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Abstract: Abatacept plus calcineurin inhibitors/methotrexate (CNI/MTX) is the first US Food and Drug Administration (FDA)-approved regimen for acute graft-versus-host disease (aGVHD) prophylaxis during unrelated-donor hematopoietic cell transplantation (URD-HCT). Using Center for International Blood and Marrow Transplant Research data, we investigated its impact in patients receiving 7/8 HLA-mismatched unrelated donor (MMUD) or 8/8 HLA-matched unrelated donor (MUD) URD-HCT between 2011 and 2018. Primary outcomes included day-180, 1-year, and 2-year overall survival (OS) and relapse-free survival (RFS) for abatacept + CNI/MTX vs CNI/MTX, CNI/MTX + antithymocyte globulin (ATG), and posttransplant cyclophosphamide-based prophylaxis (PT-Cy). For 7/8 MMUDs, day-180 OS (primary end point supporting FDA approval) was significantly higher for abatacept + CNI/MTX vs CNI/MTX (98% vs 75%; P = .0028). Two-year RFS was significantly higher for abatacept + CNI/MTX vs CNI/MTX (74% vs 49%; P = .0098) and CNI/MTX + ATG (77% vs 35%; P = .0002), and similar vs PT-Cy (72% vs 56%; P = .1058). For 8/8 MUDs, 2-year RFS for abatacept + CNI/MTX was numerically higher vs CNI/MTX (63% vs 52%; P = .1497), with an improved hazard ratio (HR) of 0.46 (0.25-0.86), and vs CNI/MTX + ATG (66% vs 55%; P = .1193; HR, 0.39 [0.21-0.73]), and was similar vs PT-Cy (68% vs 57%; P = .2356; HR, 0.54 [0.26-1.11]). For 7/8 MMUD and 8/8 MUD recipients, abatacept + CNI/MTX prophylaxis improved survival outcomes vs CNI/MTX and CNI/MTX + ATG; outcomes were similar to PT-Cy-based regimens. Abatacept + CNI/MTX may facilitate unrelated donor pool expansion for HCT., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Chronic graft-versus-host-disease (cGVHD) is divided into two subtypes: classic (absence of acute GVHD features) and overlap cGVHD ('ocGVHD'), in which both chronic and acute GVHD clinical features are present simultaneously. While worse outcomes with ocGVHD have been reported, there are few recent analyses. We performed a secondary analysis of data from the ABA2 trial (N = 185), in which detailed GVHD data were collected prospectively and systematically adjudicated. Analyses included cumulative incidence of classic versus ocGVHD, their specific organ manifestations, global disease severity scores, non-relapse mortality (NRM), disease-free survival (DFS) and overall survival (OS) in these two cGVHD subtypes. Of 92 patients who developed cGVHD, 35 were classified as ocGVHD. The 1-year cumulative incidence, organ involvement, and global severity of classic and ocGVHD were similar between ABA2 patients receiving CNI/MTX+placebo and CNI/MTX+abatacept; thus, cohorts were combined for ocGVHD evaluation. This analysis identified ocGVHD as having significantly higher severity at presentation and at maximum global severity compared to classic cGVHD. OS and DFS were significantly lower for ocGVHD versus classic cGVHD. OcGVHD is associated with increased cGVHD severity scores, and is associated with decreased OS and DFS compared to classic cGVHD, underscoring the high risks with this cGVHD subtype., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

In the ABA2 study, the T-cell costimulation blockade agent, abatacept, was safe and effective in preventing acute graft-versus-host disease (aGVHD) after unrelated-donor hematopoietic cell transplant (HCT), leading to US Food and Drug Administration approval. Here, we performed a determination of abatacept pharmacokinetics (PK), which enabled an examination of how abatacept exposure-response relationships affected clinical outcomes. We performed a population PK analysis of IV abatacept using nonlinear mixed-effect modeling and assessed the association between abatacept exposure and key transplant outcomes. We tested the association between the trough after dose 1 (Ctrough&#95;1) and grade (GR) 2 or 4 aGVHD (GR2-4 aGVHD) through day +100. An optimal Ctrough&#95;1 threshold was identified via recursive partitioning and classification tree analysis. This demonstrated that abatacept PK was characterized by a 2-compartment model with first-order elimination. The ABA2 dosing regimen was based on previous work targeting a steady-state abatacept trough of 10 μg/mL. However, a higher Ctrough&#95;1 (≥39 μg/mL, attained in ∼60% of patients on ABA2) was associated with a favorable GR2-4 aGVHD risk (hazard ratio, 0.35; 95% confidence interval, 0.19-0.65; P < .001), with a Ctrough&#95;1 <39 μg/mL associated with GR2-4 aGVHD risk indistinguishable from placebo (P = .37). Importantly, no significant association was found between Ctrough&#95;1 and key safety indicators, including relapse, and cytomegalovirus or Epstein-Barr virus viremia. These data demonstrate that a higher abatacept Ctrough&#95;1 (≥39 μg/mL) was associated with a favorable GR2-4 aGVHD risk, without any observed exposure-toxicity relationships. This trial was registered at www.clinicaltrials.gov as #NCT01743131., (© 2023 by The American Society of Hematology.)

Purpose: Severe (grade 3-4) acute graft-versus-host disease (AGVHD) is a major cause of death after unrelated-donor (URD) hematopoietic cell transplant (HCT), resulting in particularly high mortality after HLA-mismatched transplantation. There are no approved agents for AGVHD prevention, underscoring the critical unmet need for novel therapeutics. ABA2 was a phase II trial to rigorously assess safety, efficacy, and immunologic effects of adding T-cell costimulation blockade with abatacept to calcineurin inhibitor (CNI)/methotrexate (MTX)-based GVHD prophylaxis, to test whether abatacept could decrease AGVHD., Methods: ABA2 enrolled adults and children with hematologic malignancies under two strata: a randomized, double-blind, placebo-controlled stratum (8/8-HLA-matched URD), comparing CNI/MTX plus abatacept with CNI/MTX plus placebo, and a single-arm stratum (7/8-HLA-mismatched URD) comparing CNI/MTX plus abatacept versus CNI/MTX CIBMTR controls. The primary end point was day +100 grade 3-4 AGVHD, with day +180 severe-AGVHD-free-survival (SGFS) a key secondary end point. Sample sizes were calculated using a higher type-1 error (0.2) as recommended for phase II trials, and were based on predicting that abatacept would reduce grade 3-4 AGVHD from 20% to 10% (8/8s) and 30% to 10% (7/8s). ABA2 enrolled 142 recipients (8/8s, median follow-up = 716 days) and 43 recipients (7/8s, median follow-up = 708 days)., Results: In 8/8s, grade 3-4 AGVHD was 6.8% (abatacept) versus 14.8% (placebo) ( P = .13, hazard ratio = 0.45). SGFS was 93.2% (CNI/MTX plus abatacept) versus 82% (CNI/MTX plus placebo, P = .05). In the smaller 7/8 cohort, grade 3-4 AGVHD was 2.3% (CNI/MTX plus abatacept, intention-to-treat population), which compared favorably with a nonrandomized matched cohort of CNI/MTX (30.2%, P < .001), and the SGFS was better (97.7% v 58.7%, P < .001). Immunologic analysis revealed control of T-cell activation in abatacept-treated patients., Conclusion: Adding abatacept to URD HCT was safe, reduced AGVHD, and improved SGFS. These results suggest that abatacept may substantially improve AGVHD-related transplant outcomes, with a particularly beneficial impact on HLA-mismatched HCT., Competing Interests: Benjamin WatkinsConsulting or Advisory Role: Bristol Myers SquibbPatents, Royalties, Other Intellectual Property: Patent pending for “Method to prevent relapse after transplant” Muna QayedConsulting or Advisory Role: Novartis, MesoblastTravel, Accommodations, Expenses: Novartis Steve BosingerResearch Funding: GlaxoSmithKline Victor TkachevTravel, Accommodations, Expenses: Regeneron Ted A. GooleyConsulting or Advisory Role: Kiadis Pharma, Pharmacyclics, REGiMMUNE Marcelo C. PasquiniConsulting or Advisory Role: Pfizer, Medigene, Celgene, AmgenResearch Funding: Kite/Gilead, Novartis, Celgene, Bristol Myers Squibb Roger GillerResearch Funding: Bristol-Myers Squibb, Jazz Pharmaceuticals, Atara Maxim NorkinResearch Funding: Celgene Nosha FarhadfarConsulting or Advisory Role: IncyteResearch Funding: CSL Behring Michael A PulsipherHonoraria: Amgen, Bellicum Pharmaceuticals, Miltenyi BiotecConsulting or Advisory Role: Novartis, CSL Behring, Jasper Therapeutics, NovartisSpeakers' Bureau: NovartisResearch Funding: Adaptive Biotechnologies, Miltenyi BiotecTravel, Accommodations, Expenses: Medac, Bellicum Pharmaceuticals, Miltenyi Biotec Shalini ShenoyHonoraria: Novartis, JazzConsulting or Advisory Role: as listed previously, California Institute of Regenerative MedicineTravel, Accommodations, Expenses: as listed above Aleksandra PetrovicConsulting or Advisory Role: Orchard, CSL Behring Kirk R. SchultzHonoraria: ShireConsulting or Advisory Role: MesoScale Discovery, Juno TherapeuticsTravel, Accommodations, Expenses: Jazz Pharmaceuticals Gregory A. YanikResearch Funding: Jazz Pharmaceuticals Edmund K. WallerEmployment: Cambium Medical TechnologiesLeadership: Cambium Medical Technologies, Cambium Oncology, Cambium OncologyStock and Other Ownership Interests: Cambium Medicl Technologies, Cambium Oncology, Cerus, ChimerixHonoraria: Novartis, Partners, Verastem, Kite Pharma, Pharmacyclics, KaryopharmaConsulting or Advisory Role: Novartis, Verastem, Pharmacyclics, Karyopharm Therapeutics, Partners Healthcare, Kite PharmaResearch Funding: Novartis, Amgen, Juno Therapeutics, Verastem, Partners Healthcare, Partners HealthcarePatents, Royalties, Other Intellectual Property: Received Royalties from patent on preparing platelet lysate that has been licensed to Cambium Medical TechnologiesTravel, Accommodations, Expenses: Pharmacyclics John E. LevineConsulting or Advisory Role: Incyte, Novartis, Talaris, Bluebird Bio, MesoblastResearch Funding: Incyte, Kamada, BiogenPatents, Royalties, Other Intellectual Property: GVHD biomarkers patent licensed to Viracor James L. FerraraHonoraria: Incyte, Mallinckrodt, Equillium, KamdaConsulting or Advisory Role: OmerosResearch Funding: Kamada, IncytePatents, Royalties, Other Intellectual Property: Royalties from an IP licenseTravel, Accommodations, Expenses: Incyte Bruce R. BlazarStock and Other Ownership Interests: Five Prime Therapeutics, BlueRock Therapeutics, Tmunity Therapeutics, Inc, Magenta TherapeuticsHonoraria: Kadmon, REGiMMUNE, Dr Reddy's Laboratories, Incyte, GT Biopharma, bioverativConsulting or Advisory Role: Kadmon, BlueRock Therapeutics, Magenta TherapeuticsResearch Funding: Tmunity Therapeutics, Inc, Fate Therapeutics, BlueRock Therapeutics, Alpine Immune Sciences, RXI Pharmaceuticals, AbbvieTravel, Accommodations, Expenses: Incyte, Magenta Therapeutics, Dr Reddy's Laboratories, bioverativ, Intellia Therapeutics, Rheos Amelia LangstonResearch Funding: Chimerix, Astellas Pharma, Incyte, Takeda, Jazz Pharmaceuticals, Kadmon, Novartis Leslie S. KeanHonoraria: Gilead SciencesConsulting or Advisory Role: HiFiBio, Forty Seven, EMD SeronoResearch Funding: Magenta Therapeutics, Bluebird Bio, Kyocera, Regeneron, Gilead Sciences, BEAM Therapeutics, Bristol Myers SquibbPatents, Royalties, Other Intellectual Property: Licensing Fees for ABA2 clinical trial dataNo other potential conflicts of interest were reported.

Organ infiltration by donor T cells is critical to the development of acute graft-versus-host disease (aGVHD) in recipients after allogeneic hematopoietic stem cell transplant (allo-HCT). However, deconvoluting the transcriptional programs of newly recruited donor T cells from those of tissue-resident T cells in aGVHD target organs remains a challenge. Here, we combined the serial intravascular staining technique with single-cell RNA sequencing to dissect the tightly connected processes by which donor T cells initially infiltrate tissues and then establish a pathogenic tissue residency program in a rhesus macaque allo-HCT model that develops aGVHD. Our results enabled creation of a spatiotemporal map of the transcriptional programs controlling donor CD8 + T cell infiltration into the primary aGVHD target organ, the gastrointestinal (GI) tract. We identified the large and small intestines as the only two sites demonstrating allo-specific, rather than lymphodepletion-driven, T cell infiltration. GI-infiltrating donor CD8 + T cells demonstrated a highly activated, cytotoxic phenotype while simultaneously developing a canonical tissue-resident memory T cell (T RM ) transcriptional signature driven by interleukin-15 (IL-15)/IL-21 signaling. We found expression of a cluster of genes directly associated with tissue invasiveness, including those encoding adhesion molecules ( ITGB2 ), specific chemokines ( CCL3 and CCL4L1 ) and chemokine receptors ( CD74 ), as well as multiple cytoskeletal proteins. This tissue invasion transcriptional signature was validated by its ability to discriminate the CD8 + T cell transcriptome of patients with GI aGVHD from those of GVHD-free patients. These results provide insights into the mechanisms controlling tissue occupancy of target organs by pathogenic donor CD8 + T RM cells during aGVHD in primate transplant recipients., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Controlling graft-versus-host disease (GVHD) remains a major unmet need in stem cell transplantation, and new, targeted therapies are being actively developed. CD28-CD80/86 costimulation blockade represents a promising strategy, but targeting CD80/CD86 with CTLA4-Ig may be associated with undesired blockade of coinhibitory pathways. In contrast, targeted blockade of CD28 exclusively inhibits T cell costimulation and may more potently prevent GVHD. Here, we investigated FR104, an antagonistic CD28-specific pegylated-Fab', in the nonhuman primate (NHP) GVHD model and completed a multiparameter interrogation comparing it with CTLA4-Ig, with and without sirolimus, including clinical, histopathologic, flow cytometric, and transcriptomic analyses. We document that FR104 monoprophylaxis and combined prophylaxis with FR104/sirolimus led to enhanced control of effector T cell proliferation and activation compared with the use of CTLA4-Ig or CTLA4-Ig/sirolimus. Importantly, FR104/sirolimus did not lead to a beneficial impact on Treg reconstitution or homeostasis, consistent with control of conventional T cell activation and IL-2 production needed to support Tregs. While FR104/sirolimus had a salutary effect on GVHD-free survival, overall survival was not improved, due to death in the absence of GVHD in several FR104/sirolimus recipients in the setting of sepsis and a paralyzed INF-γ response. These results therefore suggest that effectively deploying CD28 in the clinic will require close scrutiny of both the benefits and risks of extensively abrogating conventional T cell activation after transplant.

One of the central challenges of transplantation is the development of alloreactivity despite the use of multiagent immunoprophylaxis. Effective control of this immune suppression-resistant T-cell activation represents one of the key unmet needs in the fields of both solid-organ and hematopoietic stem cell transplant (HCT). To address this unmet need, we have used a highly translational nonhuman primate (NHP) model to interrogate the transcriptional signature of T cells during breakthrough acute graft-versus-host disease (GVHD) that occurs in the setting of clinically relevant immune suppression and compared this to the hyperacute GVHD, which develops in unprophylaxed or suboptimally prophylaxed transplant recipients. Our results demonstrate the complex character of the alloreactivity that develops during ongoing immunoprophylaxis and identify 3 key transcriptional hallmarks of breakthrough acute GVHD that are not observed in hyperacute GVHD: (1) T-cell persistence rather than proliferation, (2) evidence for highly inflammatory transcriptional programming, and (3) skewing toward a T helper (Th)/T cytotoxic (Tc)17 transcriptional program. Importantly, the gene coexpression profiles from human HCT recipients who developed GVHD while on immunosuppressive prophylactic agents recapitulated the patterns observed in NHP, and demonstrated an evolution toward a more inflammatory signature as time posttransplant progressed. These results strongly implicate the evolution of both inflammatory and interleukin 17-based immune pathogenesis in GVHD, and provide the first map of this evolving process in primates in the setting of clinically relevant immunomodulation. This map represents a novel transcriptomic resource for further systems-based efforts to study the breakthrough alloresponse that occurs posttransplant despite immunoprophylaxis and to develop evidence-based strategies for effective treatment of this disease., (© 2016 by The American Society of Hematology.)