The Experts below are selected from a list of 324 Experts worldwide ranked by ideXlab platform

Robert Tiller - One of the best experts on this subject based on the ideXlab platform.

Shannon L Maude - One of the best experts on this subject based on the ideXlab platform.

  • efficacy and safety of ctl019 in the first us phase ii multicenter trial in pediatric relapsed refractory acute lymphoblastic leukemia results of an interim analysis
    Blood, 2016
    Co-Authors: Shannon L Maude, Michael A Pulsipher, Michael Boyer, Stephan A Grupp, Stella M Davies, Christine L Phillips, Michael R Verneris, Keith J August
    Abstract:

    Background: CTL019 is an investigational therapy derived from autologous T-cells expressing a CD19-specific chimeric antigen receptor (CAR). A single center, phase I/IIa trial of CTL019 showed complete and durable remissions in pediatric/young adult patients (pts) with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) (Maude et al NEJM 2014); these results have yet to be reproduced in a multicenter setting. Here, we report results from a 6-month interim analysis of the first multicenter phase II trial of an engineered cell therapy in leukemia. Methods: 9 US sites participated in this single-arm phase II study in pediatric/young adult pts with R/R B-ALL. Leukapheresis products were shipped for centralized manufacturing according to the University of Pennsylvania (Penn) process in an academic-industry collaboration. T cells were transduced with a lentiviral vector encoding a CAR composed of anti-CD19 scFv, CD3ζ and 4-1BB domains. Following lymphodepletion with fludarabine and cyclophosphamide, a single dose of CTL019 cells was administered (target dose 2.0-5.0×10 6 cells/kg for ≤50 kg and 1.0-2.5×10 8 cells for >50 kg). The primary endpoint was overall remission rate (ORR = CR + CRi [CRi, complete remission with incomplete blood count recovery] maintained at 2 evaluations ≥28 days apart) as determined by an Independent Review Committee. Secondary objectives included minimal residual disease (MRD), relapse-free survival (RFS), overall survival (OS) and safety. All analyses were performed on infused patient set. Results: 29/35 pts enrolled (82.9%) were infused with CTL019; 6 withdrew prior to infusion (2 manufacturing failures [1 lack of growth, 1 contamination]; 4 deaths [median, 48 days from enrollment; 2 progressive disease, 1 multi-organ failure, 1 pneumonia]). Mean bone marrow involvement at enrollment was 68.2% (SD, 27.3%; Table 1). 2 pts did not receive lymphodepleting chemotherapy due to leukopenia. Collection, manufacturing and infusion were feasible in a multicenter setting with a median time from enrollment to infusion of 37 days. Target cell dose was met in 24/33 (72.7%) manufactured products. ORR in all infused pts was 69.0% (20/29 pts; 98.95% CI 43.6, 88.1). Of the 5 pts who received CTL019 below the target dose, 2 achieved CR/CRi. Of note, deep remission with no evidence of MRD ( Conclusions: In this first multicenter trial of CAR-modified T cell therapy, CTL019 therapy was feasible and efficacious, showing a high ORR with durable remissions in pediatric/young adult pts with R/R B-ALL. Despite the high rate of toxicity with CTL019 in the R/R setting, the rate of grade 3 or 4 CRS was comparable to the single center study, and standardized management of CRS was successful in a multicenter trial with no deaths attributable to CRS. In this highly refractory population, a vast majority of eligible pts can be successfully infused in a timely fashion and outcomes appear reproducible in a multicenter setting despite a more heterogeneous population than the single center study. The trial is continuing under Novartis manufacturing. Disclosures Maude: Novartis: Consultancy. Pulsipher: Medac: Other: Travel support for a study group; Chimerix: Consultancy, Other: Advisory Board ; Jazz Pharmaceutical: Consultancy, Other: Advisory Board; Novartis: Consultancy, Other: Advisory Board, Steering Committee for Phase II Study. Grupp: Pfizer: Consultancy; Novartis: Consultancy, Research Funding. Davies: Novartis: Honoraria. Verneris: Bimogen: Other: Advisory Board. Schlis: Novartis: Honoraria. Driscoll: Novartis: Consultancy. June: Immune Design: Consultancy, Equity Ownership; Pfizer: Honoraria; Celldex: Consultancy, Equity Ownership; Novartis: Honoraria, Patents & Royalties, Research Funding; Johnson & Johnson: Honoraria; Novartis: Honoraria, Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership. Levine: GE Healthcare Bio-Sciences: Consultancy; Novartis: Patents & Royalties, Research Funding. Wood: Novartis Pharmaceuticals: Employment, Other: Stock. Yi: Novartis: Employment.

  • efficacy of humanized cd19 targeted chimeric antigen receptor car modified t cells in children and young adults with relapsed refractory acute lymphoblastic leukemia
    Blood, 2016
    Co-Authors: David M. Barrett, Shannon L Maude, Susan R Rheingold, Richard Aplenc, David T Teachey
    Abstract:

    Background Targeted immunotherapy with CTL019, CD19-specific chimeric antigen receptor (CAR)-modified T cells, can produce potent and sustained responses in children with relapsed/refractory acute lymphoblastic leukemia (ALL). However, a subset of patients has limited persistence, which can increase the risk of relapse. Most CAR single chain variable fragment (scFv) domains, including that of CTL019, are of murine origin; therefore, anti-mouse reactivity is one potential cause of immune-mediated rejection that may be overcome by fully human or humanized CAR Designs. We developed a humanized anti-CD19 scFv domain and now report on treatment with humanized CD19-directed CAR T cells (CTL119). Design A pilot/phase 1 study of CAR-modified T cells containing a humanized anti-CD19 scFv domain (CTL119) enrolled children and young adults with relapsed/refractory B-ALL with or without prior exposure to a CAR T cell product. Patients previously treated with CD19-specific CAR-modified T cells were eligible if they met 1 of 3 criteria: 1) CD19+ relapse 2) no response to prior CAR T cell therapy or 3) early B cell recovery indicating poor persistence of CAR T cells. Patient-derived T cells were transduced ex vivo with a lentiviral vector encoding a CAR composed of CD3z, 4-1BB, and humanized anti-CD19 scFv domains and activated/expanded with anti-CD3/CD28 beads. The humanized scFv domain was developed by grafting the complementary determining regions of both the heavy and light chains onto human germline acceptor frameworks. Patients received lymphodepletion with cyclophosphamide and fludarabine 1 week prior to infusion with CTL119. Results Thirty children and young adults aged 29 mo-24 yr were infused with CTL119. Eighteen patients had received prior allogeneic stem cell transplant (SCT). Eleven patients who previously received murine-derived CD19-specific CAR-modified T cells (CTL019, n=7; other, n=4) were retreated for B cell recovery (n=5), CD19+ relapse (n=5), or no response to prior CAR T cells (n=1). CNS disease or other extramedullary disease was the indication for enrollment in 6 and 3 patients, respectively. At assessment 1 month after infusion, 26/30 patients (87%) achieved a complete response (CR), defined as morphologic remission with B cell aplasia. Of 11 patients previously treated with murine CD19-specific CAR-modified T cells, 7 (64%) achieved a CR at 1 month, 4 demonstrated no response. Multiparameter flow cytometry for minimal residual disease (MRD) was negative at a detection level of 0.01% in 5/7 responding patients. Two responding patients with positive MRD progressed to CD19+ relapse at 1.6 and 3 mo. In patients with no prior exposure to a CD19 CAR T cell product, MRD-negative CR was achieved in 19/19 patients (100%). One patient relapsed with CD19+ extramedullary disease at 2.8 mo. With a median follow-up of 4.2 mo (range, 1.0-14.1 mo) for all responding patients in both cohorts, 23/26 remain in remission with 1 proceeding to SCT in remission. B cell aplasia, a functional marker of CD19-targeted CAR T cell persistence, continued for 3 months or more in 11/18 patients with adequate follow-up: 1/6 retreatment, 10/12 CAR-naive. Cytokine release syndrome (CRS) was observed in 28/30 patients and mild in most patients (grade 1, n=6; grade 2, n=18). Three patients experienced grade 3 CRS requiring supplemental oxygen or low-dose vasopressor support and 1 experienced grade 4 CRS requiring high-dose vasopressor and ventilatory support. Severe CRS was successfully managed with the IL6R antagonist tocilizumab in 3 patients. Neurologic toxicity included encephalopathy (n=5) and seizure (n=4) and was fully reversible. Conclusion In the first study of humanized anti-CD19 CAR T cells, CTL119 induced remissions in children and young adults with relapsed/refractory B-ALL, including 64% of patients previously treated with murine CD19-directed CAR T cells and 100% of CAR-naive patients. Further investigation into CAR T cell persistence and anti-CAR responses will be vital to improve durable remission rates in this highly refractory population. Disclosures Maude: Novartis: Consultancy. Barrett: Novartis: Research Funding. Teachey: Novartis: Research Funding. Shaw: Novartis: Research Funding; Vitality Institute: Research Funding. Brogdon: Novartis: Employment. Scholler: Novartis: Patents & Royalties: Royalties, Research Funding. Marcucci: Novartis: Research Funding. Levine: GE Healthcare Bio-Sciences: Consultancy; Novartis: Patents & Royalties, Research Funding. Frey: Amgen: Consultancy; Novartis: Research Funding. Porter: Novartis: Patents & Royalties, Research Funding; Genentech: Employment. Lacey: Novartis: Research Funding. Melenhorst: Novartis: Research Funding. June: Novartis: Honoraria, Patents & Royalties, Research Funding; Celldex: Consultancy, Equity Ownership; Pfizer: Honoraria; Immune Design: Consultancy, Equity Ownership; Johnson & Johnson: Honoraria; Novartis: Honoraria, Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership. Grupp: Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy, Research Funding.

  • cellular kinetics of chimeric antigen receptor t cells ctl019 in patients with relapsed refractory cd19 leukemia
    Blood, 2016
    Co-Authors: Karen Thudium Mueller, Shannon L Maude, Stephan A Grupp, Abhijit Chakraborty, Patricia A Wood, Rakesh Awasthi, Alfonso Quintascardama, Xia Han, David L Porter
    Abstract:

    Introduction CTL019 is a novel, investigational, chimeric antigen receptor (CAR) immunotherapy whereby autologous T cells are genetically modified with a chimeric antigen receptor to target CD19 on the surface of malignant as well as healthy B cells. The cellular kinetics of CTL019 have been evaluated in several trials for patients with relapsed/refractory CD19+ leukemias, including pediatric acute lymphoblastic leukemia (pALL), adult ALL (aALL), and chronic lymphocytic leukemia (CLL) (Maude 2014, Porter 2015). Methods The cellular kinetic profile of CTL019 was determined in peripheral blood (PB) and bone marrow (BM) through serial measurements using flow cytometry and quantitative real-time polymerase-chain-reaction (qPCR) assay in 3 studies comprised of (i) 55 pALL patients (NCT01626495), (ii) 28 adult CLL patients from a dose selection study (NCT01747486), and (iii) 14 CLL and 6 adult ALL patients (NCT01029366). The flow cytometry assay used a CAR19-specific anti-idiotype antibody to enumerate CTL019 T cells as a % of CD3+ T cell (Porter 2015). Cellular kinetic parameters included: maximal extent of expansion as measured by peak copies of CTL019 DNA and peak % by flow cytometry (Cmax), area under the curve at day 28 (AUC0-28d) describing expansion and persistence in the first month, and time to reach Cmax (Tmax). Parameters were derived by non-compartmental methods. Where estimable, persistence was described by the half-life (T1/2) based on the slope of the terminal phase. Results Following infusion, CTL019, expansion and persistence was evident in the patients who responded to CTL019 as measured by both PK assays across all 3 studies. Table 1 summarizes (arithmetic mean (SD)) the CTL019 kinetic parameters. With complete remission (CR/CRi), CTL019 cells undergo rapid in vivo expansion beyond the original CTL019 dose with maximal expansion at a mean of 11 days in pALL and aALL and approximately 14-18 days in adult CLL as determined by qPCR and flow cytometry (Table 1). In CR/CRi patients the transgene level-profiles in PB reveal a kinetic profile with an initial rapid expansion followed by a slower decay function with some fluctuations of transgene over time resulting in higher AUC0-28d and Cmax, while non-responder (NR) patients tend to have a lower expansion and faster decay (shorter T1/2)of CAR positive T-cells resulting in lower AUC0-28d and Cmax by, leaving the mechanism to be further explored. In pALL, significantly higher AUC0-28d and Cmax were observed in CR/CRi patients compared to NR patients by flow cytometry; however, a wide range of mean AUC0-28d and Cmax was observed in NR patients (n=3) resulting from significant expansion in one NR patient as determined by qPCR. In CLL, the exposure metrics AUC0-28d and Cmax were approximately 12 times higher in CR/CRi patients compared with PRi/NR/PD in NCT01747486; a similar trend was observed in NCT01029366. Similar findings were captured by the flow cytometry based measurements as summarized in Table 1. In pALL and CLL, CR/CRi patients tend to maintain higher levels of CTL019 transgene over longer periods of time (>6 months) compared to NR patients as demonstrated by the longer T1/2 value. Cellular kinetic parameters were not summarized by response category for aALL due to the small sample size (n=5 CR/CRi; n=1 NR). CTL019 transgene levels ranged from below the limit of quantification (BLQ) to 178,000 copies/ug in aALL patients with CR/CRi and BLQ to 21,900 copies/ug in the NR. CTL019 positive cells were also shown to traffic to BM at 1 month in responders (CR/CRi), irrespective of the disease. Conclusions Overall, significantly higher levels of in vivo proliferation and persistence were observed in patients who successfully responded to CTL019 (i.e. CR/CRi/PR) compared to NRs in both CLL and (adult and pediatric) ALL patients, as captured by both analytical measures, indicating that the kinetics of CTL019 T cells and that proliferation and persistence of CTL019 reasonably predicts response to therapy. These are the first three studies to demonstrate that cellular kinetics may predict responses to CAR based cellular therapy. These results imply that measures to increase proliferation and persistence of CAR T cells may enhance responses in resistant patients. Disclosures Mueller:Novartis Pharmaceuticals: Employment. Chakraborty:Novartis Pharmaceuticals: Employment, Equity Ownership. Wood:Novartis Pharmaceuticals: Employment, Other: Stock. Awasthi:Novartis Pharmaceuticals: Employment. Quintas-Cardama:Novartis Pharmaceuticals: Employment, Equity Ownership. Han:Novartis Pharmaceuticals: Employment, Equity Ownership. Maude:Novartis: Consultancy. Grupp:Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding. Porter:Novartis: Patents & Royalties, Research Funding; Genentech: Employment. Frey:Novartis: Research Funding; Amgen: Consultancy. Marcucci:Novartis: Research Funding. Levine:GE Healthcare Bio-Sciences: Consultancy; Novartis: Patents & Royalties, Research Funding. Melenhorst:Novartis: Research Funding. June:Celldex: Consultancy, Equity Ownership; Immune Design: Consultancy, Equity Ownership; Pfizer: Honoraria; Novartis: Honoraria, Patents & Royalties: Immunology, Research Funding; University of Pennsylvania: Patents & Royalties; Tmunity: Equity Ownership, Other: Founder, stockholder ; Johnson & Johnson: Research Funding. Lacey:Novartis: Research Funding.

Tzufen Liao - One of the best experts on this subject based on the ideXlab platform.

  • SWIM: SWIM
    Interactions, 2002
    Co-Authors: Gitta B. Salomon, Jason K. Ward, Tzufen Liao
    Abstract:

    Founded in 1996 and based in San Francisco, Swim is an interaction Design Consultancy. It assists clients with all phases of interactive product development, from product definition through final art. Swim projects include Web and client applications, interactive handheld devices, and medical products. Clients include startups and well-established companies, addressing both consumer and enterprise needs.

David T Teachey - One of the best experts on this subject based on the ideXlab platform.

  • efficacy of humanized cd19 targeted chimeric antigen receptor car modified t cells in children and young adults with relapsed refractory acute lymphoblastic leukemia
    Blood, 2016
    Co-Authors: David M. Barrett, Shannon L Maude, Susan R Rheingold, Richard Aplenc, David T Teachey
    Abstract:

    Background Targeted immunotherapy with CTL019, CD19-specific chimeric antigen receptor (CAR)-modified T cells, can produce potent and sustained responses in children with relapsed/refractory acute lymphoblastic leukemia (ALL). However, a subset of patients has limited persistence, which can increase the risk of relapse. Most CAR single chain variable fragment (scFv) domains, including that of CTL019, are of murine origin; therefore, anti-mouse reactivity is one potential cause of immune-mediated rejection that may be overcome by fully human or humanized CAR Designs. We developed a humanized anti-CD19 scFv domain and now report on treatment with humanized CD19-directed CAR T cells (CTL119). Design A pilot/phase 1 study of CAR-modified T cells containing a humanized anti-CD19 scFv domain (CTL119) enrolled children and young adults with relapsed/refractory B-ALL with or without prior exposure to a CAR T cell product. Patients previously treated with CD19-specific CAR-modified T cells were eligible if they met 1 of 3 criteria: 1) CD19+ relapse 2) no response to prior CAR T cell therapy or 3) early B cell recovery indicating poor persistence of CAR T cells. Patient-derived T cells were transduced ex vivo with a lentiviral vector encoding a CAR composed of CD3z, 4-1BB, and humanized anti-CD19 scFv domains and activated/expanded with anti-CD3/CD28 beads. The humanized scFv domain was developed by grafting the complementary determining regions of both the heavy and light chains onto human germline acceptor frameworks. Patients received lymphodepletion with cyclophosphamide and fludarabine 1 week prior to infusion with CTL119. Results Thirty children and young adults aged 29 mo-24 yr were infused with CTL119. Eighteen patients had received prior allogeneic stem cell transplant (SCT). Eleven patients who previously received murine-derived CD19-specific CAR-modified T cells (CTL019, n=7; other, n=4) were retreated for B cell recovery (n=5), CD19+ relapse (n=5), or no response to prior CAR T cells (n=1). CNS disease or other extramedullary disease was the indication for enrollment in 6 and 3 patients, respectively. At assessment 1 month after infusion, 26/30 patients (87%) achieved a complete response (CR), defined as morphologic remission with B cell aplasia. Of 11 patients previously treated with murine CD19-specific CAR-modified T cells, 7 (64%) achieved a CR at 1 month, 4 demonstrated no response. Multiparameter flow cytometry for minimal residual disease (MRD) was negative at a detection level of 0.01% in 5/7 responding patients. Two responding patients with positive MRD progressed to CD19+ relapse at 1.6 and 3 mo. In patients with no prior exposure to a CD19 CAR T cell product, MRD-negative CR was achieved in 19/19 patients (100%). One patient relapsed with CD19+ extramedullary disease at 2.8 mo. With a median follow-up of 4.2 mo (range, 1.0-14.1 mo) for all responding patients in both cohorts, 23/26 remain in remission with 1 proceeding to SCT in remission. B cell aplasia, a functional marker of CD19-targeted CAR T cell persistence, continued for 3 months or more in 11/18 patients with adequate follow-up: 1/6 retreatment, 10/12 CAR-naive. Cytokine release syndrome (CRS) was observed in 28/30 patients and mild in most patients (grade 1, n=6; grade 2, n=18). Three patients experienced grade 3 CRS requiring supplemental oxygen or low-dose vasopressor support and 1 experienced grade 4 CRS requiring high-dose vasopressor and ventilatory support. Severe CRS was successfully managed with the IL6R antagonist tocilizumab in 3 patients. Neurologic toxicity included encephalopathy (n=5) and seizure (n=4) and was fully reversible. Conclusion In the first study of humanized anti-CD19 CAR T cells, CTL119 induced remissions in children and young adults with relapsed/refractory B-ALL, including 64% of patients previously treated with murine CD19-directed CAR T cells and 100% of CAR-naive patients. Further investigation into CAR T cell persistence and anti-CAR responses will be vital to improve durable remission rates in this highly refractory population. Disclosures Maude: Novartis: Consultancy. Barrett: Novartis: Research Funding. Teachey: Novartis: Research Funding. Shaw: Novartis: Research Funding; Vitality Institute: Research Funding. Brogdon: Novartis: Employment. Scholler: Novartis: Patents & Royalties: Royalties, Research Funding. Marcucci: Novartis: Research Funding. Levine: GE Healthcare Bio-Sciences: Consultancy; Novartis: Patents & Royalties, Research Funding. Frey: Amgen: Consultancy; Novartis: Research Funding. Porter: Novartis: Patents & Royalties, Research Funding; Genentech: Employment. Lacey: Novartis: Research Funding. Melenhorst: Novartis: Research Funding. June: Novartis: Honoraria, Patents & Royalties, Research Funding; Celldex: Consultancy, Equity Ownership; Pfizer: Honoraria; Immune Design: Consultancy, Equity Ownership; Johnson & Johnson: Honoraria; Novartis: Honoraria, Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership. Grupp: Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy, Research Funding.

Stephan A Grupp - One of the best experts on this subject based on the ideXlab platform.

  • efficacy and safety of ctl019 in the first us phase ii multicenter trial in pediatric relapsed refractory acute lymphoblastic leukemia results of an interim analysis
    Blood, 2016
    Co-Authors: Shannon L Maude, Michael A Pulsipher, Michael Boyer, Stephan A Grupp, Stella M Davies, Christine L Phillips, Michael R Verneris, Keith J August
    Abstract:

    Background: CTL019 is an investigational therapy derived from autologous T-cells expressing a CD19-specific chimeric antigen receptor (CAR). A single center, phase I/IIa trial of CTL019 showed complete and durable remissions in pediatric/young adult patients (pts) with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) (Maude et al NEJM 2014); these results have yet to be reproduced in a multicenter setting. Here, we report results from a 6-month interim analysis of the first multicenter phase II trial of an engineered cell therapy in leukemia. Methods: 9 US sites participated in this single-arm phase II study in pediatric/young adult pts with R/R B-ALL. Leukapheresis products were shipped for centralized manufacturing according to the University of Pennsylvania (Penn) process in an academic-industry collaboration. T cells were transduced with a lentiviral vector encoding a CAR composed of anti-CD19 scFv, CD3ζ and 4-1BB domains. Following lymphodepletion with fludarabine and cyclophosphamide, a single dose of CTL019 cells was administered (target dose 2.0-5.0×10 6 cells/kg for ≤50 kg and 1.0-2.5×10 8 cells for >50 kg). The primary endpoint was overall remission rate (ORR = CR + CRi [CRi, complete remission with incomplete blood count recovery] maintained at 2 evaluations ≥28 days apart) as determined by an Independent Review Committee. Secondary objectives included minimal residual disease (MRD), relapse-free survival (RFS), overall survival (OS) and safety. All analyses were performed on infused patient set. Results: 29/35 pts enrolled (82.9%) were infused with CTL019; 6 withdrew prior to infusion (2 manufacturing failures [1 lack of growth, 1 contamination]; 4 deaths [median, 48 days from enrollment; 2 progressive disease, 1 multi-organ failure, 1 pneumonia]). Mean bone marrow involvement at enrollment was 68.2% (SD, 27.3%; Table 1). 2 pts did not receive lymphodepleting chemotherapy due to leukopenia. Collection, manufacturing and infusion were feasible in a multicenter setting with a median time from enrollment to infusion of 37 days. Target cell dose was met in 24/33 (72.7%) manufactured products. ORR in all infused pts was 69.0% (20/29 pts; 98.95% CI 43.6, 88.1). Of the 5 pts who received CTL019 below the target dose, 2 achieved CR/CRi. Of note, deep remission with no evidence of MRD ( Conclusions: In this first multicenter trial of CAR-modified T cell therapy, CTL019 therapy was feasible and efficacious, showing a high ORR with durable remissions in pediatric/young adult pts with R/R B-ALL. Despite the high rate of toxicity with CTL019 in the R/R setting, the rate of grade 3 or 4 CRS was comparable to the single center study, and standardized management of CRS was successful in a multicenter trial with no deaths attributable to CRS. In this highly refractory population, a vast majority of eligible pts can be successfully infused in a timely fashion and outcomes appear reproducible in a multicenter setting despite a more heterogeneous population than the single center study. The trial is continuing under Novartis manufacturing. Disclosures Maude: Novartis: Consultancy. Pulsipher: Medac: Other: Travel support for a study group; Chimerix: Consultancy, Other: Advisory Board ; Jazz Pharmaceutical: Consultancy, Other: Advisory Board; Novartis: Consultancy, Other: Advisory Board, Steering Committee for Phase II Study. Grupp: Pfizer: Consultancy; Novartis: Consultancy, Research Funding. Davies: Novartis: Honoraria. Verneris: Bimogen: Other: Advisory Board. Schlis: Novartis: Honoraria. Driscoll: Novartis: Consultancy. June: Immune Design: Consultancy, Equity Ownership; Pfizer: Honoraria; Celldex: Consultancy, Equity Ownership; Novartis: Honoraria, Patents & Royalties, Research Funding; Johnson & Johnson: Honoraria; Novartis: Honoraria, Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership. Levine: GE Healthcare Bio-Sciences: Consultancy; Novartis: Patents & Royalties, Research Funding. Wood: Novartis Pharmaceuticals: Employment, Other: Stock. Yi: Novartis: Employment.

  • cellular kinetics of chimeric antigen receptor t cells ctl019 in patients with relapsed refractory cd19 leukemia
    Blood, 2016
    Co-Authors: Karen Thudium Mueller, Shannon L Maude, Stephan A Grupp, Abhijit Chakraborty, Patricia A Wood, Rakesh Awasthi, Alfonso Quintascardama, Xia Han, David L Porter
    Abstract:

    Introduction CTL019 is a novel, investigational, chimeric antigen receptor (CAR) immunotherapy whereby autologous T cells are genetically modified with a chimeric antigen receptor to target CD19 on the surface of malignant as well as healthy B cells. The cellular kinetics of CTL019 have been evaluated in several trials for patients with relapsed/refractory CD19+ leukemias, including pediatric acute lymphoblastic leukemia (pALL), adult ALL (aALL), and chronic lymphocytic leukemia (CLL) (Maude 2014, Porter 2015). Methods The cellular kinetic profile of CTL019 was determined in peripheral blood (PB) and bone marrow (BM) through serial measurements using flow cytometry and quantitative real-time polymerase-chain-reaction (qPCR) assay in 3 studies comprised of (i) 55 pALL patients (NCT01626495), (ii) 28 adult CLL patients from a dose selection study (NCT01747486), and (iii) 14 CLL and 6 adult ALL patients (NCT01029366). The flow cytometry assay used a CAR19-specific anti-idiotype antibody to enumerate CTL019 T cells as a % of CD3+ T cell (Porter 2015). Cellular kinetic parameters included: maximal extent of expansion as measured by peak copies of CTL019 DNA and peak % by flow cytometry (Cmax), area under the curve at day 28 (AUC0-28d) describing expansion and persistence in the first month, and time to reach Cmax (Tmax). Parameters were derived by non-compartmental methods. Where estimable, persistence was described by the half-life (T1/2) based on the slope of the terminal phase. Results Following infusion, CTL019, expansion and persistence was evident in the patients who responded to CTL019 as measured by both PK assays across all 3 studies. Table 1 summarizes (arithmetic mean (SD)) the CTL019 kinetic parameters. With complete remission (CR/CRi), CTL019 cells undergo rapid in vivo expansion beyond the original CTL019 dose with maximal expansion at a mean of 11 days in pALL and aALL and approximately 14-18 days in adult CLL as determined by qPCR and flow cytometry (Table 1). In CR/CRi patients the transgene level-profiles in PB reveal a kinetic profile with an initial rapid expansion followed by a slower decay function with some fluctuations of transgene over time resulting in higher AUC0-28d and Cmax, while non-responder (NR) patients tend to have a lower expansion and faster decay (shorter T1/2)of CAR positive T-cells resulting in lower AUC0-28d and Cmax by, leaving the mechanism to be further explored. In pALL, significantly higher AUC0-28d and Cmax were observed in CR/CRi patients compared to NR patients by flow cytometry; however, a wide range of mean AUC0-28d and Cmax was observed in NR patients (n=3) resulting from significant expansion in one NR patient as determined by qPCR. In CLL, the exposure metrics AUC0-28d and Cmax were approximately 12 times higher in CR/CRi patients compared with PRi/NR/PD in NCT01747486; a similar trend was observed in NCT01029366. Similar findings were captured by the flow cytometry based measurements as summarized in Table 1. In pALL and CLL, CR/CRi patients tend to maintain higher levels of CTL019 transgene over longer periods of time (>6 months) compared to NR patients as demonstrated by the longer T1/2 value. Cellular kinetic parameters were not summarized by response category for aALL due to the small sample size (n=5 CR/CRi; n=1 NR). CTL019 transgene levels ranged from below the limit of quantification (BLQ) to 178,000 copies/ug in aALL patients with CR/CRi and BLQ to 21,900 copies/ug in the NR. CTL019 positive cells were also shown to traffic to BM at 1 month in responders (CR/CRi), irrespective of the disease. Conclusions Overall, significantly higher levels of in vivo proliferation and persistence were observed in patients who successfully responded to CTL019 (i.e. CR/CRi/PR) compared to NRs in both CLL and (adult and pediatric) ALL patients, as captured by both analytical measures, indicating that the kinetics of CTL019 T cells and that proliferation and persistence of CTL019 reasonably predicts response to therapy. These are the first three studies to demonstrate that cellular kinetics may predict responses to CAR based cellular therapy. These results imply that measures to increase proliferation and persistence of CAR T cells may enhance responses in resistant patients. Disclosures Mueller:Novartis Pharmaceuticals: Employment. Chakraborty:Novartis Pharmaceuticals: Employment, Equity Ownership. Wood:Novartis Pharmaceuticals: Employment, Other: Stock. Awasthi:Novartis Pharmaceuticals: Employment. Quintas-Cardama:Novartis Pharmaceuticals: Employment, Equity Ownership. Han:Novartis Pharmaceuticals: Employment, Equity Ownership. Maude:Novartis: Consultancy. Grupp:Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding. Porter:Novartis: Patents & Royalties, Research Funding; Genentech: Employment. Frey:Novartis: Research Funding; Amgen: Consultancy. Marcucci:Novartis: Research Funding. Levine:GE Healthcare Bio-Sciences: Consultancy; Novartis: Patents & Royalties, Research Funding. Melenhorst:Novartis: Research Funding. June:Celldex: Consultancy, Equity Ownership; Immune Design: Consultancy, Equity Ownership; Pfizer: Honoraria; Novartis: Honoraria, Patents & Royalties: Immunology, Research Funding; University of Pennsylvania: Patents & Royalties; Tmunity: Equity Ownership, Other: Founder, stockholder ; Johnson & Johnson: Research Funding. Lacey:Novartis: Research Funding.