Detection of a potent humoral response associated with immune-induced remission of chronic myelogenous leukemia

Wu, Catherine J.; Yang, Xiaofeng; McLaughlin, Stephen; Neuberg, Donna; Canning, Christine; Stein, Brady L.; Alyea, Edwin P.; Soiffer, Robert J.; Dranoff, Glenn; Ritz, Jérôme

doi:10.1172/jci10196

Cited by 125 publications

(114 citation statements)

References 58 publications

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“…All accession numbers refer to the BLAST database (http://www.ncbi.nlm.nih.gov/BLAST). hCAP-G and APOBEC3B were used for further analysis since these genes are known to have tissue-restricted expression profiles and are SEREX-defined antigens in melanoma patients (Jager et al, 2000b) and a DLI-responder with CML (Wu et al, 2000), respectively. The expression of hCAP-G mRNA is highest in the testis and low in other normal tissues.…”

Section: Hcap-g Sart-1 Apobec3bmentioning

confidence: 99%

Identification of APOBEC3B as a potential target for the graft‐versus‐lymphoma effect by SEREX in a patient with mantle cell lymphoma

et al. 2005

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SummaryRecently, a graft‐versus‐lymphoma (GVL) effect has been shown in patients allografted for mantle cell lymphoma (MCL), but the antigenic targets of this response remain unclear. We screened an MCL cDNA expression library with sera at GVL response after allogeneic haematopoietic stem cell transplantation and isolated five genes including APOBEC3B. Antibody responses to APOBEC3B were correlated with clinical response. Furthermore, APOBEC3B‐specific T‐cell response was induced with one of the HLA‐A*0201 binding peptides. In addition, APOBEC3B mRNA appeared to be upregulated in some MCL. These findings warrant further investigation of APOBEC3B as a candidate gene eliciting an effective immune response against MCL.

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Section: Hcap-g Sart-1 Apobec3bmentioning

confidence: 99%

Identification of APOBEC3B as a potential target for the graft‐versus‐lymphoma effect by SEREX in a patient with mantle cell lymphoma

et al. 2005

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“…These patients thus represent a unique opportunity to examine a consistently effective antitumor response in vivo. Although T cells are presumed to be the critical mediators of graft-versus-leukemia, our previous studies have shown that DLI initiates a complex immune response that includes a potent antibody response to a variety of leukemia-associated antigens (16). Using established methods for serological identification of tumor antigens by recombinant cDNA expression cloning (SEREX) (17,18) we identified a panel of 13 leukemia-associated antigens that were recognized by high titer antibody 1 year after response to DLI.…”

mentioning

confidence: 99%

CML66, a broadly immunogenic tumor antigen, elicits a humoral immune response associated with remission of chronic myelogenous leukemia

Yang

McLaughlin

et al. 2001

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

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This report describes a tumor-associated antigen, termed CML66, initially cloned from a chronic myelogenous leukemia (CML) cDNA expression library. CML66 encodes a 583-aa protein with a molecular mass of 66 kDa and no significant homology to other known genes. CML66 gene is localized to human chromosome 8q23, but the function of this gene is unknown. CML66 is expressed in leukemias and a variety of solid tumor cell lines. When examined by Northern blot, expression in normal tissues was restricted to testis and heart, and no expression was found in hematopoietic tissues. When examined by quantitative reverse transcription-PCR, expression in CML cells was 1.5-fold higher than in normal peripheral blood mononuclear cells. The presence of CML66-specific antibody in patient serum was confirmed by Western blot and the development of high titer IgG antibody specific for CML66 correlated with immune induced remission of CML in a patient who received infusion of normal donor lymphocytes for treatment of relapse. CML66 antibody also was found in sera from 18 -38% of patients with lung cancer, melanoma, and prostate cancer. These findings suggest that CML66 may be immunogenic in a wide variety of malignancies and may be a target for antigen-specific immunotherapy.T he therapeutic benefits of allogeneic bone marrow transplantation (BMT) derive in part from the antitumor effect of high-dose chemotherapy and radiation (1, 2). However, several clinical observations provide convincing evidence that donor immune elements also contribute to the elimination of residual leukemia after BMT. These observations include the reduced risk of relapse after BMT in patients who develop graft-versus-host disease and the increased risk of relapse in patients who receive T cell-depleted donor marrow (3,4). It also has been demonstrated that relapse after BMT often can be successfully treated by donor lymphocyte infusion (DLI) without additional therapy (5-7). The demonstration that adoptive immunotherapy with donor T cells can provide long-lasting remissions provides compelling evidence that these cells play an important role in mediating a graft-versusleukemia (GVL) response after allogeneic BMT (8, 9). Appreciation of the importance of GVL has led to the development of less intensive nonmyeloablative approaches for transplantation of allogeneic hematopoietic stem cells with subsequent infusion of donor T cells to enhance antitumor immunity (10-12). Initial reports using these approaches are encouraging and provide evidence that the therapeutic effects of DLI can be extended to provide effective immunity against solid tumors as well as hematopoietic malignancies (13).Although reconstitution with allogeneic stem cells can provide effective antitumor immunity, the mechanisms whereby donor T cells exert this activity are unknown and the target antigens of this response have not been well defined. To better characterize the antitumor effect of DLI we previously examined the reconstitution of T and B cell immunity in patients with chronic myelocyt...

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“…Studies of CML and myeloma patients demonstrate that GVL or GVM responses are correlated with the development of potent antibody response to antigens which are highly expressed on tumor cells. 32,33 These potential target antigens in CML (CML66 and CML28), and in myeloma (BCMA) have been characterized. [33][34][35][36] Therefore, CD4 þ DLI appears to have a broad effect on immunity, providing help for the expansion of cytolytic CD8 þ donor T cells and also facilitating the development of potent antibody response to potential target antigens.…”

Section: Discussionmentioning

confidence: 99%

CD8+ cell depletion of donor lymphocyte infusions using cd8 monoclonal antibody-coated high-density microparticles (CD8-HDM) after allogeneic hematopoietic stem cell transplantation: a pilot study

Alyea

Canning

Neuberg

et al. 2004

Bone Marrow Transplant

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Summary:A CD8 murine monoclonal antibody-coated high-density microparticle (HDM) has been developed, which allows for the rapid depletion of CD8 þ T cells from apheresis products by gravity sedimentation. We conducted a study to determine the efficacy and safety of CD8 depletion of donor lymphocyte infusions (DLI) to treat relapse after stem cell transplantation using the Eligix CD8-HDM Cell Separation System. Patients were targeted to receive 3 Â 10 7 CD4 þ T cells/kg. Nine patients were enrolled, three with CML, three myeloma, two CLL, and one NHL. A median of 1 Â 10 10 mononuclear cells were obtained by apheresis and processed. The median depletion of CD8 þ cells was 99.3% (97.8À499.5%). CD8 depletion was highly specific, with a median recovery of CD4 þ cells of 75%. A median of 2.9 Â 10 7 CD4 þ cells/ kg was infused. No infusional toxicity was noted. All CML patients achieved a complete molecular remission. A CLL patient demonstrated a complete response. One patient developed GVHD (grade II acute GVHD and subsequently chronic GVHD). The CD8-HDM Cell Separation System appears to be highly selective and effective in depleting CD8 þ T cells from DLI apheresis products, and CD8-depleted DLI is capable of mediating a graft-versus-leukemia effect while minimizing GVHD.

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Detection of a potent humoral response associated with immune-induced remission of chronic myelogenous leukemia

Cited by 125 publications

References 58 publications

Identification of APOBEC3B as a potential target for the graft‐versus‐lymphoma effect by SEREX in a patient with mantle cell lymphoma

Identification of APOBEC3B as a potential target for the graft‐versus‐lymphoma effect by SEREX in a patient with mantle cell lymphoma

CML66, a broadly immunogenic tumor antigen, elicits a humoral immune response associated with remission of chronic myelogenous leukemia

CD8+ cell depletion of donor lymphocyte infusions using cd8 monoclonal antibody-coated high-density microparticles (CD8-HDM) after allogeneic hematopoietic stem cell transplantation: a pilot study

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