Post-transplant cyclophosphamide alters immune signatures and leads to impaired T cell reconstitution in allogeneic hematopoietic stem cell transplant

Zhao, Chenchen; Bartock, Matthew; Jia, Bei; Shah, Neal; Claxton, David F.; Wirk, Baldeep; Rakszawski, Kevin; Nickolich, Myles; Naik, Seema; Rybka, Witold B.; Ehmann, W Christopher C.; Hohl, Raymond J.; Valentin, Jessica; Bernas-Peterson, Michelle; Gerber, Emily M.; Zimmerman, Michele L.; Mierski, Joseph; Mineishi, Shin; Zheng, Hong

doi:10.1186/s13045-022-01287-3

Cited by 32 publications

(22 citation statements)

References 13 publications

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“…The use of post-transplant CY, combined with calcineurin inhibitors and/or other immunomodulatory agents has become the standard of care for GvHD prophylaxis in haplo-HCT and has seen increasing use in other types of allo-HCT. However, as viral reactivation due to delayed immune reconstitution and relapse often lead to morbidity and mortality of patients (3,6,(28)(29)(30), some investigators have begun evaluating a reduction in the dose of post-transplant CY to limit these complications (8,10,11). Our laboratory has taken a different approach in evaluating whether partially replacing PT-CY with posttransplant bendamustine (PT-BEN) would be advantageous, which is based on our extensive research that has delineated several immunomodulatory properties of BEN on myeloid derived suppressive cells (MDSCs) and dendritic cell (DC) subsets (14)(15)(16).…”

Section: Discussionmentioning

confidence: 99%

Partially replacing cyclophosphamide with bendamustine in combination with cyclosporine A improves survival and reduces xenogeneic graft-versus-host-disease

Gilman

Cracchiolo²,

Matiatos³

et al. 2023

Front. Immunol.

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IntroductionThe use of allogeneic hematopoietic cell transplantation (allo-HCT) for treating hematological disorders is increasing, but the development of graft-versus-host disease (GvHD) remains a major cause of morbidity and mortality. The use of post-transplant cyclophosphamide (CY) has significantly improved outcomes following allo-HCT, but complications of viral reactivation due to delayed immune reconstitution or relapse remain. Other laboratories are evaluating the potential benefit of lowering the dose of CY given post-transplant, whereas our laboratory has been focusing on whether partially replacing CY with another DNA alkylating agent, bendamustine (BEN) may be advantageous in improving outcomes with allo-HCT.MethodsHere, we utilized a xenogeneic GvHD (xGvHD) model in which immunodeficient NSG mice are infused with human peripheral blood mononuclear cells (PBMCs).ResultsWe show that a lower dose of CY (25 mg/kg) given on days +3 and +4 or CY (75 mg/kg) given on only day +3 post-PBMC infusion is not sufficient for improving survival from xGvHD, but can be improved with the addition of BEN (15 mg/kg) on day +4 to day +3 CY (75 mg/kg). CY/BEN treated mice when combined with cyclosporine A (CSA) (10mg/kg daily from days +5 to +18 and thrice weekly thereafter), had improved outcomes over CY/CY +CSA treated mice. Infiltration of GvHD target organs was reduced in both CY/CY and CY/BEN treatment groups versus those receiving no treatment. CY/CY +CSA mice exhibited more severe xGvHD at day 10, marked by decreased serum albumin and increased intestinal permeability. CY/BEN treated mice had reductions in naïve, effector memory and Th17 polarized T cells. RNAseq analysis of splenocytes isolated from CY/CY and CY/BEN treated animals revealed increased gene set enrichment in multiple KEGG pathways related to cell migration, proliferation/differentiation, and inflammatory pathways, among others with CY/BEN treatment.ConclusionTogether, we illustrate that the use of CY/BEN is safe and shows similar control of xGvHD to CY/CY, but when combined with CSA, survival with CY/BEN is significantly prolonged compared to CY/CY.

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Section: Discussionmentioning

confidence: 99%

Partially replacing cyclophosphamide with bendamustine in combination with cyclosporine A improves survival and reduces xenogeneic graft-versus-host-disease

Gilman

Cracchiolo²,

Matiatos³

et al. 2023

Front. Immunol.

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“…This applies to CTX, which primarily impairs the proliferation of peripheral T cells and hinders their effector functions. In addition, post-transplant CTX alters immune signatures and leads to impaired T cell reconstitution in allogeneic hematopoietic stem cell transplant by increasing Treg while reducing naïve T cells ( Zhao et al, 2022 ). Current research suggests that the number and function of immune-infiltrating effector cells are closely related to the efficacy and prognosis ( Denkert et al, 2018 ; Paijens et al, 2021 ); similarly, the depletion of non-targeted immune cells affects the anti-tumor effect of chemotherapy.…”

Section: Immuno-adjuvant Effects Of Chemotherapeutic Agentsmentioning

confidence: 99%

Combinatorial regimens of chemotherapeutic agents: A new perspective on raising the heat of the tumor immune microenvironment

Liu

Gao

et al. 2022

Front. Pharmacol.

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Harnessing the broad immunostimulatory capabilities of chemotherapy in combination with immune checkpoint inhibitors has improved immunotherapy outcomes in patients with cancer. Certain chemotherapeutic agents can extensively modify the tumor microenvironment (TME), resulting in the reprogramming of local immune responses. Although chemotherapeutic agents with an enhanced generation of potent anti-tumor immune responses have been tested in preclinical animal models and clinical trials, this strategy has not yet shown substantial therapeutic efficacy in selected difficult-to-treat cancer types. In addition, the efficacy of chemotherapeutic agent-based monotherapy in eliciting a long-term anti-tumor immune response is restricted by the immunosuppressive TME. To enhance the immunomodulatory effect of chemotherapy, researchers have made many attempts, mainly focusing on improving the targeted distribution of chemotherapeutic agents and designing combination therapies. Here, we focused on the mechanisms of the anti-tumor immune response to chemotherapeutic agents and enumerated the attempts to advance the use of chemo-immunotherapy. Furthermore, we have listed the important considerations in designing combinations of these drugs to maximize efficacy and improve treatment response rates in patients with cancer.

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“…Infections post transplant influence the TCR diversity due to an increase in antigen-specific TCRs [30,31]. GvHD prophylaxis requires immunosupressive therapies that influence the TCR repertoire, by depleting T cells [7,8]. Conditioning regiment involving chemotherapy and radiotherapy leads to the damage of the thymus.…”

Section: G V H D P R O P H Y La X Ismentioning

confidence: 99%

“…1 can affect the TCR repertoire and thus the TCR diversity post allo-SCT and in GvHD. The donor-recipient compatibility, age of the patient, immunosuppressive therapies as part of GvHD prophylaxis, previous damage to thymus by conditioning regimen are few of the several factors contributing to the dynamics of T cell regeneration and repertoire post allo-SCT [7][8][9][10][11][38][39][40]. Additionally, conflicting results of TCR diversity could result from differences in the allowed HLA mismatches, which may not have been considered during analysis.…”

Section: Tcr Diversity In Peripheral Repertoires Of Patients Affected...mentioning

confidence: 99%

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Potential of TCR sequencing in graft-versus-host disease

Goel

Eugster

Schetelig

et al. 2022

Bone Marrow Transplant

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Graft-versus-host disease (GvHD) remains one of the major complications following allogeneic haematopoietic stem cell transplantation (allo-HSCT). GvHD can occur in almost every tissue, with the skin, liver, and intestines being the mainly affected organs. T cells are implicated in initiating GvHD. T cells identify a broad range of antigens and mediate the immune response through receptors on their surfaces (T cell receptors, TCRs). The composition of TCRs within a T cell population defines the TCR repertoire of an individual, and this repertoire represents exposure to self and non-self proteins. Monitoring the changes in the TCR repertoire using TCR sequencing can provide an indication of the dynamics of a T cell population. Monitoring the frequency and specificities of specific TCR clonotypes longitudinally in different conditions and specimens (peripheral blood, GvHD-affected tissue samples) can provide insights into factors modulating immune reactions following allogeneic transplantation and will help to understand the underlying mechanisms mediating GvHD. This review provides insights into current studies of the TCR repertoire in GvHD and potential future clinical implications of TCR sequencing.

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Post-transplant cyclophosphamide alters immune signatures and leads to impaired T cell reconstitution in allogeneic hematopoietic stem cell transplant

Cited by 32 publications

References 13 publications

Partially replacing cyclophosphamide with bendamustine in combination with cyclosporine A improves survival and reduces xenogeneic graft-versus-host-disease

Partially replacing cyclophosphamide with bendamustine in combination with cyclosporine A improves survival and reduces xenogeneic graft-versus-host-disease

Combinatorial regimens of chemotherapeutic agents: A new perspective on raising the heat of the tumor immune microenvironment

Potential of TCR sequencing in graft-versus-host disease

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