Role of indirect allo- and autoreactivity in anti-tumor responses induced by recipient leukocyte infusions (RLI) in mixed chimeras prepared with nonmyeloablative conditioning

Rubio, Marie‐Thérèse; Zhao, Genshi; Buchli, Jennifer; Chittenden, Meredith; Sykes, Megan

doi:10.1016/j.clim.2006.03.004

Cited by 18 publications

(12 citation statements)

References 24 publications

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“…Antitumor responses of RLI in murine mixed chimeras (MCs) depend on host-vs.-graft reaction (HVGR), which in turn provokes immune responses to tumor-associated antigens expressed by recipient leukemia cells (Rubio et al, 2005, Rubio et al, 2006). Thus, we first assessed the potential of lymphopenia to promote HVGR.…”

Section: Resultsmentioning

confidence: 99%

Modeling Human Leukemia Immunotherapy in Humanized Mice

Xia

Yoshihara

et al. 2016

eBioMedicine

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The currently available human tumor xenograft models permit modeling of human cancers in vivo, but in immunocompromised hosts. Here we report a humanized mouse (hu-mouse) model made by transplantation of human fetal thymic tissue plus hematopoietic stem cells transduced with a leukemia-associated fusion gene MLL-AF9. In addition to normal human lymphohematopoietic reconstitution as seen in non-leukemic hu-mice, these hu-mice showed spontaneous development of B-cell acute lymphoblastic leukemia (B-ALL), which was transplantable to secondary recipients with an autologous human immune system. Using this model, we show that lymphopenia markedly improves the antitumor efficacy of recipient leukocyte infusion (RLI), a GVHD-free immunotherapy that induces antitumor responses in association with rejection of donor chimerism in mixed allogeneic chimeras. Our data demonstrate the potential of this leukemic hu-mouse model in modeling leukemia immunotherapy, and suggest that RLI may offer a safe treatment option for leukemia patients with severe lymphopenia.

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Section: Resultsmentioning

confidence: 99%

Modeling Human Leukemia Immunotherapy in Humanized Mice

Xia

Yoshihara

et al. 2016

eBioMedicine

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“…Since GVHD does not occur in patients or animals that lose chimerism 61-64 , the intentional rejection of engrafted donor bone marrow might provide an interesting strategy for separating GVHD and GVT effects. Our studies in the animal model showed that HVG alloresponses leading to the rejection of engrafted donor bone marrow induce anti-tumor responses 65 , which are associated with development of tumor-specific cell-mediated cytotoxicity 68 . Anti-tumor effects are dependent on IFN-γ produced largely by CD8+ T cells 65,69 and on host invariant NKT cells, which are not required as a source of IFN-γ, but which induce NK cell and dendritic cell activation 67 .…”

Section: Hct As Tumor Immunotherapymentioning

confidence: 81%

Emerging concepts in haematopoietic cell transplantation

Sykes

2012

Nat Rev Immunol

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110

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Haematopoietic cell transplantation (HCT) is the most widely used cellular therapy. It is the only known cure for some hematologic malignancies and has recently been used for additional indications, such as allograft tolerance induction and treatment of autoimmune diseases. Recent advances have enabled HCT in a wider range of patients with improved outcomes. This Review summarizes the latest developments in this therapy, focusing on issues that will impact future advancement.

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“…Prolonged survival was seen among mice challenged with several host strain-specific tumor cell lines after the induction of mixed chimerism and RLI-induced or spontaneous graft rejection (compared with mice treated with conditioning alone, conditioning and RLI, or conditioning and bone marrow transplantation without RLI, thus showing the importance of the initial induction of mixed chimerism followed by graft rejection). Antitumor responses were determined to be mediated by RLI-derived interferon-γproducing CD8 T cells and recipient CD4 cells and were associated with development of tumor-specific cytotoxicity (16). …”

Section: Discussionmentioning

confidence: 99%

Long-Term Follow-Up of Recipients of Combined Human Leukocyte Antigen-Matched Bone Marrow and Kidney Transplantation for Multiple Myeloma With End-Stage Renal Disease

Sykes²,

et al. 2011

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Background Specific tolerance after combined kidney and bone marrow transplantation for multiple myeloma with end-stage renal disease through mixed lymphohematopoietic chimerism has been achieved, as evidenced by prolonged normal renal function without ongoing immunosuppression. Methods To achieve potent antimyeloma responses and induce tolerance for the renal allograft, seven patients (median age: 48 years [range: 34–55 years]) with multiple myeloma and end-stage renal disease underwent a combined human leukocyte antigen-matched kidney and bone marrow transplant with lead follow-up time of more than 12 years. Preparative therapy for the transplant consisted of high-dose cyclophosphamide, equine antithymocyte globulin and pretransplant thymic irradiation. Cyclosporine as the sole posttransplant immunosuppressive therapy was tapered and discontinued as early as day 73 posttransplant. Results All seven patients achieved mixed chimerism. One patient developed acute graft-versus-host disease and two chronic graft-versus-host disease. Five of seven patients are alive, four with no evidence of myeloma from 4 to 12.1 years posttransplant. Three patients have normal or near-normal renal function without needing systemic immunosuppression. Two patients with normal renal function off immunosuppression were returned to immunosuppressive therapy without evidence of rejection because of the occurrence of chronic graft-versus-host disease. Conclusions These long-term follow-up data show that sustained renal allograft tolerance and prolonged antimyeloma responses are achievable after human leukocyte antigen-matched kidney and bone marrow transplantation and the induction of mixed lymphohematopoietic chimerism.

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Role of indirect allo- and autoreactivity in anti-tumor responses induced by recipient leukocyte infusions (RLI) in mixed chimeras prepared with nonmyeloablative conditioning

Cited by 18 publications

References 24 publications

Modeling Human Leukemia Immunotherapy in Humanized Mice

Modeling Human Leukemia Immunotherapy in Humanized Mice

Emerging concepts in haematopoietic cell transplantation

Long-Term Follow-Up of Recipients of Combined Human Leukocyte Antigen-Matched Bone Marrow and Kidney Transplantation for Multiple Myeloma With End-Stage Renal Disease

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