In vivo CAMPATH-1H prevents GvHD following nonmyeloablative stem-cell transplantation

Kottaridis, PD; Milligan, Donald; Chopra, Rajesh; Chakraverty, Ronjon; Chakrabarti, Suparno; Robinson, Stephen; Peggs, Karl S.; Verfuerth, Stephanie; Pettengell, Ruth; Marsh, Judith; Schey, Steve; Mahendra, Premini; Morgan, Gareth J.; Hale, Geoff; Waldmann, Herman; Elvira, M C Ruiz de; Williams, Catherine; Devereux, Stephen; Linch, David C.; Goldstone, Anthony H.; Mackinnon, Stephen

doi:10.1080/146532401753174025

Cited by 235 publications

(320 citation statements)

References 16 publications

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“…The in vivo use of ATG, with its prolonged half-life, as part of the conditioning regimen in our study might have contributed to the low incidence of GVHD. This finding is in agreement with the results of studies by Kottaridis and colleagues, and Chakraverty and colleagues, using the humanized monoclonal antibody CAMPATH-1H (Kottaridis et al, 2000;Chakraverty et al, 2002), and also Kröger and colleagues using ATG (Kröger et al, 2002). The GVHD prophylaxis used was effective for the prevention of GVHD, not only in recipients of a graft from an HLA-identical sibling, but also from HLA-matched and partially mismatched unrelated donors.…”

Section: Discussionsupporting

confidence: 90%

Follow‐up of patients with progressive multiple myeloma undergoing allografts after reduced‐intensity conditioning

Einsele¹,

Schäfer²,

Hebart³

et al. 2003

Br J Haematol

107

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Summary. Allogeneic stem cell transplantation (allo‐SCT) after reduced‐intensity conditioning was evaluated in 22 patients (median age 53, range 36–66 years) with multiple myeloma with progression after an autologous SCT. Seven patients received a transplant from a human leucocyte antigen (HLA)‐identical sibling and 15 patients (68%) from an unrelated donor [including 3/22 (14%) from a HLA‐mismatched unrelated donor]. Graft‐versus‐host disease (GVHD) prophylaxis consisted of serotherapy with antithymocyte globulin (ATG) and cyclosporine (CSA) (n = 12) or CSA plus mycophenolate mofetil (n = 10). Despite of heavy pretreatment, the transplant‐related mortality (TRM) for all grafted patients was acceptable at 5/22 patients (23%). Seven of 21 patients (33%) that were evaluated developed grade II GVHD and one (5%) patient developed grade III/IV acute GVHD. Seven patients developed chronic GVHD (cGVHD), but only one was extensive. Eleven patients died of progressive disease within a median of 7 months (2–19 months) post transplant. Thirteen of all 22 patients (59%) achieved a partial or complete remission with six of these 13 patients (46%) remaining event free at a median of 24 months (range 8–36 months) post allografting. Estimated 2 year overall and event‐free survival was, respectively, 25·5% and 22·0% for the whole patient group, and 62·5% and 57·1% for patients with chemosensitive disease. Chemorefractory disease prior to allogeneic stem cell transplantation (P = 0·0182) and absence of cGVHD (P = 0·069) were associated with shorter event‐free survival. Thus long‐term disease control can be achieved, but is restricted to patients responding to prior salvage chemotherapy.

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Section: Discussionsupporting

confidence: 90%

Follow‐up of patients with progressive multiple myeloma undergoing allografts after reduced‐intensity conditioning

Einsele¹,

Schäfer²,

Hebart³

et al. 2003

Br J Haematol

107

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“…Recently, several mAbs that predominantly act by ADCC and CDC have been approved for the treatment of cancer patients. These include chimaeric IgG1 mAb rituximab (Rituxan s ) binding to the B-cell differentiation antigen CD20 for the treatment of Bcell lymphomas (Grillo-Lopez et al, 1999;Smith, 2003), humanised IgG1 mAb trastuzumab (Herceptin s ) targeting HER-2 (human epithelial growth factor receptor type 2) overexpressed in a subgroup of breast cancers (Vogel et al, 2001), humanised IgG1 alemtuzumab (Campath s ) targeting the differentiation antigen CD52 for the treatment of B-cell chronic lymphocytic leukaemia (Hale et al, 1998;Kottaridis et al, 2000;Faulkner et al, 2004) and edrecolomab (Panorex s ), a murine IgG2a mAb targeting Ep-CAM (epithelial cell adhesion molecule), which gained temporary approval in Germany for the treatment of colorectal carcinoma (Riethmuller et al, 1994;Gruber et al, 1996;Schwartzberg, 2001;White et al, 2001). Several other mAbs are currently at advanced stages of clinical development.…”

mentioning

confidence: 99%

Cellular and complement-dependent cytotoxicity of Ep-CAM-specific monoclonal antibody MT201 against breast cancer cell lines

Prang¹,

Preithner²,

Brischwein³

et al. 2005

Br J Cancer

130

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MT201 is a fully human monoclonal IgG1 antibody with moderate affinity for epithelial cell adhesion molecule (Ep-CAM) being clinically developed for the treatment of carcinomas. Like many other clinically validated IgG1 monoclonal antibodies, MT201 primarily acts by antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Here, we analysed ADCC and CDC induced by MT201 and, as reference, trastuzumab against a panel of nine human breast cancer cell lines expressing distinct surface levels of Ep-CAM and human epithelial growth factor receptor type 2 antigen. Maximal cell lysis by ADCC by MT201 and trastuzumab in the presence of peripheral mononuclear cells did not significantly differ when averaged over the nine cell lines, but showed marked differences with respect to individual cell lines. The extent of cell lysis at intermediate surface target density was highly variable, suggesting a dominant influence of other susceptibility factors. Only one breast cancer cell line was eliminated via CDC, but only by MT201. Resistance to CDC appeared to correlate with high expression levels of complement resistance factors. Our present data as well as recent data on the prevalence and prognostic relevance of Ep-CAM expression in metastatic breast cancer suggest that Ep-CAM-specific monoclonal IgG1 antibodies may have a significant therapeutic potential in the treatment of breast cancer.

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“…15,17,18 The in vivo administration of alemtuzumab results in profound immunosuppression, significantly reducing GVHD when compared with T-cell replete transplants for a variety of haematological malignancies. 12,13,[18][19][20][21][22][23][24][25] Conversely, as a result of the depletion of the lymphocytes and APCs involved in GVL as well as GVHD, alemtuzumab has been associated with increased risk of relapse 26 In addition, alemtuzumab is associated with poor immune recovery post transplant, 26 and it is now apparent that an increased risk of infections after transplant with alemtuzumab is a significant cause of morbidity and mortality. 27,28 Balancing these competing effects in favour of low non-relapse mortality is the goal of the effective use of alemtuzumab.…”

Section: Introductionmentioning

confidence: 99%

“…4,8 Reduced-intensity conditioning (RIC) regimens have been developed that allow stable engraftment and low non-relapse mortality allowing allografting to be feasible in older patients. [9][10][11][12] Although these protocols are better tolerated, GVHD and infection remain considerable barriers to successful outcomes.…”

Section: Introductionmentioning

confidence: 99%

Alemtuzumab markedly reduces chronic GVHD without affecting overall survival in reduced-intensity conditioning sibling allo-SCT for adults with AML

Malladi

Peniket

Littlewood

et al. 2008

Bone Marrow Transplant

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By retrospective analysis of 88 patients from the British Society of Blood and Marrow Transplantation registry, we investigated the effect of in vivo T-cell depletion in HLA-identical sibling reduced-intensity conditioning (RIC) allografts for adult AML by comparing patients who received alemtuzumab with those without alemtuzumab conditioning. Both groups were equivalent for age, sex, karyotype and disease status at transplant. With a median follow-up of 27 months (3-72 months) and 48 months (7-72 months), the 2-and 5-year overall survival, with or without alemtuzumab, is 60 and 60% (P ¼ 0.80) and 61 and 53%, respectively (P ¼ 0.85). The 2-year nonrelapse mortality is 12% with alemtuzumab, and 17% without alemtuzumab (P ¼ 0.49). The 2-year relapse rate is 35% with alemtuzumab compared with 19% without alemtuzumab (P ¼ 0.28). Grades II-IV acute GVHD occurred in 22% (8/37) without alemtuzumab compared with 14% (7/51) given alemtuzumab (P ¼ 0.25). Extensive chronic GVHD occurred in 47% (14/30) not given alemtuzumab compared with 4% (2/45) who were given alemtuzumab (P ¼ 0.001). Among evaluable patients, the risk of infections was higher in those treated with alemtuzumab compared with those not treated with alemtuzumab (79 vs 57%, respectively, P ¼ 0.02). In conclusion, alemtuzumab has a beneficial effect by reducing chronic GVHD without affecting overall survival. Further studies are warranted before alemtuzumab can be recommended as standard in RIC allografts for AML.

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In vivo CAMPATH-1H prevents GvHD following nonmyeloablative stem-cell transplantation

Cited by 235 publications

References 16 publications

Follow‐up of patients with progressive multiple myeloma undergoing allografts after reduced‐intensity conditioning

Follow‐up of patients with progressive multiple myeloma undergoing allografts after reduced‐intensity conditioning

Cellular and complement-dependent cytotoxicity of Ep-CAM-specific monoclonal antibody MT201 against breast cancer cell lines

Alemtuzumab markedly reduces chronic GVHD without affecting overall survival in reduced-intensity conditioning sibling allo-SCT for adults with AML

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