Hematopoietic Cell Transplants as Dynamical Systems: Effect of Early-Term Immune Suppression Intensity on Long-Term T Cell Recovery

Zelikson

Sabo

Serrano

et al. 2022

Preprint

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Reduced intensity conditioning (RIC) is fraught with risk for disease relapse. This may be overcome by donor T cell alloreactivity. Reducing the duration of intense immune suppression in the early term following transplantation may create an immunologic environment favoring rapid T cell reconstitution to influence longer term transplant outcomes. Twenty-six patients were adaptively randomized based on donor-derived T cell recovery, between 2 different dosing schedules of mycophenolate mofetil (MMF): MMF for 30 days post-transplant, with filgrastim for cytokine support (MMF30 arm, 11 patients), or MMF for 15 days post-transplant, with sargramostim (MMF15 arm, 15 patients). All patients were treated with anti-thymocyte globulin at a dose of 1.7 mg/kg/day from day - 9 through day -7 and total body irradiation, 450 cGy given in 3 fractions. Patients were well matched between the study arms and underwent HLA matched related and unrelated donor hematopoietic cell transplantation (HCT). The MMF15 arm demonstrated superior T cell recovery in the first month. This difference persisted through the first year for total T cells, T cell subsets and NK cells. T cell repertoire tended to be more diverse in the MMF15 arm. The long term superior immune recovery in the MMF15 arm is consistent with a disproportionate impact of early interventions in HCT. Clinically, shorter course MMF post-transplant was not associated with increased risk of acute or chronic graft vs. host disease (GVHD), and relapse and there was a trend toward improved overall survival in the MMF15 arm. Reducing the duration of intense immunosuppression in the early term and the use of sargramostim following allogeneic HCT is feasible and leads to superior long-term T cell recovery. This regimen should be studied to improve immune recovery in large cohorts of patients undergoing HCT with RIC.

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Graft CD8 T‐cell‐based risk system predicts survival in antithymocyte globulin‐based myeloablative haploidentical peripheral blood stem cell transplantation

Zhu,

Yang,

et al. 2024

Clin & Trans Imm

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ObjectiveThis study investigated the cellular composition of peripheral blood grafts for anti‐thymocyte globulin (ATG)‐based myeloablative haploidentical haematopoietic stem cell transplantation (haplo‐HSCT).MethodsClinical characteristics were retrospectively evaluated in a training cohort with ATG‐based myeloablative haplo‐HSCT between January 2016 and February 2020 and confirmed in a validation cohort between March 2020 and June 2021.ResultsA higher dose of graft CD8+ T cells (≥ 0.85 × 108 kg−1) was significantly improved overall survival (OS; hazard ratio [HR], 1.750; P = 0.002) and disease‐free survival (DFS; HR, 1.751; P < 0.001) in the training cohort, according to multivariate Cox regression analysis. Higher doses of mononuclear cells (MNCs) demonstrated better OS (HR, 1.517; P = 0.038) and DFS (HR, 1.532; P = 0.027). Older patient age (> 46 years), older donor age (≥ 50 years) and a higher refined disease risk index (rDRI) were also related to OS. A graft CD8+ T‐cell risk system based on graft CD8+ T‐cell dose, donor age and rDRI was constructed using a nomogram model after LASSO Cox regression analysis. It showed acceptable discrimination, with a C‐index of 0.62 and 0.63, respectively. Graft CD8+ T‐cell dose was negatively correlated with donor age (P < 0.001) and positively correlated with a higher lymphocyte percentage in the peripheral blood before mobilisation (P < 0.001).ConclusionA higher CD8+ T‐cell dose in peripheral blood‐derived grafts improves patients' survival with ATG‐based myeloablative haplo‐HSCT. Younger donors with higher lymphocyte percentages improved patients' survival with an intermediate rDRI risk.

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Dynamical Systems Modeling of Early-Term Immune Reconstitution with Different Antithymocyte Globulin Administration Schedules in Allogeneic Stem Cell Transplantation

Cited by 7 publications

References 24 publications

Allogeneic haematopoietic cell transplants as dynamical systems: influence of early‐term immune milieu on long‐term T‐cell recovery

Allogeneic haematopoietic cell transplants as dynamical systems: influence of early‐term immune milieu on long‐term T‐cell recovery

Allogeneic Hematopoietic Cell Transplants as Dynamical Systems: Effect of Early-Term Immune Suppression Intensity on Long-Term T Cell Recovery

Graft CD8 T‐cell‐based risk system predicts survival in antithymocyte globulin‐based myeloablative haploidentical peripheral blood stem cell transplantation

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