Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia

Cooley, Sarah; Weisdorf, Daniel J.; Guethlein, Lisbeth A.; Klein, John P.; Wang, Tao; Le, Chap T.; Marsh, Steven G.E.; Geraghty, Daniel E.; Spellman, Stephen R.; Haagenson, Michael; Ladner, Martha; Trachtenberg, Elizabeth; Parham, Peter; Miller, Jeffrey S.

doi:10.1182/blood-2010-05-283051

Cited by 534 publications

(531 citation statements)

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“…Licensed (or unlicensed) human NK cells appear to be relevant to several clinical conditions and for adoptive immunotherapy (for recent examples, see refs. [38][39][40][41]. Of particular relevance, human NK cells with self-specific KIRs can be educated after BM transplantation in a manner related to the studies presented here (42), suggesting that relevant trans interactions between KIRs on NK cells and HLA class I on hematopoietic cells should be considered in the appropriate clinical context.…”

Section: Discussionmentioning

confidence: 99%

Natural killer cell licensing in mice with inducible expression of MHC class I

Ebihara

Jonsson

Yokoyama

2013

Proc. Natl. Acad. Sci. U.S.A.

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Mouse natural killer (NK) cells acquire effector function by an education process termed "licensing" mediated by inhibitory Ly49 receptors which recognize self-MHC class I. Ly49 receptors can bind to MHC class I on targets (in trans) and also to MHC class I on the NK-cell surface (in cis). Which of these interactions regulates NKcell licensing is not yet clear. Moreover, there are no clear phenotypic differences between licensed and unlicensed NK cells, perhaps because of the previously limited ability to study NK cells with synchronized licensing. Here, we produced MHC class I-deficient mice with inducible MHC class I consisting of a single-chain trimer (SCT), ovalbumin peptide-β2 microgloblin-H2K b (SCT-K b ). Only NK cells with a Ly49 receptor with specificity for SCT-K b were licensed after MHC class I induction. NK cells were localized consistently in red pulp of the spleen during induced NK-cell licensing, and there were no differences in maturation or activation markers on recently licensed NK cells. Although MHC class I-deficient NK cells were licensed in hosts following SCT-K b induction, NK cells were not licensed after induced SCT-K b expression on NK cells themselves in MHC class I-deficient hosts. Furthermore, hematopoietic cells with induced SCT-K b licensed NK cells more efficiently than stromal cells. These data indicate that trans interaction with MHC class I on hematopoietic cells regulates NK-cell licensing, which is not associated with other obvious phenotypic changes.tolerance | immunity | lymphocytes

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Section: Discussionmentioning

confidence: 99%

Natural killer cell licensing in mice with inducible expression of MHC class I

Ebihara

Jonsson

Yokoyama

2013

Proc. Natl. Acad. Sci. U.S.A.

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“…However, there are strategies that could be employed to enhance the GVL response. These maneuvers include early withdrawal of immunosuppression, use of ex vivo activated/expanded T-or NK cells, 49,50 or enhancement of antitumor effector T cell function by following a prior auto-HCT. The 3-year NRM was 41% after MAC allo-HCT, compared with 20% after RIC allo-HCT.…”

Section: Evidence For a Graft Vs Dlbcl Effectmentioning

confidence: 99%

Allogeneic hematopoietic cell transplantation for diffuse large B cell lymphoma: who, when and how?

Klyuchnikov

Bacher

Kroll

et al. 2013

Bone Marrow Transplant

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Despite overall improvements in outcomes of patients with diffuse large B cell lymphoma (DLBCL), B30-40% of patients develop relapsed or refractory disease. For patients with chemo refractory disease, or recurrent disease following autologous hematopoietic SCT (auto-HCT), the prognosis is poor, with no consensus on the optimal therapy. Currently, owing to the graft vs lymphoma effect, hematopoietic allogeneic hematopoietic cell transplantation (allo-HCT) is the only potentially curative option for such patients. In addition, many patients who are considered today for auto-HCT actually have a low likelihood of benefit. For example, a patient with prior rituximab exposure who relapses within 1 year of diagnosis and has a second-line age-adjusted International Prognosis Index of 2 or 3 at relapse has a o25% chance of being cured by auto-HCT. It is possible that such patients may be better served with an allo-HCT. Unfortunately, in many cases, allo-HCT applicability is limited by patient age, comorbidities, performance status and treatment-related toxicities. Recent attempts to improve the efficacy of auto-HCT, such as incorporating radio-immunotherapy into the conditioning regimen, have not resulted in improved outcomes. However, incorporation of novel agents such as antiprogrammed death-1 antibodies as maintenance therapy after auto-HCT show promise. Allo-HCT in relapsed/refractory DLBCL patients can result in a 30-40% PFS rate at 3 years, in part due to a graft vs DLBCL effect. While reduced-intensity/nonmyeloablative conditioning is increasingly being used, certain patients may benefit from myeloablative conditioning. We present an algorithm intended to discriminate which relapsed and refractory DLBCL patients are most likely to benefit from auto-HCT vs allo-HCT. New approaches, using novel agents that target the molecular heterogeneity in DLBCL, will be an essential component of moving the field forward. Lastly, we propose a prospective registry-based study as the only feasible mechanism to define the optimal position of allo-HCT in the overall treatment strategy for DLBCL. It is hoped that this review will promote the development of prospective multicenter efforts to determine whether such patients do, in fact, benefit from earlier and/or more effective implementation of allo-HCT.

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“…The main requirement for selection of an unrelated donor is well recognized to be one who is a match at 10/10 (or 8/8) HLA alleles. 20,21 Selecting a donor based on secondary selection donor characteristics, such as donor age 22 or other (non-classic HLA) genetic factors, [23][24][25] can further enhance outcomes.…”

Section: Discussionmentioning

confidence: 99%

Caspase-8 polymorphisms result in reduced Alemtuzumab-induced T-cell apoptosis and worse survival after transplantation

Shaw

Lee

Krishnamurthy

et al. 2014

Bone Marrow Transplant

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Allo-SCT using unrelated donors is a curative treatment for patients with hematological disorders. The best donor is one matched for 10/10 HLA alleles, however studies have shown an additional survival benefit when considering other genetic factors. It has been shown that a six-nucleotide insertion/deletion polymorphism in the CASP8 gene promoter results in reduced susceptibility of T lymphocytes to undergo apoptosis. In 186 SCT recipients, we found a significantly better OS in those who received a transplant from a WT/WT donor compared with donors with a deletion (3 years: 52 vs 34%; P = 0.03; multivariate analysis; RR 0.61; 95% CI 0.38-0.98, P = 0.04). This was more marked when both the patient and the donor had a deletion (3 years OS: 62% compared with 36%, P = 0.01). As the majority of these patients received Alemtuzumab during conditioning, we went on to analyze the in vitro effect of the polymorphism on Alemtuzumab-induced apoptosis. We showed statistically significantly higher percentages of apoptotic naïve CD4 (P o 0.0005) and CD8 (P o 0.0005) T cells in WT/WT donors in comparison with donors with a deletion. These data imply an unrecognized role for the CASP8 promoter polymorphism on survival following unrelated SCT particularly in the context of T-cell depletion with Alemtuzumab.

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Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia

Cited by 534 publications

References 50 publications

Natural killer cell licensing in mice with inducible expression of MHC class I

Natural killer cell licensing in mice with inducible expression of MHC class I

Allogeneic hematopoietic cell transplantation for diffuse large B cell lymphoma: who, when and how?

Caspase-8 polymorphisms result in reduced Alemtuzumab-induced T-cell apoptosis and worse survival after transplantation

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