Optimizing Donor Selection for Haploidentical Transplantation Utilizing the Four-Group T Cell Epitope (TCE-4) Algorithm for Prediction of HLA-DPB1 Non-Permissive Mismatches

An HLA-DPB1 non-permissive mismatch (npmm) has been associated with higher risks of acute graft-versus-host disease and non-relapse mortality after matched unrelated donor transplantation (MUDT) and thus avoiding HLA-DPB1 npmm is important in unrelated donor selection. In contrast, HLA-DPB1 npmm by the 3-group T cell epitope algorithm (TCE-3) has been shown to be protective in the context of haploidentical donor transplantation (HIDT) using post-transplant cyclophosphamide (PTCy) (Solomon et al. BBMT 2018). Additional HLA-DPB1 "permissiveness" models, also based on cross-reactive patterns of alloreactive T cells against HLA-DPB1 alleles, include the TCE-4 (based on 4 TCE groups) and functional distance (FD, based on net difference in distance between key amino acid polymorphisms) algorithms. Lastly, an expression model is based on the surface expression of the recipient mismatched HLA-DPB1 (RDP) allele according to variants of a biallelic SNP. The present analysis had 2 major aims: to 1) determine which HLA-DPB1 permissiveness model (TCE-3, TCE-4, FD, expression) provides the best tool for haploidentical donor selection and 2) analyze the role of vector (GVH vs. HVG direction) on the effect of an HLA-DPB1 npmm. A total of 322 patients with acute leukemia, MDS, lymphoma, CLL or CML, receiving a HIDT-PTCy from a single institution were evaluated with a median follow-up time of 45 months [range 6, 184]. Baseline characteristics included a median age of 50 years [19, 80], 47% non-white, HCT-CI ≥3 in 50%, PBSC graft in 80%, and myeloablative conditioning in 49%. The number of donor-recipient pairs having an HLA-DPB1 npmm according to the TCE-3, TCE-4, FD and expression was 82 (25%), 130 (40%), 54 (17%) and 99 (31%) respectively. In univariate analysis, HLA-DPB1 npmm identified by the TCE-3 and TCE-4 models were statistically associated with improved overall survival (OS) (p=0.041 and p=0.004 respectively), whereas FD risk and RDP expression were not (see figure). For disease-free survival (DFS), only the TCE-4 model showed a statistically significant association (p=0.022). Directionality of the HLA-DP npmm (GVH vs. HVG vector) had no significant impact on survival following HIDT-PTCy, a finding similar to the context of MUDT (Fleischhauer BMT 2017). In multivariate Cox analysis, adjusting for patient/donor age, gender, race, HLA-DR mismatch and transplant year, HLA-DPB1 npmm by the TCE-4 model had the most significant association with improved OS (HR 0.59, p=0.012), with TCE-3 being less predictive (HR 0.65, p=0.07) (see figure). Furthermore, HLA-DPB1 npmm by TCE-4 led to improved DFS (HR 0.69, p=0.046) and trends for lower cumulative incidences of relapse/progression (HR 0.73, p=0.16) and NRM (HR 0.54, p=0.09). In summary, the presence of an HLA-DP npmm in either the GVH or HVG direction continues to be associated with improved survival following HIDT-PTCy in a large single institution retrospective analysis with extended follow-up. Compared to the original TCE-3 model, a TCE-4-predicted HLA-DPB1 npmm is more strongly associated with overall survival. This fact, combined with the larger number of HLA-DPB1 npmm donors identified by the TCE-4 model, suggests that it may be a better selection tool for optimal haploidentical donor identification. Figure 1 Figure 1. Disclosures Solh: Partner Therapeutics: Research Funding; Jazz Pharmaceuticals: Consultancy; BMS: Consultancy; ADCT Therapeutics: Consultancy, Research Funding.

128 KIR haplotype can inform donor selection production of allogeneic memory-like CAR NK cells for clinical application

BackgroundNK cells expanded on membrane-bound (mb) IL-15 and 41BBL expressing K562 stimulatory cells (NKSTIM) for clinical use can be genetically modified to express activating chimeric receptors.1 2 3 NK cells activated in the presence of IL-12, IL-15 and IL-18 develop cytokine induced memory-like (CIML) phenotype and function; these cells have shown clinical promise.4 Additionally, HSCT AML transplants using NK KIR Haplotype Group B donors with better and best Group B profiles (≥2 activating genes) show better survival.5 6 Here we investigate whether KIR profiles impact healthy allogeneic donor NK cell function and phenotype when these cells are expanded on NKSTIM in the presence of IL-12 and IL-18 (12–18).MethodsHealthy donor PBMC NK were genotyped for HLA and KIR and expanded on K562-mbIL15-41BBL stimulatory cells with IL-2 alone or with IL-2 plus IL-12 and IL-18 (12–18). Expanded NK were transduced with CAR constructs including CD19, and then evaluated for NK cell expansion, cytokine secretion, RNA profiles, cytotoxicity against tumor lines, and cell surface phenotypes. Expanded CD19 NK donors with varying numbers of activating KIR vs inhibitory KIR were tested for effector function, and these donors were then tested for in vivo efficacy and pharmacokinetics. A KIR ranking score was developed by considering both the number of activating and inhibitory KIR genes expressed by each donor. This score was correlated with functional properties of CAR NK cells.ResultsAddition of 12–18 to the K562-mbIL15-41BBL stimulatory cells improves CD19-CAR NK potency 2-fold relative to the stimulatory cell line alone (P=.02) while NK cell expansion is unchanged. 12–18 also drove an increase in effector cytokine accumulation on exposure of CAR-NK to CD19 tumor. CIML CAR NK cells from donors with higher KIR scoring also had higher cytotoxicity (Pearson’s R=0.74, P=0.006); this correlation was not observed following expansion in the absence of 12–18. 12–18 also drove more potent in vivo activity against tumor with an increased presence of circulating NK cells over 4 weeks in the mice.ConclusionsCIML CAR NK cells derived from donors with favorable KIR scoring have greater cytotoxic activity, effector cytokine production, and in vivo pharmacokinetics and efficacy. These findings may provide an important criterion for donor selection in the development of more robust and potent engineered NK cells for clinical use.ReferencesLapteva N, Durett AG, Sun J, Rollins LA, Huye LL, Fang J, Dandekar V, Mei Z, Jackson K, Vera J, Ando J, Ngo MC, Coustan-Smith E, Campana D, Szmania S, Garg T, Moreno-Bost A, Vanrhee F, Gee AP, Rooney CM. Large-scale ex vivo expansion and characterization of natural killer cells for clinical applications. Cytotherapy 2012;14(9):1131–1143.Chihaya I, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Blood 2005;106:376–383.Yang Y, Connolly J, Shimasaki N, Mimura K, Kono K, Campana D. A Chimeric Receptor with NKG2D Specificity Enhances Natural Killer Cell Activation and Killing of Tumor Cells. Cancer Res 2013;73(6):1777–1786.Romee R, Rosario M, Berrien-Elliott MM, Wagner JA, Jewell BA, Schappe T, Leong JW, Abdel-Latif S, Schneider SE, Willey S, Neal CC, Yu L, Oh ST, Lee YS, Mulder A, Claas F, Cooper MA, Fehniger TA. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Sci Trans Med 2016;8(357): 357ra123.Cooley S, Weisdorf DJ, Guethlein LA, Klein JP, Wang T, Le CT, Marsh SGE, Geraghty D, Spellman S, Haagenson MD, Ladner M, Trachtenberg E, Parham P, and Miller JS. Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia. Blood 2010;116(14):2414–2419.Cooley S, Weisdorf DJ, Guethlein LA, Klein JP, Wang T, Marsh SGE, Spellman S, Haagenson MD, Saeturn K, Ladner M, Trachtenberg E, Parham P, and Miller JS. Donor Killer Cell Ig-like Receptor B Haplotypes, Recipient HLA-C1, and HLA-C Mismatch Enhance the Clinical Benefit of Unrelated Transplantation for Acute Myelogenous Leukemia. JI, 2014;192(10):4592–600.Ethics ApprovalAnimal studies were conducted with IACUC approval.

Retrospective analysis of donor deferral for plateletpheresis at a regional transfusion center, in North-West India

Background: Single donor platelet (SDP) is one of the valuable component for thrombocytopenic patients for obtaining good post transfusion count increment, good yield of product is required. Proper donor selection has a crucial role in in safety and quality of product therefore proper screening of donor is mandatory. The aim was to find out reasons and frequency of plateletpheresis donor deferral and to encourage safety of donor for recruitment of new SDP donors.Methods: A retrospective analysis of data was done over a period of 1 year from June 2018 to May 2019 from the data centre of the institute.Results: Out of 1365 donors, 1200 were selected for plateletpheresis procedure and remaining 165 donors were deferred for various reasons. The predominant age of donors ranges from 25-35 years. Among the deferred donors temporary donors accounted for 93.33% and permanently deferred donors were 6.61. Most common cause for deferral were poor venous access 52 (31.51%). Low platelet counts 32 (19.39), low Hb 26 (15.75%), underweight 24 (14.54%), under medication 9 (5.45%), alcohol intake within 24 hours 6 (3.63%) and others like tattoos, infections/inflammations at phlebotomy sites 5 (3.03%) and most common reason for permanent deferral were sero-positivity for HbsAg 6 (3.63%), chronic diseases 4 (2.42%) (cardiovascular diseases bronchial asthma), others 1 (0.6%).Conclusions: For obtaining good yield of product, proper donor screening is required. Temporary deferred donors should be counselled properly and encouraged for further donation when comes under selection criteria. Donor selection criteria for apheresis may be revised.

The consensus from The Chinese Society of Hematology on indications, conditioning regimens and donor selection for allogeneic hematopoietic stem cell transplantation: 2021 update

The consensus recommendations in 2018 from The Chinese Society of Hematology (CSH) on indications, conditioning regimens and donor selection for allogeneic hematopoietic stem cell transplantation (allo-HSCT) facilitated the standardization of clinical practices of allo-HSCT in China and progressive integration with the world. There have been new developments since the initial publication. To integrate recent developments and further improve the consensus, a panel of experts from the CSH recently updated the consensus recommendations, which are summarized as follows: (1) there is a new algorithm for selecting appropriate donors for allo-HSCT candidates. Haploidentical donors (HIDs) are the preferred donor choice over matched sibling donors (MSDs) for patients with high-risk leukemia or elderly patients with young offspring donors in experienced centers. This replaces the previous algorithm for donor selection, which favored MSDs over HIDs. (2) Patients with refractory/relapsed lymphoblastic malignancies are now encouraged to undergo salvage treatment with novel immunotherapies prior to HSCT. (3) The consensus has been updated to reflect additional evidence for the application of allo-HSCT in specific groups of patients with hematological malignancies (intermediate-risk acute myeloid leukemia (AML), favorable-risk AML with positive minimal residual disease, and standard-risk acute lymphoblastic leukemia). (4) The consensus has been updated to reflect additional evidence for the application of HSCT in patients with nonmalignant diseases, such as severe aplastic anemia and inherited diseases. (5) The consensus has been updated to reflect additional evidence for the administration of anti-thymocyte globulin, granulocyte colony-stimulating factors and post-transplantation cyclophosphamide in HID-HSCT.