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Inotuzumab ozogamicin murine analog-mediated B-cell depletion reduces anti-islet allo- and autoimmune responses.

ABSTRACT: B cells participate in the priming of the allo- and autoimmune responses, and their depletion can thus be advantageous for islet transplantation. Herein, we provide an extensive study of the effect of B-cell depletion in murine models of islet transplantation. Islet transplantation was performed in hyperglycemic B-cell-deficient(?MT) mice, in a purely alloimmune setting (BALB/c into hyperglycemic C57BL/6), in a purely autoimmune setting (NOD.SCID into hyperglycemic NOD), and in a mixed allo-/autoimmune setting (BALB/c into hyperglycemic NOD). Inotuzumab ozogamicin murine analog (anti-CD22 monoclonal antibody conjugated with calicheamicin [anti-CD22/cal]) efficiently depleted B cells in all three models of islet transplantation examined. Islet graft survival was significantly prolonged in B-cell-depleted mice compared with control groups in transplants of islets from BALB/c into C57BL/6 (mean survival time [MST]: 16.5 vs. 12.0 days; P = 0.004), from NOD.SCID into NOD (MST: 23.5 vs. 14.0 days; P = 0.03), and from BALB/c into NOD (MST: 12.0 vs. 5.5 days; P = 0.003). In the BALB/c into B-cell-deficient mice model, islet survival was prolonged as well (MST: ?MT = 32.5 vs. WT = 14 days; P = 0.002). Pathology revealed reduced CD3(+) cell islet infiltration and confirmed the absence of B cells in treated mice. Mechanistically, effector T cells were reduced in number, concomitant with a peripheral Th2 profile skewing and ex vivo recipient hyporesponsiveness toward donor-derived antigen as well as islet autoantigens. Finally, an anti-CD22/cal and CTLA4-Ig-based combination therapy displayed remarkable prolongation of graft survival in the stringent model of islet transplantation (BALB/c into NOD). Anti-CD22/cal-mediated B-cell depletion promotes the reduction of the anti-islet immune response in various models of islet transplantation.

SUBMITTER: Carvello M

PROVIDER: S-EPMC3237644 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Inotuzumab ozogamicin murine analog-mediated B-cell depletion reduces anti-islet allo- and autoimmune responses.

Carvello Michele M Petrelli Alessandra A Vergani Andrea A Lee Kang Mi KM Tezza Sara S Chin Melissa M Orsenigo Elena E Staudacher Carlo C Secchi Antonio A Dunussi-Joannopoulos Kyri K Sayegh Mohamed H MH Markmann James F JF Fiorina Paolo P

Diabetes 20111110 1

B cells participate in the priming of the allo- and autoimmune responses, and their depletion can thus be advantageous for islet transplantation. Herein, we provide an extensive study of the effect of B-cell depletion in murine models of islet transplantation. Islet transplantation was performed in hyperglycemic B-cell-deficient(μMT) mice, in a purely alloimmune setting (BALB/c into hyperglycemic C57BL/6), in a purely autoimmune setting (NOD.SCID into hyperglycemic NOD), and in a mixed allo-/aut ...[more]

PMID: 22076927

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Project description:BACKGROUND:The prognosis for adults with relapsed acute lymphoblastic leukemia is poor. We sought to determine whether inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, results in better outcomes in patients with relapsed or refractory acute lymphoblastic leukemia than does standard therapy. METHODS:In this phase 3 trial, we randomly assigned adults with relapsed or refractory acute lymphoblastic leukemia to receive either inotuzumab ozogamicin (inotuzumab ozogamicin group) or standard intensive chemotherapy (standard-therapy group). The primary end points were complete remission (including complete remission with incomplete hematologic recovery) and overall survival. RESULTS:Of the 326 patients who underwent randomization, the first 218 (109 in each group) were included in the primary intention-to-treat analysis of complete remission. The rate of complete remission was significantly higher in the inotuzumab ozogamicin group than in the standard-therapy group (80.7% [95% confidence interval {CI}, 72.1 to 87.7] vs. 29.4% [95% CI, 21.0 to 38.8], P<0.001). Among the patients who had complete remission, a higher percentage in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease (0.01% marrow blasts) (78.4% vs. 28.1%, P<0.001); the duration of remission was longer in the inotuzumab ozogamicin group (median, 4.6 months [95% CI, 3.9 to 5.4] vs. 3.1 months [95% CI, 1.4 to 4.9]; hazard ratio, 0.55 [95% CI, 0.31 to 0.96]; P=0.03). In the survival analysis, which included all 326 patients, progression-free survival was significantly longer in the inotuzumab ozogamicin group (median, 5.0 months [95% CI, 3.7 to 5.6] vs. 1.8 months [95% CI, 1.5 to 2.2]; hazard ratio, 0.45 [97.5% CI, 0.34 to 0.61]; P<0.001); the median overall survival was 7.7 months (95% CI, 6.0 to 9.2) versus 6.7 months (95% CI, 4.9 to 8.3), and the hazard ratio was 0.77 (97.5% CI, 0.58 to 1.03) (P=0.04). In the safety population, the most frequent grade 3 or higher nonhematologic adverse events with inotuzumab ozogamicin were liver-related. Veno-occlusive liver disease of any grade occurred in 15 patients (11%) who received inotuzumab ozogamicin and in 1 patient (1%) who received standard therapy. CONCLUSIONS:The rate of complete remission was higher with inotuzumab ozogamicin than with standard therapy, and a higher percentage of patients in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease. Both progression-free and overall survival were longer with inotuzumab ozogamicin. Veno-occlusive liver disease was a major adverse event associated with inotuzumab ozogamicin. (Funded by Pfizer; INO-VATE ALL ClinicalTrials.gov number, NCT01564784.).

Project description:INTRODUCTION:No head-to-head studies have compared inotuzumab ozogamicin (InO) and blinatumomab (Blina) for the treatment of adults with relapsed or refractory B cell precursor acute lymphoblastic leukemia (ALL). Indirect treatment comparisons (ITCs), namely network meta-analysis (NMA), anchored matching-adjusted indirect comparison (MAIC), and simulated treatment comparison (STC), were conducted to compare the relative efficacy of these therapies. METHODS:Patient-level data from a study that evaluated InO with standard of care (SoC) chemotherapy (INO-VATE-ALL) and published data from a study that evaluated Blina with SoC chemotherapy (TOWER) were used in the analyses. Endpoints evaluated included remission rate defined as complete remission or complete remission with incomplete hematologic recovery (CR/CRi), hematopoietic stem cell transplantation (HSCT), overall survival (OS), and event-free survival (EFS). For each outcome, treatment-effect modifiers were adjusted for in the anchored MAIC and STC analyses. RESULTS:Analyses showed statistically significant higher rates of remission and HSCT with InO compared to Blina irrespective of the ITC method used or measure of the effect (i.e., odds ratio [OR] or rate difference). The treatment effects derived from the MAIC and STC analyses were consistent and stronger than those estimated from the NMA. A trend favoring InO was detected for EFS. The ITC results for OS suggest no difference between InO and Blina. CONCLUSION:Results from these ITCs indicated a statistically significant advantage for InO over Blina for rates of remission and HSCT in adults with relapsed or refractory B cell precursor ALL. It was not possible to fully adjust for all treatment-effect modifiers, and the similarity in chemotherapy regimens used in the SoC comparator arms of the INO-VATE-ALL and TOWER studies is worthy of further exploration. Both studies, however, used chemotherapy regimens that have a low response rate; therefore, no significant differences in efficacy outcomes are expected between SoC arms. FUNDING:Pfizer Inc, New York, NY. Plain language summary available for this article.

Dataset Information

Inotuzumab ozogamicin murine analog-mediated B-cell depletion reduces anti-islet allo- and autoimmune responses.

Publications

Inotuzumab ozogamicin murine analog-mediated B-cell depletion reduces anti-islet allo- and autoimmune responses.

Similar Datasets

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