Allogeneic cell-mediated immunotherapy of leukemia with immune donor lymphocytes to upregulate antitumor effects and downregulate antihost responses

Ji, Yachun; Weiss, Lola; Zeira, Michael; Abdul-Hai, Ali; Reich, Shoshana; Schuger, Lucia; Slavin, Shimon

doi:10.1038/sj.bmt.1704150

Cited by 23 publications

(10 citation statements)

References 37 publications

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“…21,22), or specifically immune donor lymphocytes (23). We have reported similar observations in patients resistant to DLI successfully treated with donor lymphocytes activated nonspecifically with rIL-2 in vivo or in vitro (6) or donor lymphocytes alloactivated in vitro (24).…”

Section: Introductionsupporting

confidence: 61%

“…These observations imply that temporary engraftment of MHC mismatched effector cells for z2 weeks may be sufficient to induce effective GVL effects against MRD before development of irreversible GVHD. We have also documented that the time required for elimination of MRD following DLI may be shorter if donor cells are activated nonspecifically with rIL-2 (22), or activated specifically against the tumor in mixed lymphocyte-tumor cultures (23). Based on the aforementioned consideration, by extrapolation, successful clinical application of a similar strategy for the treatment of MRD following BMT may be accomplished, depending on a delicate balance between the timing of administration and the intensity of alloreactivity induced by DLI, with the need to assess optimal timing of cyclophosphamide administration to avoid severe and irreversible GVHD.…”

Section: Discussionmentioning

confidence: 99%

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Induction of Early Post-Transplant Graft-versus-Leukemia Effects Using Intentionally Mismatched Donor Lymphocytes and Elimination of Alloantigen-Primed Donor Lymphocytes for Prevention of Graft-versus-Host Disease

Yung¹,

Weiss²,

Abdul-Hai³

et al. 2005

Cancer Research

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Graft-versus-leukemia (GVL) effects can be induced in tolerant mixed chimeras prepared with nonmyeloablative conditioning. GVL effects can be amplified by post-grafting donor lymphocyte infusion (DLI). Unfortunately, DLI is frequently associated with graft-versus-host disease (GVHD). We investigated the feasibility of induction of potent GVL effects by DLI using intentionally mismatched lymphocytes followed by elimination of alloreactive donor T cells by cyclophosphamide for prevention of lethal GVHD following induction of very short yet most potent GVL effects. Mice inoculated with B-cell leukemia (BCL 1 ) and mismatched donor lymphocytes were treated 2 weeks later with low-dose or high-dose cyclophosphamide. All mice receiving cyclophosphamide 2 weeks after DLI survived GVHD, and no residual disease was detected by PCR; all control mice receiving DLI alone died of GVHD. Analysis of host ( female) and donor (male) DNA showed that cyclophosphamide treatment eradicated most alloreactive donor cells, yet mixed chimerism was converted to full donor chimerism following transient selflimited GVHD. Our working hypothesis suggests that short-term yet effective and safe adoptive immunotherapy of leukemia may be accomplished early post-transplantation using alloreactive donor lymphocytes, with prevention of GVHD by elimination of GVL effector cells. (Cancer Res 2005; 65(21): 9735-40)

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Section: Introductionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Induction of Early Post-Transplant Graft-versus-Leukemia Effects Using Intentionally Mismatched Donor Lymphocytes and Elimination of Alloantigen-Primed Donor Lymphocytes for Prevention of Graft-versus-Host Disease

Yung¹,

Weiss²,

Abdul-Hai³

et al. 2005

Cancer Research

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“…18,19 Up to now, however, all the previous studies were depends on the graft-versus-leukemia or graft-versus-tumor response mediated by immunologically competent donor cells in a circumstance of allogeneic HSCT or purely ALI. [19][20][21] Generally, the competent donor cells, which were harvested from identical twin, MHC-identical sibling or MHC partial matched donor, are as the effecter cells to kill the host tumor. In the present study, we tested if an antitumor immunity mediated by tumor-bearing host immune cells could be induced by an inactivated MHC mismatched allogeneic leukocytes which were inactivated to prevent GVHD.…”

Section: Discussionmentioning

confidence: 99%

A simple and effective method for cancer immunotherapy by inactivated allogeneic leukocytes infusion

Guo

Zhou

et al. 2008

Intl Journal of Cancer

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Allogeneic mixed leukocytes reaction has been reported to activate vast numbers of T lymphocytes and produce large amounts of type 1 cytokines that are linked to an initiation of antitumor immunity. Using poor immunogeneic B16-F10 and Lewis lung carcinoma (LLC) tumor model, we evaluated the effects of inactivated allogeneic leukocytes infusion (ALI) on the generation of antitumor immune response, as well as its effect on the primary and metastatic tumor. Allogeneic response promoted the generation of both specific and nonspecific antitumor immunity in an in vitro mixed lymphocytes-tumor cell culture system. Introveinous infusion of mitotically inactivated allogeneic leukocytes resulted in increased type-1 cytokines (including IL-2 and IFN-c) release, proliferation of various lymphocyte subsets, and generation of both specific and nonspecific antitumor immune response. As a result of such immune response, ALI caused a delayed tumor growth and a prolonged survival in established B16-F10 melanoma model. In LLC pulmonary spontaneous metastases model, ALI treatment significantly reduced postoperative tumor metastasis as the lung weights were far smaller than control group (0.16 vs. 0.34 g). Furthermore, after primary tumor resection and ALI treatment, 62.5% mice obtained long-term survival (>120 days) and there were no tumor growths in these mice when they were rechallenged with the same tumor. These experiments demonstrate that inactivated ALI could activate innate and adoptive antitumor immune response. It would be a simple, effective and secured method for cancer immunotherapy. ' 2008 Wiley-Liss, Inc.Key words: cancer; immunotherapy; alloantigen; metastasis Allogeneic transplantation (including heametopoietic stem cell transplantation) has been used as a successful therapeutic modality for various diseases, including malignancies. 1 Nevertheless, there is always a major limitation in the allogeneic transplantation: either host vs. graft (HVG) or graft vs. host (GVH). With a clear manifestation of the mechanisms of transplantation immunology, it is well recognized that alloantigen, a potent immunostimulator, elicits strong and rapid cellular and humoral immune responses, plays a key role in HVG or GVH. However, both HVG and GVH biology share several mechanisms that contribute to antitumor effects that occur outside of allogeneic transplantation, including IFN-g secreting type 1 T cells, 2 antigen presenting cells (APCs) activation, 3 and fas-and perforin-based cytolysis. 4 Therefore, it is possible to harness these characteristics as a therapeutic modality for malignancy.Actually, hematopoietic stem-cell transplantation (HSCT) is under study as a immunotherapeutic modality and achieve considerable effect in a wide range of hematologic and nonhematologic malignancies. 1,5 The basis of this treatment rests on an immune mechanism called the graft-versus-leukemia or graft-versus-tumor effect. Presumably, alloreactive T cells (CD4 and CD8 T cells) in the allograft participate in these phenomena, but the relevant antige...

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“…ELISA reagents were purchased as Opt. EIA Cytokine ELISA sets from BD Biosciences (San Diego, CA, USA) and were used according to the manufacturer's protocol as previously described [16].…”

Section: Cytokine Assaymentioning

confidence: 99%

Cannabidiol lowers incidence of diabetes in non-obese diabetic mice

Weiss¹,

Zeira²,

Reich³

et al. 2006

Autoimmunity

184

132

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Cannabidinoids are components of the Cannabis sativa (marijuana) plant that have been shown capable of suppressing inflammation and various aspects of cell-mediated immunity. Cannabidiol (CBD), a non-psychoactive cannabidinoid has been previously shown by us to suppress cell-mediated autoimmune joint destruction in an animal model of rheumatoid arthritis. We now report that CBD treatment significantly reduces the incidence of diabetes in NOD mice from an incidence of 86% in non-treated control mice to an incidence of 30% in CBD-treated mice. CBD treatment also resulted in the significant reduction of plasma levels of the pro-inflammatory cytokines, IFN-g and TNF-a. Th1-associated cytokine production of in vitro activated T-cells and peritoneal macrophages was also significantly reduced in CBD-treated mice, whereas production of the Th2-associated cytokines, IL-4 and IL-10, was increased when compared to untreated control mice. Histological examination of the pancreatic islets of CBD-treated mice revealed significantly reduced insulitis. Our results indicate that CBD can inhibit and delay destructive insulitis and inflammatory Th1-associated cytokine production in NOD mice resulting in a decreased incidence of diabetes possibly through an immunomodulatory mechanism shifting the immune response from Th1 to Th2 dominance.

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Allogeneic cell-mediated immunotherapy of leukemia with immune donor lymphocytes to upregulate antitumor effects and downregulate antihost responses

Cited by 23 publications

References 37 publications

Induction of Early Post-Transplant Graft-versus-Leukemia Effects Using Intentionally Mismatched Donor Lymphocytes and Elimination of Alloantigen-Primed Donor Lymphocytes for Prevention of Graft-versus-Host Disease

Induction of Early Post-Transplant Graft-versus-Leukemia Effects Using Intentionally Mismatched Donor Lymphocytes and Elimination of Alloantigen-Primed Donor Lymphocytes for Prevention of Graft-versus-Host Disease

A simple and effective method for cancer immunotherapy by inactivated allogeneic leukocytes infusion

Cannabidiol lowers incidence of diabetes in non-obese diabetic mice

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