Adoptive transfer of T-cell precursors enhances T-cell reconstitution after allogeneic hematopoietic stem cell transplantation

Zakrzewski, Johannes L.; Kochman, Adam A.; Lu, Sydney X.; Terwey, Theis H.; Kim, Theo D.; Hubbard, Vanessa M.; Muriglan, Stephanie J.; Suh, David; Smith, Odette M.; Grubin, Jeremy; Patel, Niral; Chow, Andrew; Cabrera-Pérez, Javier; Radhakrishnan, Radhika; Diab, Adi; Perales, Miguel Angel; Rizzuto, Gabrielle; Menet, Ewa; Pamer, Eric G.; Heller, Glen; Zúñiga‐Pflücker, Juan Carlos; Alpdoğan, Önder; Brink, Marcel R.M. van den

doi:10.1038/nm1463

Cited by 172 publications

(165 citation statements)

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“…Among approaches being considered, the use of Notch ligand-based approaches that may preferentially expand lymphoid progenitors deserves special consideration given our findings. 47,48 Additional strategies, already demonstrated to have efficacy in murine models and in human clinical trials, include the use of thymoprotective agents (eg, keratinocyte growth factor or related family members) [49][50][51] and the use of thymopoietic factors (eg, androgen ablation using leuprolide, IL-7 administration, and growth hormone administration). 52,53 Finally, the ex vivo expansion of naive cord blood cells in the presence of viral antigens may offer a solution to the elusive goal of adoptively transferring antigenspecific memory to CB recipients.…”

Section: Discussionmentioning

confidence: 99%

Delayed immune reconstitution after cord blood transplantation is characterized by impaired thymopoiesis and late memory T-cell skewing

Komanduri

John

Lima

et al. 2007

Blood

293

252

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Advances in immune assessment, including the development of T-cell receptor excision circle (TREC) assays of thymopoiesis, cytokine-flow cytometry assays of T-cell function, and higher-order phenotyping of T-cell maturation subsets have improved our understanding of T-cell homeostasis. Limited data exist using these methods to characterize immune recovery in adult cord blood (CB) transplant recipients, in whom infection is a leading cause of mortality. We now report the results of a single-center prospective study of T-cell immune recovery after cord blood transplantation (CBT) in a predominantly adult population. Our primary findings include the following: (1) Prolonged T lymphopenia and compensatory expansion of B and natural killer (NK) cells was evident; (2) CB transplant recipients had impaired functional recovery, although we did observe posttransplantation de novo T-cell responses to cytomegalovirus (CMV) in a subset of patients; (3) Thymopoietic failure characterized post-CBT immune reconstitution, in marked contrast to results in other transplant recipients; and (4) Thymopoietic failure was associated with late memory T-cell skewing. Our data suggest that efforts to improve outcomes in adult CB transplant recipients should be aimed at optimizing T-cell immune recovery. Strategies that improve the engraftment of lymphoid precursors, protect the thymus during pretransplant conditioning, and/or augment the recovery of thymopoiesis may improve outcomes after CBT. IntroductionUmbilical cord blood (CB), first demonstrated to have clinical utility by Gluckman et al as a source of hematopoietic stem cells in the setting of Fanconi anemia, 1 was later demonstrated to have utility as a source of unrelated donor stem cells for patients lacking matched-sibling donors. [2][3][4][5] Over the past decade, a large number of studies have demonstrated the clinical utility of CB transplantation (CBT) as a treatment for both malignant and nonmalignant diseases of children and adults. 4,6 The establishment of international cord blood banks, advances in supportive care and donor graft selection, and novel clinical approaches aimed at improving engraftment (eg, ex vivo expansion of CB-derived progenitors 7,8 and the infusion of pooled unrelated units 9 ) have improved outcomes and led to a dramatic increase in the number of CBTs performed worldwide.CB grafts obtained from matched unrelated donors offer advantages over bone marrow or peripheral blood stem cells (PBSC) such as noninvasive procurement, more rapid availability without the need for the more prolonged process of screening and obtaining stem cells from a matched unrelated donor (MUD), and the apparently greater tolerance for incompletely human leukocyte antigen (HLA)-matched products. 10 These advantages are paramount for recipients in historically underrepresented minority groups, for whom the prospect of locating a MUD registry donor remains relatively diminished. At our institution, more than twice the proportion of CB transplant recipients are minorities relati...

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Section: Discussionmentioning

confidence: 99%

Delayed immune reconstitution after cord blood transplantation is characterized by impaired thymopoiesis and late memory T-cell skewing

Komanduri

John

Lima

et al. 2007

Blood

293

252

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“…Transfer of these T cell precursors, along with the allograft, to lethally irradiated allogeneic HSCT recipients resulted in increased thymic cellularity and chimerism, as well as enhanced peripheral T and NK cell reconstitution [52]. Combination of T cell precursor administration and treatment with KGF had additive effects on thymic reconstitution.…”

Section: Committed Precursor Cells Generated By Notch-based Culturementioning

confidence: 98%

“…Notch-based culture systems such as the OP9-DL1 (a mouse bone marrow stromal cell line transduced to express DL1) system [51] can be utilized to generate large numbers of early T cell precursors from hematopoietic stem cells [52]. Transfer of these T cell precursors, along with the allograft, to lethally irradiated allogeneic HSCT recipients resulted in increased thymic cellularity and chimerism, as well as enhanced peripheral T and NK cell reconstitution [52].…”

Section: Committed Precursor Cells Generated By Notch-based Culturementioning

confidence: 99%

Enhancing T cell reconstitution after hematopoietic stem cell transplantation: A brief update of the latest trends

Zakrzewski

Goldberg

Smith

et al. 2008

Blood Cells, Molecules, and Diseases

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Hematopoietic stem cell transplantation (HSCT) is associated with a period of immune incompetence that particularly affects the T cell lineage. Strategies to enhance T cell reconstitution could significantly improve the survival of HSCT recipients by decreasing the incidence of fatal infectious complications and by enhancing graft-versus-tumor activity. In recent years, a variety of promising strategies have been established in preclinical models to improve T cell recovery in particular after allogeneic T cell-depleted HSCT, without aggravating graft-versus-host disease while preserving or even improving graft-versus-tumor activity. These therapies include treatment with keratinocyte growth factor (KGF), growth hormone (GH), LHRH agonists, interleukin 7 (IL-7) and interleukin 15 (IL-15). Thanks to the establishment of Notch-based culture systems, adoptive cellular therapies with T lineage-committed precursor cells have become feasible, since early T cell progenitors can now easily be generated in vitro in large quantities and have been proven to be very effective in enhancing T cell reconstitution and anti-tumor activity after allogeneic T cell-depleted HSCT. The translation of most of these strategies into clinical trials is likely and in some cases Phase I/II studies are already underway.

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“…It has since been recognized as a unique immune response that is critical for the therapy of hematologic and other malignancies (4,5). Multiple cell types such as NK cells, CD4 + , and CD8 + T cells have been implicated in the GVT mechanisms (6)(7)(8). Among them, CD8 + T cells were shown to be a major contributor for GVT activity because of the strong alloantigen specificity (9,10).…”

mentioning

confidence: 99%

A TLR5 Agonist Enhances CD8+ T Cell-Mediated Graft-versus-Tumor Effect without Exacerbating Graft-versus-Host Disease

Ding

Bian

Leigh

et al. 2012

The Journal of Immunology

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Allogeneic hematopoietic cell transplantation is an established treatment for hematologic and nonhematologic malignancies. Donor-derived immune cells can identify and attack host tumor cells, producing a graft-versus-tumor (GVT) effect that is crucial to the effectiveness of the transplantation therapy. CBLB502 is a novel agonist for TLR5 derived from Salmonella flagellin. On the basis of TLR5-mediated immunomodulatory function, we examined the effect of CBLB502 on GVT activity. Using two tumor models that do not express TLR5, and thereby do not directly respond to CBLB502, we found that CBLB502 treatment significantly enhanced allogeneic CD8+ T cell-mediated GVT activity, which was evidenced by decreased tumor burden and improved host survival. Importantly, histopathologic analyses showed that CBLB502 treatment did not exacerbate the moderate graft-versus-host disease condition caused by the allogeneic CD8+ T cells. Moreover, mechanistic analyses showed that CBLB502 stimulates CD8+ T cell proliferation and enhances their tumor killing activity mainly indirectly through a mechanism that involves the IL-12 signaling pathway and the CD11c+ and CD11b+ populations in the bone marrow cells. This study demonstrates a new beneficial effect of CBLB502, and suggests that TLR5-mediated immune modulation may be a promising approach to improve GVT immunity without exacerbating graft-versus-host disease.

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Adoptive transfer of T-cell precursors enhances T-cell reconstitution after allogeneic hematopoietic stem cell transplantation

Cited by 172 publications

References 38 publications

Delayed immune reconstitution after cord blood transplantation is characterized by impaired thymopoiesis and late memory T-cell skewing

Delayed immune reconstitution after cord blood transplantation is characterized by impaired thymopoiesis and late memory T-cell skewing

Enhancing T cell reconstitution after hematopoietic stem cell transplantation: A brief update of the latest trends

A TLR5 Agonist Enhances CD8+ T Cell-Mediated Graft-versus-Tumor Effect without Exacerbating Graft-versus-Host Disease

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