Adenosine Selectively Depletes Alloreactive T Cells to Prevent GVHD While Conserving Immunity to Viruses and Leukemia

Whitehill, Greg; Amarnath, Shoba; Muranski, Pawel; Keyvanfar, Keyvan; Battiwalla, Minoo; Barrett, A. John; Chinnassamy, Dhanalakshmi

doi:10.1038/mt.2016.147

Cited by 9 publications

(8 citation statements)

References 37 publications

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“…In theory, in HID‐SCT, stronger alloimmune response would be achieved by leukemic cells which express HLA mismatched from donors and result in a decrease in relapse rate. However, since little is known about the mechanisms underlying the stronger GVL effect of HID‐SCT compared to that of ISD‐SCT [27‐29], there may be some other possible reasons for the higher relapse rate in the ISD‐SCT group compared to the HID‐SCT group in the current study. First, in the present study, both groups of patients received CSA, MTX, and MMF as GVHD prophylaxis.…”

Section: Discussionmentioning

confidence: 87%

Haploidentical‐ versus identical‐sibling transplant for high‐risk pediatric AML: A multi‐center study

Zheng

Zhang

et al. 2020

Cancer Communications

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Background Human leukocyte antigen‐identical sibling donor (ISD)‐hematopoietic stem cell transplantation (SCT) is a potentially curative treatment for high‐risk pediatric acute myeloid leukemia (AML). A haploidentical donor (HID) is readily available to almost all children. Previous studies have demonstrated that patients with HID‐SCT had similar outcomes compared to ISD‐SCT for pediatric and adult AML. However, the role of HID‐SCT in high‐risk pediatric AML is unclear. Methods To compare the overall survival of high‐risk AML children who underwent either HID‐SCT or ISD‐SCT, we analyzed 179 cases of high‐risk AML patients under 18 years of age treated with either ISD‐SCT (n = 23) or HID‐SCT (n = 156). Granulocyte colony‐stimulating factor plus anti‐thymocyte globulin‐based regimens were used for HID‐SCT. We also analyzed the subgroup data of AML patients at first complete remission (CR1) before SCT with known cytogenetic risk. Results The numbers of adverse cytogenetic risk recipients were 8 (34.8%) and 13 (18.8%) in the ISD‐SCT group and the HID‐SCT group, and the number of patients with disease status beyond CR1 were 6 (26.1%) and 14 (20.3%) in the two groups. The cumulative rates of grades II‐IV acute graft‐versus‐host disease (GVHD) were 13.0% in the ISD‐SCT group and 34.8% in the HID‐SCT group (P = 0.062), with a three‐year cumulative rates of chronic GVHD at 14.1% and 34.9%, respectively (P = 0.091). The relapse rate in the ISD‐SCT group was significantly higher than that in the HID‐SCT group (39.1% vs. 16.4%, P = 0.027); with non‐relapse mortality at 0.0% and 10.6% (P = 0.113), respectively. The three‐year overall survival rates were 73.0% for the ISD‐SCT group and 74.6% for the HID‐SCT group (P = 0.689). In subgroup analysis, the three‐year relapse rate in the ISD‐SCT group was higher than that in the HID‐SCT group (50.0% vs. 9.2%, P = 0.001) and the three‐year DFS in the ISD‐SCT group (50.0%) was lower than that in the HID‐SCT group (81.2%) (P = 0.021). Conclusions Unmanipulated HID‐SCT achieved DFS and OS outcomes comparable to those of ISD‐SCT for high‐risk pediatric AML patients with potentially higher rate but manageable GVHD.

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Section: Discussionmentioning

confidence: 87%

Haploidentical‐ versus identical‐sibling transplant for high‐risk pediatric AML: A multi‐center study

Zheng

Zhang

et al. 2020

Cancer Communications

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“…We then addressed whether the treatment with Salp15 would impact the activity rather than the size of the Treg population. The ectoenzyme CD73 is expressed by Tregs and mediates the production of adenosine, an immunosuppressive molecule on T cells 29 – 31 . We observed that expression levels of Nt5e (which encodes CD73) were increased upon the treatment of CD4 T cells with Salp15 (Fig.…”

Section: Resultsmentioning

confidence: 99%

The immunosuppressive effect of the tick protein, Salp15, is long-lasting and persists in a murine model of hematopoietic transplant

Tomás-Cortázar

Martín-Ruiz

Barriales

et al. 2017

Sci Rep

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Salp15, a salivary protein of Ixodes ticks, inhibits the activation of naïve CD4 T cells. Treatment with Salp15 results in the inhibition of early signaling events and the production of the autocrine growth factor, interleukin-2. The fate of the CD4 T cells activated in the presence of Salp15 or its long-term effects are, however, unknown. We now show that Salp15 binding to CD4 is persistent and induces a long-lasting immunomodulatory effect. The activity of Salp15 results in sustained diminished cross-antigenic antibody production even after interruption of the treatment with the protein. Transcriptionally, the salivary protein provokes an acute effect that includes known activation markers, such as Il2 or Cd44, and that fades over time. The long-term effects exerted by Salp15 do not involve the induction of either anergy traits nor increased populations of regulatory T cells. Similarly, the treatment with Salp15 does not result in B cell anergy or the generation of myeloid suppressor cells. However, Salp15 induces the increased expression of the ectoenzyme, CD73, in regulatory T cells and increased production of adenosine. Our study provides a profound characterization of the immunomodulatory activity of Salp15 and suggests that its long-term effects are due to the specific regulation of CD73.

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“…In theory, choosing a donor with greater HLA disparity from the recipient could mitigate the relapse risk induced by a greater allo-immune GVL effect [5,16,28]. However, apart from donor type, many factors can influence GVL [2,22,23,25], including disease type and remission status before HSCT, patient age, conditioning regimen, GVHD prophylaxis, number of T cells infused, presence of GVHD, use of immunotherapy and targeted drugs, and other factors.…”

Section: Discussionmentioning

confidence: 99%

Haploidentical donor is preferred over matched sibling donor for pre-transplantation MRD positive ALL: a phase 3 genetically randomized study

Chang¹,

Wang

et al. 2020

J Hematol Oncol

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Background: Previous reports suggest a benefit associated with haploidentical donor transplantation (HIDT) compared to matched sibling donor transplantation (MSDT) in certain contexts, and the choice of optimal candidates warrants further investigation. Methods: We designed a prospective genetically randomized study to evaluate donor options between acute lymphoblastic leukemia (ALL) patients positive for measurable residual disease (MRD) pre-transplantation who underwent HIDT (n = 169) or MSDT (n = 39). Results: The cumulative incidence of positive MRD post-transplantation was 26% (95% CI, 19-33%) and 44% (95% CI, 28-60%) for HIDT and MSDT, respectively (P = 0.043). Compared to the HIDT cohort, the MSDT cohort had a higher 3-year cumulative incidence of relapse (CIR; 47%, 95% CI, 31-63% vs. 23%, 95% CI, 17-29%; P = 0.006) and lower 3-year probability of leukemia-free survival (LFS; 43%, 95% CI, 27-59% vs. 65%, 95% CI, 58-72%; P = 0.023) and overall survival (OS; 46%, 95% CI, 30-62% vs. 68%, 95% CI, 61-75%; P = 0.039), without a difference in non-relapse-mortality (10%, 95% CI, 1-19% vs. 11%, 95% CI, 6-16%; P = 0.845). Multivariate analysis showed that HIDT is associated with a low CIR (HR = 0.364; 95% CI, 0.202-0.655; P = 0.001) and better LFS (HR = 0.414; 95% CI, 0.246-0.695; P = 0.001) and OS (HR = 0.380; 95% CI, 0.220-0.656; P = 0.001). Conclusions: HIDT is better than MSDT in view of favorable anti-leukemia activity for patients with pre-transplantation MRD positive ALL. The current study paves the way to determine that haploidentical donors are the preferred choice regardless of available matched sibling donors in a subgroup population.

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Adenosine Selectively Depletes Alloreactive T Cells to Prevent GVHD While Conserving Immunity to Viruses and Leukemia

Cited by 9 publications

References 37 publications

Haploidentical‐ versus identical‐sibling transplant for high‐risk pediatric AML: A multi‐center study

Haploidentical‐ versus identical‐sibling transplant for high‐risk pediatric AML: A multi‐center study

The immunosuppressive effect of the tick protein, Salp15, is long-lasting and persists in a murine model of hematopoietic transplant

Haploidentical donor is preferred over matched sibling donor for pre-transplantation MRD positive ALL: a phase 3 genetically randomized study

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