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John M. Lambert - One of the best experts on this subject based on the ideXlab platform.
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phase i multi dose escalation study of the anti CD19 maytansinoid immunoconjugate sar3419 administered by intravenous iv infusion every 3 weeks to patients with relapsed refractory b cell non hodgkin s lymphoma nhl
Blood, 2009Co-Authors: Anas Younes, Silvana De Castro Farial, Jorge Romaguera, Amanda Copeland, Luis Fayad, Michelle A. Fanale, Larry W. Kwak, Leo I Gordon, Frederick B Hagemeister, John M. LambertAbstract:Abstract 585 France SAR3419 (huB4-DM4)is an antibody–drug conjugate composed of a humanized IgG1 monoclonal antibody, huB4, which specifically targets the CD19 Antigen, conjugated through a disulfide link to the maytansinoid derivative DM4, a potent tubulin inhibitor. After binding to the CD19 Antigen, SAR3419 undergoes internalization, resulting in intracellular release of DM4 that binds to the vinca site. Based on encouraging in vitro and in vivo preclinical activity, a multi-dose phase I study was initiated to determine the maximum tolerated dose, to evaluate the safety, pharmacokinetic properties and anti-tumor activity of SAR3419 in patients with relapsed/refractory B-cell NHL expressing the CD19 Antigen. Patients received SAR3419 by IV infusion once every 21 days. Patients were eligible if they had CD19+ relapsed or refractory B-cell lymphoma irrespective of the number of prior treatment regimens, including previous allogeneic stem cell transplant. To date, 29 patients have been enrolled on 7 dose levels ranging from 10-270 mg/m2. The histologic subtypes were follicular (FL;12), small lymphocytic (SLL;5), marginal zone (MZL;2) mantle cell (MCL;5) and diffuse large B-cell (DLBCL;4). The median number of prior treatment regimens was 4 (range 1-11), and 7 patients had prior autologous or allogeneic stem cell transplantation. The dose limiting toxicity (DLT) was reversible severe blurred vision, associated with microcystic epithelial corneal changes. This DLT was first observed in one patient at 208 mg/m2 during cycle 2 (grade 4). Consequently, patients having received the first dose of 270 mg/m2 continued on treatment at the dose of 208 mg/m2. 4 out of the remaining 8 patients treated with 208 mg/m2 experienced at least one episode of reversible grade 3 blurred vision during cycle 2 or a later cycle, requiring treatment with topical steroids and dose delay of 1-2 weeks to allow recovery. Therefore, an additional 15 patients will be dosed at the previous dose cohort of 160 mg/m2 to confirm the safety and to collect preliminary data on the efficacy of this dose. A total of 25 patients have completed at least 2 cycles of treatment with SAR3419 and are evaluable for tumor response. Seventeen (68%) patients demonstrated reduction in their tumor measurements ranging between 7% and 86%, of whom 5 patients achieved partial (n=2) or complete (n=3) remissions. Seven (53%) of 13 patients with rituximab refractory disease demonstrated reduction in their tumor measurement ranging between 15% and 86%. Pharmacokinetic profile of SAR3419 is characterized by linear kinetics, low clearance from 0.4 to 0.7 L/day/m 2 and an elimination half-life in the range of 3 to 7 days. Low levels of free DM4 and DM4-methyl were detectable only at and above the dose of 80 mg/m2 (LOQ = 1ng/mL). Their exposure increased with the dose. Collectively, these results demonstrate evidence of acceptable safety and clinical activity of SAR3419 in patients with relapsed B-cell malignancies including those who were refractory to rituximab. Furthermore, the lack of significant hematologic toxicity may provide an opportunity for combining SAR3419 with other active regimens for the treatment of lymphoma. Enrolment continues in the extension cohort at 160 mg/m2. Disclosures: Younes: sanofi Aventis: Honoraria, Research Funding. Off Label Use: SAR3419. Lambert: ImmunoGen: Employment. Bagulho: Sanofi-Aventis: Employment. Morariu-Zamfir: Sanofi-Aventis: Employment.
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Elimination of B-lineage leukemia and lymphoma cells from bone marrow grafts using anti-B4-blocked-ricin immunotoxin
Journal of Clinical Immunology, 1995Co-Authors: Denis C. Roy, John M. Lambert, Claude Perreault, Robert Bélanger, Martin Gyger, Christiane Houillier, Walter A. Blättler, Jerome RitzAbstract:Bone marrow is the primary site of disease in patients with acute lymphoblastic leukemia (ALL) and is frequently involved in patients with non-Hodgkin's lymphoma (NHL). At the time of autologous bone marrow transplantation, marrow grafts from patients with leukemia and lymphoma are often still contaminated by malignant cells, even when such patients achieve complete clinical remission. In this study, we evaluated the potential of anti-B4-blocked-ricin (anti-B4-bR) immunotoxin to eliminate residual ALL and NHL cells from bone marrow. Anti-B4-bR binds to the CD19 Antigen, which is B-lineage specific, and, at concentrations of 5×10^−9 M or greater, could eliminate more than 3 logs of CD19+ Nalm-6 or Namalwa cells in a 20-fold excess of normal irradiated bone marrow after only 5 hr of incubation. This activity was abrogated by the addition of anti-B4 but not by the presence of galactose, which is the natural ligand for native ricin. Also, when used at these high concentrations, anti-B4-bR showed little nonspecific toxicity against normal hematopoietic progenitors. In conclusion, a single short exposure to anti-B4-bR is capable of inducing high levels of depletion of CD19+ leukemia and lymphoma cells without significant nonspecific toxicity against normal marrow progenitors. Therefore, anti-B4-bR offers an interesting approach to the elimination of B-lineage malignant cells prior to autologous bone marrow transplantation.
Roch Houot - One of the best experts on this subject based on the ideXlab platform.
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phase i ii study of the anti CD19 maytansinoid immunoconjugate sar3419 administered weekly to patients pts with relapsed refractory b cell non hodgkin lymphoma nhl
Journal of Clinical Oncology, 2011Co-Authors: B Coiffier, Vincent Ribrag, Jehan Dupuis, H Tilly, C Haioun, F Morschhauser, T Lamy, Christiane Copiebergman, Oana Brehar, Roch HouotAbstract:8017 Background: SAR3419 (huB4-DM4) is an antibody–drug conjugate composed of a humanized IgG1 monoclonal antibody, huB4, which specifically targets the CD19 Antigen, conjugated through a disulfide link to the maytansinoid derivative DM4, a potent tubulin inhibitor. After binding to the CD19 Antigen, SAR3419 undergoes internalization and intracellular release of DM4. Methods: In this phase I/II study SAR3419 was administered by intravenous infusion, weekly for 8 to 12 doses, to pts with relapsed/refractory B-cell NHL expressing CD19. Results: Forty-four pts were enrolled at 7 dose levels from 10 to 70 mg/m². Main histologies were follicular (18; 41%) and diffuse large B-cell (17; 39%). Median number of prior regimens was 3 (1-8) and 19 pts had received prior transplantation. Twenty-eight pts were enrolled in the dose escalation part. Of 6 pts at 70 mg/m², 1 pt had a protocol defined dose limiting toxicity of neutropenia and 2 pts had grade 2 significant toxicities with late onset: blurred vision associate...
Larry W. Kwak - One of the best experts on this subject based on the ideXlab platform.
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Antitumor efficacy of BAFF-R targeting CAR T cells manufactured under clinic-ready conditions
Cancer Immunology Immunotherapy, 2020Co-Authors: Zhenyuan Dong, Xiuli Wang, Wesley A Cheng, D. Lynne Smith, Brian Huang, Tiantian Zhang, Wen-chung Chang, Stephen J. Forman, Larry W. KwakAbstract:B-cell malignancies can potentially be cured by CD19 chimeric Antigen receptor (CAR) T-cell therapy. Although clinical response rates can be up to 93% in acute lymphoblastic leukemia, treatment-related Antigen loss and lack of therapeutic persistence contribute to disease relapse. These shortcomings of current CAR T-cell therapy indicate the need for biologically relevant target selection and for improving the efficacy and persistence of the CAR T cells, which we have addressed by developing a novel B-cell activating factor receptor (BAFF-R) CAR T-cell therapy with improved therapeutic persistence. BAFF-R is a B-cell survival receptor and highly expressed in B-cell malignancies. We developed a prototype CAR T cell that efficiently and specifically eliminated BAFF-R expressing human B-cell tumors in several xenogeneic mouse models, including models of CD19 Antigen loss. We proceeded with translational development and validation of BAFF-R CAR T cells produced under current good manufacturing practices (cGMP). cGMP-grade BAFF-R CAR T cells underwent in vitro and in vivo validation in established models to confirm that the potency and efficacy of our original research modeling was replicated. Food and Drug Administration required release testing was performed to ensure our BAFF-R CAR T cells meet specifications for new drug products. Completing and exceeding these requirements, the data fully support the initiation of a first-in-human Phase 1 trial for BAFF-R-positive relapsed/refractory (r/r) B-ALL.
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phase i multi dose escalation study of the anti CD19 maytansinoid immunoconjugate sar3419 administered by intravenous iv infusion every 3 weeks to patients with relapsed refractory b cell non hodgkin s lymphoma nhl
Blood, 2009Co-Authors: Anas Younes, Silvana De Castro Farial, Jorge Romaguera, Amanda Copeland, Luis Fayad, Michelle A. Fanale, Larry W. Kwak, Leo I Gordon, Frederick B Hagemeister, John M. LambertAbstract:Abstract 585 France SAR3419 (huB4-DM4)is an antibody–drug conjugate composed of a humanized IgG1 monoclonal antibody, huB4, which specifically targets the CD19 Antigen, conjugated through a disulfide link to the maytansinoid derivative DM4, a potent tubulin inhibitor. After binding to the CD19 Antigen, SAR3419 undergoes internalization, resulting in intracellular release of DM4 that binds to the vinca site. Based on encouraging in vitro and in vivo preclinical activity, a multi-dose phase I study was initiated to determine the maximum tolerated dose, to evaluate the safety, pharmacokinetic properties and anti-tumor activity of SAR3419 in patients with relapsed/refractory B-cell NHL expressing the CD19 Antigen. Patients received SAR3419 by IV infusion once every 21 days. Patients were eligible if they had CD19+ relapsed or refractory B-cell lymphoma irrespective of the number of prior treatment regimens, including previous allogeneic stem cell transplant. To date, 29 patients have been enrolled on 7 dose levels ranging from 10-270 mg/m2. The histologic subtypes were follicular (FL;12), small lymphocytic (SLL;5), marginal zone (MZL;2) mantle cell (MCL;5) and diffuse large B-cell (DLBCL;4). The median number of prior treatment regimens was 4 (range 1-11), and 7 patients had prior autologous or allogeneic stem cell transplantation. The dose limiting toxicity (DLT) was reversible severe blurred vision, associated with microcystic epithelial corneal changes. This DLT was first observed in one patient at 208 mg/m2 during cycle 2 (grade 4). Consequently, patients having received the first dose of 270 mg/m2 continued on treatment at the dose of 208 mg/m2. 4 out of the remaining 8 patients treated with 208 mg/m2 experienced at least one episode of reversible grade 3 blurred vision during cycle 2 or a later cycle, requiring treatment with topical steroids and dose delay of 1-2 weeks to allow recovery. Therefore, an additional 15 patients will be dosed at the previous dose cohort of 160 mg/m2 to confirm the safety and to collect preliminary data on the efficacy of this dose. A total of 25 patients have completed at least 2 cycles of treatment with SAR3419 and are evaluable for tumor response. Seventeen (68%) patients demonstrated reduction in their tumor measurements ranging between 7% and 86%, of whom 5 patients achieved partial (n=2) or complete (n=3) remissions. Seven (53%) of 13 patients with rituximab refractory disease demonstrated reduction in their tumor measurement ranging between 15% and 86%. Pharmacokinetic profile of SAR3419 is characterized by linear kinetics, low clearance from 0.4 to 0.7 L/day/m 2 and an elimination half-life in the range of 3 to 7 days. Low levels of free DM4 and DM4-methyl were detectable only at and above the dose of 80 mg/m2 (LOQ = 1ng/mL). Their exposure increased with the dose. Collectively, these results demonstrate evidence of acceptable safety and clinical activity of SAR3419 in patients with relapsed B-cell malignancies including those who were refractory to rituximab. Furthermore, the lack of significant hematologic toxicity may provide an opportunity for combining SAR3419 with other active regimens for the treatment of lymphoma. Enrolment continues in the extension cohort at 160 mg/m2. Disclosures: Younes: sanofi Aventis: Honoraria, Research Funding. Off Label Use: SAR3419. Lambert: ImmunoGen: Employment. Bagulho: Sanofi-Aventis: Employment. Morariu-Zamfir: Sanofi-Aventis: Employment.
Barbara Savoldo - One of the best experts on this subject based on the ideXlab platform.
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inducible caspase 9 selectively modulates the toxicities of CD19 specific chimeric Antigen receptor modified t cells
Molecular Therapy, 2017Co-Authors: Iulia Diaconu, Brandon Ballard, Ming Zhang, Yuhui Chen, John A West, Gianpietro Dotti, Barbara SavoldoAbstract:Immunotherapy with T cells expressing the chimeric Antigen receptor (CAR) specific for the CD19 Antigen (CD19.CAR-Ts) is a very effective treatment in B cell lymphoid malignancies. However, B cell aplasia and cytokine release syndrome (CRS) secondary to the infusion of CD19.CAR-Ts remain significant drawbacks. The inclusion of safety switches into the vector encoding the CAR is seen as the safest method to terminate the effects of CD19.CAR-Ts in case of severe toxicities or after achieving long-term sustained remissions. By contrast, the complete elimination of CD19.CAR-Ts when CRS occurs may jeopardize clinical responses as CRS and antitumor activity seem to concur. We have demonstrated, in a humanized mouse model, that the inducible caspase-9 (iC9) safety switch can eliminate CD19.CAR-Ts in a dose-dependent manner, allowing either a selective containment of CD19.CAR-T expansion in case of CRS or complete deletion on demand granting normal B cell reconstitution.
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cd28 costimulation improves expansion and persistence of chimeric Antigen receptor modified t cells in lymphoma patients
Journal of Clinical Investigation, 2011Co-Authors: Barbara Savoldo, Carlos A Ramos, Martha P Mims, Michael J Keating, George Carrum, Rammurti T Kamble, Catherine M BollardAbstract:Targeted T cell immunotherapies using engineered T lymphocytes expressing tumor-directed chimeric Antigen receptors (CARs) are designed to benefit patients with cancer. Although incorporation of costimulatory endodomains within these CARs increases the proliferation of CAR-redirected T lymphocytes, it has proven difficult to draw definitive conclusions about the specific effects of costimulatory endodomains on the expansion, persistence, and antitumor effectiveness of CAR-redirected T cells in human subjects, owing to the lack of side-by-side comparisons with T cells bearing only a single signaling domain. We therefore designed a study that allowed us to directly measure the consequences of adding a costimulatory endodomain to CAR-redirected T cells. Patients with B cell lymphomas were simultaneously infused with 2 autologous T cell products expressing CARs with the same specificity for the CD19 Antigen, present on most B cell malignancies. One CAR encoded both the costimulatory CD28 and the ζ-endodomains, while the other encoded only the ζ-endodomain. CAR+ T cells containing the CD28 endodomain showed strikingly enhanced expansion and persistence compared with CAR+ T cells lacking this endodomain. These results demonstrate the superiority of CARs with dual signal domains and confirm a method of comparing CAR-modified T cells within individual patients, thereby avoiding patient-to-patient variability and accelerating the development of optimal T cell immunotherapies.
B Coiffier - One of the best experts on this subject based on the ideXlab platform.
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phase i ii study of the anti CD19 maytansinoid immunoconjugate sar3419 administered weekly to patients pts with relapsed refractory b cell non hodgkin lymphoma nhl
Journal of Clinical Oncology, 2011Co-Authors: B Coiffier, Vincent Ribrag, Jehan Dupuis, H Tilly, C Haioun, F Morschhauser, T Lamy, Christiane Copiebergman, Oana Brehar, Roch HouotAbstract:8017 Background: SAR3419 (huB4-DM4) is an antibody–drug conjugate composed of a humanized IgG1 monoclonal antibody, huB4, which specifically targets the CD19 Antigen, conjugated through a disulfide link to the maytansinoid derivative DM4, a potent tubulin inhibitor. After binding to the CD19 Antigen, SAR3419 undergoes internalization and intracellular release of DM4. Methods: In this phase I/II study SAR3419 was administered by intravenous infusion, weekly for 8 to 12 doses, to pts with relapsed/refractory B-cell NHL expressing CD19. Results: Forty-four pts were enrolled at 7 dose levels from 10 to 70 mg/m². Main histologies were follicular (18; 41%) and diffuse large B-cell (17; 39%). Median number of prior regimens was 3 (1-8) and 19 pts had received prior transplantation. Twenty-eight pts were enrolled in the dose escalation part. Of 6 pts at 70 mg/m², 1 pt had a protocol defined dose limiting toxicity of neutropenia and 2 pts had grade 2 significant toxicities with late onset: blurred vision associate...