scholarly journals Phase 1 Clinical Results of the ZUMA-1 (KTE-C19-101) Study: A Phase 1-2 Multi-Center Study Evaluating the Safety and Efficacy of Anti-CD19 CAR T Cells (KTE-C19) in Subjects with Refractory Aggressive Non-Hodgkin Lymphoma (NHL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3991-3991 ◽  
Author(s):  
Frederick L. Locke ◽  
Sattva S. Neelapu ◽  
Nancy L Bartlett ◽  
Tanya Siddiqi ◽  
Julio C. Chavez ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Research Funding ◽  
Phase 1 ◽  
Complete Response ◽  
Employment Equity ◽  
Car T Cells ◽  
Car T ◽  
Equity Ownership ◽  
Line Chemotherapy

Abstract This study is supported in part by funding from The Leukemia & Lymphoma Society (LLS) Therapy Acceleration Program® Introduction: A single institution study conducted at the National Cancer Institute (NCI) using anti-CD19 CAR T cells with CD28 and CD3-zeta signaling domains showed durable remissions in subjects with relapsed/refractory advanced B cell malignancies, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL) and transformed follicular lymphoma (TFL) (Kochenderfer et al. Blood 2012, J Clin Onc 2014, ASH 2014). KTE-C19 utilizes the same anti-CD19 CAR construct as investigated in the NCI study in a 6-8 day manufacturing process (Better et al. ASCO 2014). The ZUMA-1 trial is a phase 1-2 multicenter, open-label study evaluating the safety and efficacy of KTE-C19 in subjects with refractory aggressive B-cell NHL. Preliminary phase 1 results presented. Methods: Subjects received KTE-C19 at a target dose of 2 x 106 (minimum 1 x 106) anti-CD19 CAR T cells/kg after a fixed dose conditioning chemotherapy regimen of cyclophosphamide and fludarabine. The primary objective of phase 1 is to evaluate the safety of KTE-C19 as determined by the incidence of dose-limiting toxicities (DLT). Cytokine release syndrome (CRS) was graded per revised criteria (Lee et al. Blood 2014). Key secondary objectives include evaluating the overall response rate (ORR=CR+PR) per Cheson 2007, duration of response, levels of CAR T cells in the blood, and levels of serum cytokines. Key inclusion criteria include ≥ 18 years old, ECOG 0-1, and chemotherapy-refractory disease defined as stable disease or progressive disease as best response to last line of therapy, or disease progression ≤ 12 months after autologous stem cell transplant (ASCT). Subjects must have received at least prior anti-CD20 therapy and an anthracycline containing regimen. Results: As of 28 July 2015, 6 subjects were dosed in the phase 1 portion of the study. All subjects are evaluable for safety with a median follow up time of 4.8 weeks post KTE-C19 infusion and 3 subjects have had 1 month tumor assessments. Two subjects experienced only grade (gr) 1-2 KTE-C19 related events. Three subjects had gr 3 KTE-C19 related events as highest gr toxicities; all these events were reversible within 3 days. CRS and neurotoxicity were managed with supportive care, tocilizumab and systemic steroids. One subject experienced a DLT of gr 4 encephalopathy and gr 4 CRS. This subject died within 30 days of KTE-C19 cell infusion; the death was due to an intracranial hemorrhage deemed unrelated to KTE-C19 per the investigator. Of the 3 subjects assessed for response at one month, 2 achieved a complete response and one achieved a partial response. Key safety and efficacy findings are summarized in the table. Biomarker and translational endpoints are included in a separate abstract. Enrollment is ongoing and updated trial results will be presented. Conclusions: Preliminary phase I results ofthe ZUMA-1 study demonstrate that KTE-C19 can be centrally manufactured and administered in a multicenter trial. The predominant toxicities include CRS and neurotoxicity which are generally reversible. Complete and partial responses have been observed in subjects with refractory disease at 1 month after KTE-C19 administration. This potentially pivotal study is the first enrolling multicenter anti-CD19 CAR T cell trial in refractory aggressive NHL. Clinical trial: NCT02348216. Table 1. Subject Sex/Age/ECOG Disease Type Treatment History Gr 3 or Higher KTE-C19-Related Adverse Events Response at 1 Month 101-002-001 M/59/0 DLBCL Relapse ≤ 12 mo after ASCT Gr 3 encephalopathy (resolved) Partial Response 101-002-003 M/69/1 DLBCL Refractory to 2nd line chemotherapy Gr 3 tremor (resolved) Gr 3 delirium (resolved) Gr 3 agitation (resolved) Gr 3 restlessness (resolved) Gr 3 somnolence (resolved) Complete Response 101-009-001 F/29/1 PMBCL Refractory to 1st, 2nd, 3rd line chemotherapy Gr 4 CRS Gr 4 encephalopathy N/A 101-003-001 M/67/1 DLBCL Relapse ≤ 12 mo after ASCT None Complete Response 101-002-004 M/69/0 DLBCL Refractory to 4th line chemotherapy Gr 3 encephalopathy (resolved) Assessment not yet reached 101-003-002 F/34/0 DLBCL Relapse ≤ 12 mo after ASCT None Assessment not yet reached mo - months M - male, F - female N/A - not applicable Disclosures Locke: Kite Pharma: Other: Scientific Advisory Boards. Off Label Use: Tocilizumab for CRS per Blood et al. 2014. Bartlett:Kite: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Seattle Genetics: Consultancy, Research Funding; Colgene: Research Funding; Millennium: Research Funding; MERC: Research Funding; Gilead: Consultancy, Research Funding; Insight: Research Funding; Medimmune: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding. Siddiqi:Seattle Genetics: Speakers Bureau; Kite pharma: Other: attended advisory board meeting; Pharmacyclics/Jannsen: Speakers Bureau. Navale:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership. Aycock:Kite Pharma: Employment, Equity Ownership. Wiezorek:Kite Pharma: Employment, Equity Ownership, Other: Officer of Kite Pharma. Go:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership.

scholarly journals A Phase 1 Study with Point-of-Care Manufacturing of Dual Targeted, Tandem Anti-CD19, Anti-CD20 Chimeric Antigen Receptor Modified T (CAR-T) Cells for Relapsed, Refractory, Non-Hodgkin Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4193-4193 ◽  
Author(s):  
Nirav N Shah ◽  
Fenlu Zhu ◽  
Carolyn Taylor ◽  
Dina Schneider ◽  
Winfried Krueger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Research Funding ◽  
Phase 1 ◽  
Third Party ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Equity Ownership

Abstract Background: CAR-T cell therapy directed against the CD19 antigen is a breakthrough treatment for patients (pts) with relapsed/refractory (R/R) B-cell NHL. Despite impressive outcomes, not all pts respond and many that respond still relapse. Affordability and accessibility are further considerations that limit current commercial models of CAR-T products. Commercial CAR-T manufacturing is complex, time consuming, and expensive with a supply chain starting at the treating center with apheresis of mononuclear cells, cryopreservation, and shipping to and from a centralized third-party manufacturing site. We addressed these limitations in a Phase 1 clinical trial evaluating a first-in-human bispecific tandem CAR-T cell directed against both CD19 and CD20 (CAR-20.19-T) antigens for pts with R/R B-cell NHL. Through dual targeting we hope to improve response rates and durability of response while limiting antigen escape. We eliminated third party shipping logistics utilizing the CliniMACS Prodigy, a compact tabletop device that allows for automated manufacturing of CAR-T cells within a GMP compliant environment within the hospital. Most materials and reagents used to produce the CAR-T cell product were single-sourced from the device manufacturer. Methods: Phase 1 (NCT03019055), single center, dose escalation + expansion study to demonstrate feasibility and safety of locally manufactured second generation 41BB + CD3z CAR-20.19-T cells via the CliniMACS Prodigy. Feasibility was measured by ability to generate a target CAR-20.19-T cell dose for a minimum of 75% of subjects. Safety was assessed by the presence of dose limiting toxicities (DLTs) through 28 days post-infusion. Dose was escalated in a 3+3 fashion with a starting dose of 2.5 x 10^5 cells/kg, a target DLT rate <33%, and a goal treatment dose of 2.5 x 10^6 cells/kg. Adults with R/R Diffuse Large B-cell Lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL) or Chronic Lymphocytic Leukemia (CLL) were eligible. CAR-T production was set for a 14-day manufacturing process. Day 8 in-process testing was performed to ensure quality and suitability of CAR-T cells for a potential fresh infusion. On Day 10, pts eligible for a fresh CAR-T infusion initiated lymphodepletion (LDP) chemotherapy with fludarabine 30 mg/m2 x 3 days and cyclophosphamide 500 mg/m2 x 1 day, and cells were administered after harvest on Day 14. Pts ineligible for fresh infusion received cryopreserved product and LDP was delayed accordingly. Results: 6 pts have been enrolled and treated with CAR-20.19-T cells: 3 pts at 2.5 x 10^5 cells/kg and 3 pts at 7.5 x 10^5 cells/kg. Median age was 53 years (48-62). Underlying disease was MCL in 3 pts, DLBCL in 2 pts, and CLL in 1 patient. Baseline data and prior treatments are listed in Table 1. CAR-T production was successful in all runs and all pts received their target dose. Three pts received fresh CAR-T cells and 3 pts received CAR-T cells after cryopreservation. To date there are no DLTs to report. No cases of Grade 3/4 cytokine release syndrome (CRS) or neurotoxicity (NTX) were observed. One patient had Grade 2 CRS and Grade 2 NTX requiring intervention. The other had self-limited Grade 1 CRS and Grade 1 NTX. Median time to development of CRS was Day +11 post-infusion. All pts had neutrophil recovery (ANC>0.5 K/µL) by Day 28. Response at Day 28 (Table 2) is as follows: 2/6 pts achieved a complete response (CR), 2/6 achieved a partial response (PR), and 2/6 had progressive disease (PD). One subject with a PR subsequently progressed at Day 90. The 3 pts who did progress all underwent a repeat biopsy, and all retained either CD19 or CD20 positivity. Pts are currently being enrolled at the target dose (2.5 x 10^6 cells/kg) and updated results will be provided at ASH. Conclusions: Dual targeted anti-CD19 and anti-CD20 CAR-T cells were successfully produced for all pts demonstrating the feasibility of a point-of-care manufacturing process via the CliniMACS Prodigy device. With no DLTs or Grade 3-4 CRS or NTX to report, and 2/6 heavily pre-treated pts remaining in CR at 3 and 9 months respectively our approach represents a feasible and promising alternative to existing CAR-T models and costs. Down-regulation of both target antigens was not identified in any patient following CAR-T infusion, and in-process studies suggest that a shorter manufacturing timeline is appropriate for future trials (10 days). Disclosures Shah: Juno Pharmaceuticals: Honoraria; Lentigen Technology: Research Funding; Oncosec: Equity Ownership; Miltenyi: Other: Travel funding, Research Funding; Geron: Equity Ownership; Exelexis: Equity Ownership. Zhu:Lentigen Technology Inc., A Miltenyi Biotec Company: Research Funding. Schneider:Lentigen Technology Inc., A Miltenyi Biotec Company: Employment. Krueger:Lentigen Technology Inc., A Miltenyi Biotec Company: Employment. Worden:Lentigen Technology Inc., A Miltenyi Biotec Company: Employment. Hamadani:Sanofi Genzyme: Research Funding, Speakers Bureau; Merck: Research Funding; Janssen: Consultancy; MedImmune: Consultancy, Research Funding; Cellerant: Consultancy; Celgene Corporation: Consultancy; Takeda: Research Funding; Ostuka: Research Funding; ADC Therapeutics: Research Funding. Johnson:Miltenyi: Research Funding. Dropulic:Lentigen, A Miltenyi Biotec company: Employment. Orentas:Lentigen Technology Inc., A Miltenyi Biotec Company: Other: Prior Employment. Hari:Takeda: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Kite Pharma: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Spectrum: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Amgen Inc.: Research Funding; Sanofi: Honoraria, Research Funding.

scholarly journals Initial Results from a Phase 1 Clinical Study of bb21217, a Next-Generation Anti Bcma CAR T Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 488-488 ◽  
Author(s):  
Nina Shah ◽  
Melissa Alsina ◽  
David S Siegel ◽  
Sundar Jagannath ◽  
Deepu Madduri ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Employment Equity ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Equity Ownership

Abstract Introduction: Immunomodulatory chimeric antigen receptor (CAR) T cell therapy directed against B-cell maturation antigen (BCMA) has shown promising results for the treatment of relapsed refractory multiple myeloma (RRMM) in several phase 1 clinical studies in patients with advanced disease. Persistence of CAR T cells post infusion may be one determinant of duration of response. bb21217 is a next-generation anti-BCMA CAR T cell therapy based on investigational therapy bb2121 (Friedman 2018, Hum Gene Ther 29:585). It uses the same scFv, 4-1BB costimulatory motif and CD3-zeta T cell activation domain as bb2121 with the addition of phosphoinositide 3 kinase inhibitor bb007 during ex vivo culture to enrich the drug product for T cells displaying a memory-like phenotype. Evidence suggests that CAR T cells with this phenotype may be more persistent and more potent than unselected CAR T cells. CRB-402 is a first-in-human clinical study of bb21217 in patients with RRMM designed to assess the safety, pharmacokinetics, efficacy and duration of effect of bb21217. Methods: CRB-402 (NCT03274219) is an ongoing, multi-center phase 1 dose escalation trial of bb21217 in approximately 50 patients with RRMM who have received ≥ 3 prior regimens, including a proteasome inhibitor and an immuno-modulatory agent, or are double-refractory. During dose escalation, enrollment is restricted to patients with ≥ 50% BCMA expression by IHC on malignant plasma cells. Peripheral blood mononuclear cells are collected via leukapheresis and sent to a central facility for transduction, expansion and release testing prior to being returned to the site for infusion. Patients undergo lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) daily for 3 days, then receive bb21217 as a single infusion. Planned dose levels are 150, 450, 800, and 1,200 x 106 CAR+ T cells. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Additional outcome measures are quality and duration of clinical response assessed according to the IMWG Uniform Response Criteria for MM, evaluation of minimal residual disease (MRD), progression-free and overall survival, and quantification of CAR+ cells in blood. Results: Asof June 15, 2018, 8 patients (median age 64 [min;max 54 to 70]) have received bb21217. All patients to date received a dose of 150 x 106 CAR+ T cells. Four had high tumor burden, defined as ≥ 50% bone marrow plasma cells pre-infusion. Patients had a median of 9 (min;max 4 to 17) prior lines of therapy and 7/8 had prior autologous stem cell transplant; 50% had high-risk cytogenetics. Four of 8 (50%) had previously received Bort/Len/Car/Pom/Dara. Median follow-up after bb21217 infusion was 16 weeks (2 to 27 weeks) and 7 patients were evaluable for initial (1-month) clinical response. As of data cut-off, 5 of 8 patients developed cytokine release syndrome (CRS; 1 Grade 1, 3 Grade 2, 1 Grade 3) and responded to supportive care or tocilizumab. This included 1 patient with high tumor burden who experienced DLTs consisting of grade 3 CRS and grade 4 encephalopathy with signs of posterior reversible encephalopathy syndrome on MRI. This patient received tocilizumab, corticosteroids and cyclophosphamide, improved neurologically and achieved a sCR. Following this event, the dose escalation cohort was divided into two groups based on tumor burden and dosing continued at 150x106 CAR+ T cells. No deaths occurred. With 1 to 6 months since treatment, 6 of 7 patients had demonstrated clinical response per IMWG criteria: currently 1 sCR, 3 VGPR, 2 PR. MRD negative results at 10-5 nucleated cells were obtained by next-generation sequencing in 3 of 3 evaluable responders. Robust CAR+ T cell expansion during the first 30 days was observed in 7 of 7 evaluable patients. Two of 2 patients evaluable at 6 months had detectable CAR vector copies. Conclusions: Early efficacy results with bb21217 CAR T therapy in RRMM at a dose of 150 x 106 CAR+ T cells are encouraging, with 6 of 7 patients demonstrating clinical responses. The adverse events observed to date are consistent with known toxicities of CAR T therapies. CAR+ T cells were measurable at 6 months post treatment in both evaluable patients. Enrollment in the study is ongoing; longer follow-up and data in more patients will establish whether treatment with bb21217 results in sustained CAR+ T cell persistence and responses. Disclosures Shah: Kite: Consultancy; Indapta Therapeutics: Consultancy; University of California San Francisco: Employment; Nekktar: Consultancy; Teneobio: Consultancy; Sanofi: Consultancy; Janssen: Research Funding; Indapta Therapeutics: Equity Ownership; Amgen: Consultancy; Bluebird: Research Funding; Celgene: Research Funding; Bristol Myers Squibb: Consultancy; Takeda: Consultancy; Sutro Biopharma: Research Funding; Nkarta: Consultancy. Siegel:Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Jagannath:Multiple Myeloma Research Foundation: Speakers Bureau; Merck: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Medicom: Speakers Bureau. Kaufman:Karyopharm: Other: data monitoring committee; BMS: Consultancy; Janssen: Consultancy; Abbvie: Consultancy; Roche: Consultancy. Turka:bluebird bio, Inc: Employment, Equity Ownership. Lam:bluebird bio, Inc: Employment, Equity Ownership. Massaro:bluebird bio, Inc: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties: multiple; Mersana: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; SITC: Membership on an entity's Board of Directors or advisory committees; Arcus Biosicences: Membership on an entity's Board of Directors or advisory committees. Petrocca:bluebird bio, Inc: Employment, Equity Ownership. Berdeja:Glenmark: Research Funding; Novartis: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Bristol-Myers Squibb: Research Funding; Bluebird: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Teva: Research Funding; Sanofi: Research Funding. Raje:AstraZeneca: Research Funding; Takeda: Consultancy; Merck: Consultancy; Janssen: Consultancy; Celgene: Consultancy; BMS: Consultancy; Amgen Inc.: Consultancy; Research to Practice: Honoraria; Medscape: Honoraria.

scholarly journals High Rates of Minimal Residual Disease-Negative (MRD−) Complete Responses (CR) in Adult and Pediatric and Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia (R/R ALL) Treated With KTE-C19 (Anti-CD19 Chimeric Antigen Receptor [CAR] T Cells): Preliminary Results of the ZUMA-3 and ZUMA-4 Trials

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2803-2803 ◽  
Author(s):  
Bijal Shah ◽  
Van Huynh ◽  
Leonard S. Sender ◽  
Daniel W. Lee ◽  
Januario E. Castro ◽  
...  
Keyword(s):  
T Cells ◽  
Research Funding ◽  
Low Dose ◽  
Lymphoblastic Leukemia ◽  
Phase 1 ◽  
Employment Equity ◽  
Car T Cells ◽  
Car T ◽  
Equity Ownership ◽  
Support Research

Abstract Background: Acute lymphoblastic leukemia (ALL) exhibits a bimodal age distribution with 60% of cases occurring in children and adolescents (<20 y) and 25% in older adults (>45 y; Howlader SEER Cancer Statistics 2015). Most adults and 15-20% of children will relapse following initial therapy with subsequent poor outcomes. (Bassan, JCO 2012; Locatelli, Blood 2012). Promising results have been observed in studies of anti-CD19 CAR T cells in patients with B cell malignancies, including those treated with KTE-C19, a CD28/CD3ζ anti-CD19 CAR T cell studied in the multicenter ZUMA-1 trial (Neelapu ASCO 2016). However, studies of anti-CD19 CAR T cell therapy in R/R ALL have also observed high incidences of severe CRS in patients with high leukemic burden (Lee, Lancet 2015; Maude NEJM 2014). We present a preliminary analysis of the phase 1 portions of ZUMA-3 and ZUMA-4 which to date have enrolled adult and pediatric patients, respectively with high leukemic burden (M3 marrow). Methods: The primary objective of phase 1 of these multicenter trials is to evaluate the safety of KTE-C19. Eligible patients with R/R ALL are aged ≥18 y (ZUMA-3) or 2-21 y (ZUMA-4) with ≥25% marrow blasts, and adequate renal, hepatic, and cardiac function. Patients are required to have an Eastern Cooperative Oncology Group performance score 0-1 (ZUMA-3) or a Lansky or Karnofsky performance status of >80% (ZUMA-4). Patients with Ph+ ALL and low-burden central nervous system disease are eligible. Patients with Burkitt lymphoma or chronic myeloid leukemia in blast crisis, extramedullary disease only, active graft-versus-host disease, or clinically significant infection are not eligible. KTE-C19 is administered at a target dose of either 1 or 2 × 106 anti-CD19 CAR T cells/kg after low-dose conditioning with fludarabine (25 mg/m2/day for 3 days) and cyclophosphamide (900 mg/m2/day [CyFlu]; Wayne ASCO 2016; Shah ESMO 2016). Results: As of July 8, 2016, 6 patients have enrolled and 5 patients (3 adult and 2 pediatric) have been treated with KTE-C19. KTE-C19 was successfully manufactured in a centralized, streamlined 6-8-day process for 5 patients with approximately a 2-week turnaround time from the time of apheresis to delivery of KTE-C19 to site for patient infusion (Choi, ASGCT 2016). In one 2-year-old patient with peripheral white blood cells >150,000/μL and >99% leukemic blasts in the apheresis collection, KTE-C19 could not be manufactured. All 5 treated patients had high burden disease with a median 85% of marrow blasts (range, 48%-100%) at screening. All 5 patients received bridging chemotherapy prior to dosing with KTE-C19. No patient experienced a dose-limiting toxicity. Cytokine release syndrome (CRS) was reported in all adult (grade 1, n=1; grade 2, n=2) and pediatric (grade 2, n=2) patients; neurotoxicity (NT) was reported in adults only (grade 3, n=2; grade 4, n=1). CRS and NT were successfully managed to resolution with either tocilizumab, corticosteroids, and/or siltuximab in addition to other supportive care for all 5 patients. MRD- remission has been observed in all 5 patients who received KTE-C19 by day 28, with some remissions occurring as early as day 7. Four of 5 patients have had a CR/CR with partial hematologic recovery to date, and 1 of 5 patients with MRD- remission was showing recovering counts. CAR T cells expanded in blood within 2 weeks after infusion and were also detected in bone marrow and/or cerebrospinal fluid. Additional patients and clinical and correlative biomarker data will be presented. Conclusions: The administered dose of KTE-C19 after low-dose CyFlu conditioning has been tolerable and to date appears safe for further analysis in adult and pediatric patients with high leukemic burden R/R ALL. Initial results demonstrate promising efficacy, and the central manufacturing process is deemed feasible. The phase 1 portions of ZUMA-3 and ZUMA-4 are ongoing with planned expansion to phase 2. Clinical trial information: NCT02614066 (ZUMA-3); NCT02625480 (ZUMA-4). Disclosures Shah: Pfizer: Consultancy, Speakers Bureau; Bayer: Honoraria, Speakers Bureau; Plexus Communications: Honoraria; Rosetta Genomics: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxalta: Honoraria, Speakers Bureau. Lee:Juno: Honoraria. Wierda:Novartis: Research Funding; Abbvie: Research Funding; Acerta: Research Funding; Gilead: Research Funding; Genentech: Research Funding. Schiller:Incyte Corporation: Research Funding. Gökbuget:Pfizer: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Sabatino:Kite: Employment, Equity Ownership. Bot:Kite Pharma: Employment, Equity Ownership. Rossi:Kite Pharma: Employment, Equity Ownership. Jiang:Kite Pharma: Employment, Equity Ownership. Navale:Kite Pharma: Employment, Equity Ownership. Stout:Kite Pharma: Employment, Equity Ownership. Aycock:Kite Pharma: Employment, Equity Ownership. Wiezorek:Kite Pharma: Employment, Equity Ownership. Jain:Kite Pharma: Employment, Equity Ownership. Wayne:Spectrum Pharmaceuticals: Honoraria, Other: Travel Support, Research Funding; Kite Pharma: Honoraria, Other: Travel support, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel Support; Medimmune: Honoraria, Other: Travel Support, Research Funding; NIH: Patents & Royalties.

scholarly journals Phase 1 Results of ZUMA-3: KTE-C19, an Anti-CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy, in Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia (R/R ALL)

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 888-888
Author(s):  
Bijal D. Shah ◽  
Wendy Stock ◽  
William G Wierda ◽  
Olalekan Oluwole ◽  
Houston Holmes ◽  
...  
Keyword(s):  
T Cells ◽  
Research Funding ◽  
Phase 1 ◽  
Adult Patients ◽  
Employment Equity ◽  
Efficacy Analysis ◽  
Car T Cells ◽  
Car T ◽  
Equity Ownership ◽  
Grade 3

Abstract Background : Approximately 45% of new ALL cases occur in adults ≥ 20 years of age (Howlader et al. SEER Cancer Statistics. 2015), and approximately 50% of adult patients relapse with poor subsequent outcomes (Oriol et al. Haematologica. 2010; Basson et al. JCO. 2011). Promising early efficacy and manageable safety were previously reported with anti-CD19 CAR T cells (KTE-C19) in adult patients with R/R ALL (Shah et al. ASCO 2017. #3024). Here we report updated results of the ZUMA-3 trial. Methods : Adult patients (≥ 18 years of age) with R/R ALL (Philadelphia+ eligible), &gt; 5% bone marrow (BM) lymphoblasts; Eastern Cooperative Oncology Group performance status (ECOG) 0-1; and adequate renal, hepatic, and cardiac function were eligible. Patients with active graft-versus-host disease or clinically significant infection were not eligible. Patients received a target dose of 1 × 106 CAR T cells/kg or 2 × 106 CAR T cells/kg after lymphodepletion with 25 mg/m2/day fludarabine for 3 days and 900 mg/m2/day cyclophosphamide given on the last day. The primary endpoint of phase 1 was incidence of dose-limiting toxicities (DLTs). Key secondary endpoints included incidence of adverse events (AEs), incidence of minimal residual disease-negative (MRD-) responses, duration of remission (DOR), relapse-free survival (RFS), and overall survival (OS). Exploratory endpoints included levels of anti-CD19 CAR T cells in blood and levels of cytokines in serum. Results : As of the data cut-off date (DCO; April 26, 2017), 22 patients have been enrolled, and 16 patients received KTE-C19 on study. Four patients had not received treatment by the DCO, 1 patient did not receive KTE-C19 due to an AE after conditioning, and 1 patient received KTE-C19 under compassionate use. All 16 patients who received KTE-C19 prior to the DCO were included in the safety analysis, and all patients who had the opportunity to be followed for 8 weeks prior to the DCO were included in the efficacy analysis (n = 11). Of the 16 patients dosed with KTE-C19, 63% were male, 56% had ECOG 1, and 50% had received ≥ 2 previous lines of treatment, including 3 patients with prior blinatumomab. Nineteen percent of patients had undergone prior allogeneic stem cell transplant, 31% had R/R to ≥ second-line therapy, 31% had primary refractory disease, and 19% experienced first relapse within 12 months of first remission. Most patients (81%) had baseline BM blasts ≥ 60%. Six patients received the 2 × 106 cells/kg dose and 10 received the 1 × 106 cells/kg dose. No DLTs were observed. One patient experienced a grade 5 event of cytokine release syndrome (CRS) at the 2 × 106 cells/kg dose, and no other KTE-C19-related grade 5 AEs were observed. In the 16 patients who received KTE-C19, all of whom were followed for at least 4 weeks, the most common grade ≥ 3 AEs were hypotension (56%), anemia (50%), pyrexia (50%), and decreased platelet counts (44%). Grade ≥ 3 CRS and neurologic events (NE) were reported in 25% and 63% of patients, respectively. Tocilizumab (toci) or steroids were given for AE management in 94% and 75% of patients, respectively. In the 11 patients eligible for the efficacy analysis, objective response rate was 82%, including 8 (73%) patients with a complete remission (CR or CR with partial hematopoietic recovery), and 1 (9%) with blast-free BM. All remissions were MRD- as determined by flow cytometry. All 5 (100%) of the other patients who were too early for inclusion in the efficacy analysis had MRD- bone marrow with varying degrees of count recovery at the time of the DCO. Median follow-up was 6.8 months; 4 patients relapsed 63 - 168 days after treatment with KTE-C19. Efficacy was comparable between patients who recieved KTE-C19 doses of 1 × 106 and 2 × 106 CAR T cells/kg. Data from additional patients, including those treated with a lower dose of 0.5 × 106 CAR T cells/kg, as well as updated safety, efficacy, biomarker, and product characteristic analyses across dosing groups will be presented. Conclusions : In this ongoing phase 1 study, KTE-C19 has shown promising efficacy in adult patients with R/R ALL. The safety profile was generally manageable and additional approaches to improve the benefit:risk profile are being explored. ZUMA-3 continues to enroll additional patients at the 0.5 × 106 CAR T cells/kg dose level. Disclosures Wierda: AbbVie: Consultancy, Honoraria, Research Funding; Karyopharm: Research Funding; Genentech/Roche: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; Juno: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Kite: Research Funding; GSK/Novartis: Consultancy, Honoraria, Research Funding; Emergent: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Janssen: Research Funding; The University of Texas MD Anderson Cancer Center: Employment; Acerta: Research Funding. Oluwole: Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Schiller: Kite Pharma: Research Funding. Topp: Regeneron: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Research Funding; Celgene: Other: Travel; Macrogenics: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Research Funding. Kersten: Kite Pharma: Honoraria; Novartis: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Millenium/Takeda: Honoraria, Research Funding; Mundipharma: Honoraria; Gilead Sciences: Honoraria; BMS: Honoraria; MSD: Honoraria; Amgen: Honoraria. Mojadidi: Kite Pharma: Employment, Equity Ownership. Xue: Kite Pharma: Employment, Equity Ownership. Mardiros: Kite Pharma: Employment, Equity Ownership. Jiang: Kite Pharma: Employment, Equity Ownership. Shen: Kite Pharma: Employment, Equity Ownership. Aycock: Kite Pharma: Employment, Equity Ownership. Stout: Kite Pharma: Employment, Equity Ownership. Wiezorek: Kite Pharma: Employment, Equity Ownership. Jain: Kite Pharma: Employment, Equity Ownership.

scholarly journals Transcend NHL 001: Immunotherapy with the CD19-Directed CAR T-Cell Product JCAR017 Results in High Complete Response Rates in Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4192-4192 ◽  
Author(s):  
Jeremy S. Abramson ◽  
Lia Palomba ◽  
Leo I Gordon ◽  
Matthew Lunning ◽  
Jon Arnason ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Research Funding ◽  
Employment Equity ◽  
Car T Cells ◽  
Car T Cell ◽  
Non Hodgkin Lymphoma ◽  
Car T ◽  
Equity Ownership

Abstract Background: Based on promising results seen in patients treated with CD19-directed CAR-T cells in relapsed or refractory (R/R) pediatric B-cell acute lymphoblastic leukemia (Gardner, ASCO 2016) and adult B-cell non-Hodgkin lymphoma (Turtle, ASCO 2016), we are conducting a multicenter phase 1 trial of JCAR017 in R/R diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) (ClinicalTrials.gov Identifier: NCT02631044). JCAR017 is a second-generation, CD19-directed CAR-T cell product of defined cellular composition consisting of a 1:1 ratio of CD8+:CD4+ CAR+ T cells. Methods: Patients with R/R DLBCL (de novo or transformed from indolent lymphoma), follicular lymphoma grade 3B, or MCL and adequate organ function are eligible. There was no minimum absolute lymphocyte count (ALC) requirement for apheresis and no test expansion required. Treatment includes lymphodepletion (fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2 daily for 3 days) and JCAR017 given 2-7 days post-lymphodepletion at a starting dose of 5 x 107 CAR+ T cells (DL1). Single-dose and two-dose schedules are being evaluated. Primary objectives include safety and pharmacokinetics (PK) of JCAR017 measured by flow cytometry and quantitative PCR. Secondary objectives include complete and overall response (CR, OR) rates and duration of response (DOR). Response is assessed using the Lugano (2014) criteria. Results: As of August 1, 2016, 39 patients have been enrolled and 28 patients apheresed. Fourteen patients have been treated, all at DL1. Eight were male and 6 female. Thirteen patients had DLBCL and 1 had MCL. Median age was 61 years (range 37-79) and median number of prior therapies was 5 (range 2-9). Ten patients had undergone prior transplant (7 autologous; 3 allogeneic). Of the 14 patients, there were no cases of severe cytokine release syndrome (sCRS); 3 patients had low grade CRS (21%) (2 grade 1; 1 grade 2) and none required treatment with tocilizumab. Two of the 14 treated patients (14%) had neurotoxicity: 1 grade 4 encephalopathy and 1 grade 4 seizure. Both were in patients with DLBCL and were dose-limiting toxicities. Two deaths were seen in the DLBCL group and were due to disease progression. Twelve patients had at least 1 post-treatment response assessment; 11 patients with DLBCL and 1 with MCL. The patient with MCL had progressive disease at day 29 (D29). In the DLBCL group, response rates were: 82% (9/11) OR, 73% (8/11) CR, 9% (1/11) PR and 18% (2/11) PD at the time of post-treatment assessment on D29. All but one patient who achieved a CR were in remission at the time of this data cut. One DLBCL patient in CR had a parenchymal brain lesion in the right temporal lobe that also completely resolved. Of note, this patient had no CRS or neurotoxicity associated with JCAR017 treatment. The PK profile of JCAR017 in the peripheral blood and bone marrow show cellular expansion in all patients with persistence out to at least 3 months in patients with adequate follow up. Exploratory biomarker analyses will be presented at the meeting along with updated clinical data. Conclusions: Treatment with the defined cellular composition product JCAR017 following lymphodepletion with fludarabine and cyclophosphamide results in high CR rates in patients with heavily pretreated DLBCL, including the first report of a CR in a patient with secondary CNS lymphoma. Observed toxicities are manageable and compare favorably to other reported CAR T-cell products. Disclosures Abramson: Gilead: Consultancy; Kite Pharma: Consultancy; Abbvie: Consultancy; Seattle Genetics: Consultancy. Gordon:Northwestern University: Patents & Royalties: Patent for gold nanoparticles pending. Lunning:Celgene: Consultancy; Bristol-Myer-Squibb: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy; Juno: Consultancy; AbbVie: Consultancy; Gilead: Consultancy; TG Therapeutics: Consultancy; Spectrum: Consultancy. Arnason:Gilead: Consultancy. Forero-Torres:Genentech/Roche: Research Funding; Seattle Genetics: Research Funding; Juno: Research Funding; Incyte: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Albertson:Juno Therapeutics: Employment, Equity Ownership. Sutherland:Juno therapeutics: Employment. Xie:Juno Therapeutics: Employment, Equity Ownership. Snodgrass:Juno therapeutics: Employment. Siddiqi:Pharmacyclics, LLC, an AbbVie Company: Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Speakers Bureau; Kite pharma: Other: Funded travel, 1 day registration, and 1 night hotel stay for EHA2016 so I could present trial data there.

scholarly journals JCARH125, Anti-BCMA CAR T-cell Therapy for Relapsed/Refractory Multiple Myeloma: Initial Proof of Concept Results from a Phase 1/2 Multicenter Study (EVOLVE)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 957-957 ◽  
Author(s):  
Sham Mailankody ◽  
Myo Htut ◽  
Kelvin P. Lee ◽  
William Bensinger ◽  
Todd Devries ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Research Funding ◽  
Phase 1 ◽  
Employment Equity ◽  
Car T Cells ◽  
Car T ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: B-cell maturation antigen (BCMA) is expressed on malignant plasma cells and is an attractive therapeutic target for multiple myeloma. BCMA CAR T-cells, antibody drug conjugates and bispecific T-cell engagers have demonstrated substantial preclinical and clinical activity to date. JCARH125 is a BCMA-targeting CAR T product containing a lentiviral CAR construct with a fully human scFv, optimized spacer, 4-1BB co-stimulatory and CD3z activation domains. The construct has shown minimal tonic signaling and lack of inhibition by soluble BCMA. JCARH125 is generated using a manufacturing process developed to optimize various aspects, including increased consistency of cell health, in the drug product. Methods: EVOLVE (NCT03430011) is a multi-center, phase 1/2 trial of JCARH125 in patients with relapsed and/or refractory multiple myeloma, who have received 3 or more prior regimens, which must include autologous stem cell transplant, a proteasome inhibitor, immunomodulatory drug and an anti-CD38 monoclonal antibody, unless not a candidate (i.e. contraindicated) to receive one or more of the above treatments. Lymphodepleting chemotherapy (LDC) consisting of 3 days of fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) is given 2 to 7 days prior to JCARH125 infusion. A single dose of JCARH125 is given on day 1. Dose escalation is determined using the modified toxicity probability interval 2 (mTPI-2). A minimum of 3 patients are evaluated at each dose level (DL). The first 2 DLs evaluated were 50 and 150x 106 CAR+ T cells. Additional DLs are planned, followed by an expansion at the recommended phase 2 dose (RP2D). The primary objectives of the phase 1 portion are safety and identifying a RP2D. Results: At the time of the July 12, 2018 data analysis, 19 patients have been enrolled (i.e. apheresed) and 13 patients dosed with JCARH125. Only one patient was unable to receive JCARH125, due to sepsis after LDC, leading to death before JCARH125 administration. Eight patients were evaluable for safety (≥ 1 mo follow-up). (n = 5 DL1; n = 3 DL2). Three patients (all from DL1) were evaluable for confirmed response (≥ 2 mo follow-up) per International Myeloma Working Group (IMWG) criteria. Data reported here are from these initial 8 patients. Median follow-up is 5 weeks (range 4 - 13 weeks). Median age is 53 years (range 36 - 66) with a median time from diagnosis of 4 years (range 2 - 12). Patients had received a median of 10 prior regimens (range 4 - 15). Of these 8 patients, 4 (50%) were refractory (no response or progression within 60 days of last therapy) to bortezomib, carfilzomib, lenalidomide, pomalidomide and an anti-CD38 monoclonal antibody. Seven of 8 (88%) had prior autologous stem cell transplant and 4 of 8 (50%) have IMWG high risk cytogenetics. As of the data cut, no DLTs have been observed at the first 2 DLs. Cytokine release syndrome (CRS), all grade 1 or 2, was observed in 6 of 8 (75%) patients. Median onset of CRS was 9 days (range 4 - 10) with a median duration of 4.5 days (range 2 - 19 days). None of the patients with grade 2 CRS required vasopressor support and only 1 patient received tocilizumab. No patients had grade ≥ 3 CRS. Three of 8 (38%) patients experienced neurologic adverse events (AE). Two patients had grade 1 events, and 1 had a grade 3 event (lethargy), which resolved within 24 hours after receiving steroids. Onset of neurologic AEs was 9,11 and 12 days with a duration of 2, 3 and 1 days respectively. Notably, the patient who experienced grade 3 neurotoxicity (NT), developed secondary plasma cell leukemia (PCL) just prior to receiving LDC. All 8 patients have evidence of objective response (≥ MR), including the patient with secondary PCL. 3 patients, all treated at DL1 (50 x 106 CAR+ T-cells), have confirmed responses (1 PR, 2 sCR) with the remainder unconfirmed (1 CR, 2 VGPR, 1 PR, 1 MR). As of the data cut, no patients have progressed. Additional clinical and translational data on at least 30 patients and additional follow up of at least 4 months will be available at time of presentation. Conclusion: At initial lower dose levels, JCARH125 showed an acceptable safety profile with no DLTs reported thus far. Incidence of grade ≥ 3 NT was low and no grade ≥ 3 CRS has occurred with clear clinical activity. Although durability of response and response rate in a greater number of patients remain to be determined, early experience with JCARH125 support a favorable risk-benefit profile and rapid clinical development. Disclosures Mailankody: Takeda: Research Funding; Janssen: Research Funding; Physician Education Resource: Honoraria; Juno: Research Funding. Bensinger:celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Speakers Bureau; Takeda: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Devries:Junot Therapeutics: Employment. Piasecki:Juno Therapeutics: Employment, Equity Ownership; Cascadian Therapeutics: Patents & Royalties; Amgen: Patents & Royalties. Ziyad:Juno Therapeutics: Employment, Equity Ownership. Blake:Celgene: Employment, Equity Ownership. Byon:Juno Therapeutics: Employment, Equity Ownership. Jakubowiak:Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria.

A Novel and Highly Potent CAR T Cell Drug Product for Treatment of BCMA-Expressing Hematological Malignances

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3094-3094 ◽  
Author(s):  
Alena A. Chekmasova ◽  
Holly M. Horton ◽  
Tracy E. Garrett ◽  
John W. Evans ◽  
Johanna Griecci ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Lines ◽  
Drug Product ◽  
Single Chain ◽  
Employment Equity ◽  
Car T Cells ◽  
Car T ◽  
Equity Ownership

Abstract Recently, B cell maturation antigen (BCMA) expression has been proposed as a marker for identification of malignant plasma cells in patients with multiple myeloma (MM). Nearly all MM and some lymphoma tumor cells express BCMA, while normal tissue expression is restricted to plasma cells and a subset of mature B cells. Targeting BCMA maybe a therapeutic option for treatment of patients with MM and some lymphomas. We are developing a chimeric antigen receptor (CAR)-based therapy for the treatment of BCMA-expressing MM. Our anti-BCMA CAR consists of an extracellular single chain variable fragment (scFv) antigen recognition domain derived from an antibody specific to BCMA, fused to CD137 (4-1BB) co-stimulatory and CD3zeta chain signaling domains. Selection of our development candidate was based on the screening of four distinct anti-BCMA CARs (BCMA01-04) each comprised of unique single chain variable fragments. One candidate, BCMA02 (drug product name bb2121) was selected for further studies based on the robust frequency of CAR-positive cells, increased surface expression of the CAR molecule, and superior in vitro cytokine release and cytolytic activity against the MM cell lines. In addition to displaying specific activity against MM (U226-B1, RPMI-8226 and H929) and plasmacytoma (H929) cell lines, bb2121 was demonstrated to react to lymphoma cell lines, including Burkitt's (Raji, Daudi, Ramos), chronic lymphocytic leukemia (Mec-1), diffuse large B cell (Toledo), and a Mantle cell lymphoma (JeKo-1). Based on receptor density quantification, bb2121 can recognize tumor cells expressing less than 1000 BCMA molecules per cell. The in vivo pharmacology of bb2121 was studied in NSG mouse models of human MM and Burkitt's lymphoma. NSG mice were injected subcutaneously (SC) with 107 RPMI-8226 MM cells. After 18 days, mice received a single intravenous (IV) administration of vehicle or anti-CD19Δ (negative control, anti-CD19 CAR lacking signaling domain) or anti-BCMA CAR T cells, or repeated IV administration of bortezomib (Velcade®; 1 mg/kg twice weekly for 4 weeks). Bortezomib, which is a standard of care for MM, induced only transient reductions in tumor size and was associated with toxicity, as indicated by substantial weight loss during dosing. The vehicle and anti-CD19Δ CAR T cells failed to inhibit tumor growth. In contrast, treatment with bb2121 resulted in rapid and sustained elimination of the tumors, increased body weights, and 100% survival. Flow cytometry and immunohistochemical analysis of bb2121 T cells demonstrated trafficking of CAR+ T cells to the tumors (by Day 5) followed by significant expansion of anti-BCMA CAR+ T cells within the tumor and peripheral blood (Days 8-10), accompanied by tumor clearance and subsequent reductions in circulating CAR+ T cell numbers (Days 22-29). To further test the potency of bb2121, we used the CD19+ Daudi cell line, which has a low level of BCMA expression detectable by flow cytometry and receptor quantification analysis, but is negative by immunohistochemistry. NSG mice were injected IV with Daudi cells and allowed to accumulate a large systemic tumor burden before being treated with CAR+ T cells. Treatment with vehicle or anti-CD19Δ CAR T cells failed to prevent tumor growth. In contrast, anti-CD19 CAR T cells and anti-BCMA bb2121 demonstrated tumor clearance. Adoptive T cell immunotherapy approaches designed to modify a patient's own lymphocytes to target the BCMA antigen have clear indications as a possible therapy for MM and could be an alternative method for treatment of other chemotherapy-refractory B-cell malignancies. Based on these results, we will be initiating a phase I clinical trial of bb2121 for the treatment of patients with MM. Disclosures Chekmasova: bluebird bio, Inc: Employment, Equity Ownership. Horton:bluebird bio: Employment, Equity Ownership. Garrett:bluebird bio: Employment, Equity Ownership. Evans:bluebird bio, Inc: Employment, Equity Ownership. Griecci:bluebird bio, Inc: Employment, Equity Ownership. Hamel:bluebird bio: Employment, Equity Ownership. Latimer:bluebird bio: Employment, Equity Ownership. Seidel:bluebird bio, Inc: Employment, Equity Ownership. Ryu:bluebird bio, Inc: Employment, Equity Ownership. Kuczewski:bluebird bio: Employment, Equity Ownership. Horvath:bluebird bio: Employment, Equity Ownership. Friedman:bluebird bio: Employment, Equity Ownership. Morgan:bluebird bio: Employment, Equity Ownership.

scholarly journals Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-Bcma CAR T Cell Therapy

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 740-740 ◽  
Author(s):  
Jesus G. Berdeja ◽  
Yi Lin ◽  
Noopur Raje ◽  
Nikhil Munshi ◽  
David Siegel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Employment Equity ◽  
Car T Cells ◽  
Car T ◽  
Clinical Responses ◽  
Equity Ownership ◽  
Dose Levels

Abstract Introduction: Chimeric antigen receptor (CAR) T cell therapies have demonstrated robust and sustained clinical responses in several hematologic malignancies. Data suggest that achieving acceptable benefit:risk profiles depends on several factors, including the specificity of the antigen target and characteristics of the CAR itself, including on-target, off-tumor activity.To test the safety and efficacy of CAR T cells in relapsed and/or refractory multiple myeloma (RRMM), we have designed a second-generation CAR construct targeting B cell maturation antigen (BCMA) to redirect T cells to MM cells. BCMA is a member of the tumor necrosis factor superfamily that is expressed primarily by malignant myeloma cells, plasma cells, and some mature B cells. bb2121 consists of autologous T cells transduced with a lentiviral vector encoding a novel CAR incorporating an anti-BCMA scFv, a 4-1BB costimulatory motif and a CD3-zeta T cell activation domain. Methods: CRB-401 (NCT02658929) is a multi-center phase 1 dose escalation trial of bb2121 in patients with RRMM who have received ≥ 3 prior regimens, including a proteasome inhibitor and an immunomodulatory agent, or are double-refractory, and have ≥ 50% BCMA expression on malignant cells. Peripheral blood mononuclear cells are collected via leukapheresis and shipped to a central facility for transduction, expansion, and release testing prior to being returned to the site for infusion. Patients undergo lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) daily for 3 days then receive 1 infusion of bb2121. The study follows a standard 3+3 design with planned dose levels of 50, 150, 450, 800, and 1,200 x 106 CAR+ T cells. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Additional outcome measures were quality and duration of clinical response assessed according to the IMWG Uniform Response Criteria for Multiple Myeloma, evaluation of minimal residual disease (MRD), overall and progression-free survival, quantification of bb2121 in blood, and quantification of circulating soluble BCMA over time. Results: Asof May 4, 2017, 21 patients (median 58 [37 to 74] years old) with a median of 5 (1 to 16) years since MM diagnosis, had been infused with bb2121, and 18 patients were evaluable for initial (1-month) clinical response. Patients had a median of 7 prior lines of therapy (range 3 to 14), all with prior autologous stem cell transplant; 67% had high-risk cytogenetics. Fifteen of 21 (71%) had prior exposure to, and 6 of 21 (29%) were refractory to 5 prior therapies (Bort/Len/Car/Pom/Dara). Median follow-up after bb2121 infusion was 15.4 weeks (range 1.4 to 54.4 weeks). As of data cut-off, no DLTs and no treatment-emergent Grade 3 or higher neurotoxicities similar to those reported in other CAR T clinical studies had been observed. Cytokine release syndrome (CRS), primarily Grade 1 or 2, was reported in 15 of 21 (71%) patients: 2 patients had Grade 3 CRS that resolved in 24 hours and 4 patients received tocilizumab, 1 with steroids, to manage CRS. CRS was more common in the higher dose groups but did not appear related to tumor burden. One death on study, due to cardiopulmonary arrest more than 4 months after bb2121 infusion in a patient with an extensive cardiac history, was observed while the patient was in sCR and was assessed as unrelated to bb2121. The overall response rate (ORR) was 89% and increased to 100% for patients treated with doses of 150 x 106 CAR+ T cells or higher. No patients treated with doses of 150 x 106 CAR+ T cells or higher had disease progression, with time since bb2121 between 8 and 54 weeks (Table 1). MRD negative results were obtained in all 4 patients evaluable for analysis. CAR+ T cell expansion has been demonstrated consistently and 3 of 5 patients evaluable for CAR+ cells at 6 months had detectable vector copies. A further 5 months of follow up on reported results and initial data from additional patients will be presented. Conclusions: bb2121 shows promising efficacy at dose levels above 50 x 106 CAR+ T cells, with manageable CRS and no DLTs to date. ORR was 100% at these dose levels with 8 ongoing clinical responses at 6 months and 1 patient demonstrating a sustained response beyond one year. These initial data support the potential of CAR T therapy with bb2121 as a new treatment paradigm in RRMM. CT.gov study NCT02658929, sponsored by bluebird bio and Celgene Disclosures Berdeja: Teva: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; BMS: Research Funding; Takeda: Research Funding; Vivolux: Research Funding; Amgen: Research Funding; Constellation: Research Funding; Bluebird: Research Funding; Curis: Research Funding. Siegel: Celgene, Takeda, Amgen Inc, Novartis and BMS: Consultancy, Speakers Bureau; Merck: Consultancy. Jagannath: MMRF: Speakers Bureau; Bristol-Meyers Squibb: Consultancy; Merck: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Medicom: Speakers Bureau. Turka: bluebird bio: Employment, Equity Ownership. Lam: bluebird bio: Employment, Equity Ownership. Hege: Celgene Corporation: Employment, Equity Ownership. Morgan: bluebird bio: Employment, Equity Ownership, Patents & Royalties. Quigley: bluebird bio: Employment, Equity Ownership, Patents & Royalties. Kochenderfer: Bluebird bio: Research Funding; N/A: Patents & Royalties: I have multiple patents in the CAR field.; Kite Pharma: Research Funding.

scholarly journals Development and Evaluation of a Human Single Chain Variable Fragment (scFv) Derived Bcma Targeted CAR T Cell Vector Leads to a High Objective Response Rate in Patients with Advanced MM

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 742-742 ◽  
Author(s):  
Eric L Smith ◽  
Sham Mailankody ◽  
Arnab Ghosh ◽  
Reed Masakayan ◽  
Mette Staehr ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Employment Equity ◽  
Advisory Committees ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Equity Ownership

Abstract Patients with relapsed/refractory MM (RRMM) rarely obtain durable remissions with available therapies. Clinical use of BCMA targeted CAR T cell therapy was first reported in 12/2015 for RRMM, and based on small numbers, preliminary results appear promising. Given that host immune anti-murine CAR responses have limited the efficacy of repeat dosing (Turtle C. Sci Trans Med 2016), our goal was to develop a human BCMA targeted CAR T cell vector for clinical translation. We screened a human B cell derived scFv phage display library containing 6x1010 scFvs with BCMA expressing NIH 3T3 cells, and validated results on human MM cell lines. 57 unique and diverse BCMA specific scFvs were identified containing light and heavy chain CDR's each covering 6 subfamilies, with HCDR3 length ranges from 5-18 amino acids. 17 scFvs met stringent specificity criteria, and a diverse set was cloned into CAR vectors with either a CD28 or a 4-1BB co-stimulatory domain. Donor T cells transduced with BCMA targeted CAR vectors that conveyed particularly desirable properties over multiple in vitro assays, including: cytotoxicity on human MM cell lines at low E:T ratios (&gt;90% lysis, 1:1, 16h), robust proliferation after repeat antigen stimulation (up to 700 fold, stimulation q3-4d for 14d), and active cytokine profiling, were selected for in vivo studies using a marrow predominant human MM cell line model in NSG mice. A single IV injection of CAR T cells, either early (4d) or late (21d) after MM engraftment was evaluated. In both cases survival was increased when treated with BCMA targeted CAR T cells vs CD19 targeted CAR T cells (median OS at 60d NR vs 35d p&lt;0.05). Tumor and CAR T cells were imaged in vivo by taking advantage of luciferase constructs with different substrates. Results show rapid tumor clearance, peak (&gt;10,000 fold) CAR T expansion at day 6, followed by contraction of CAR T cells after MM clearance, confirming the efficacy of the anti-BCMA scFv/4-1BB containing construct. Co-culture with primary cells from a range of normal tissues did not activate CAR T cells as noted by a lack of IFN release. Co-culture of 293 cells expressing this scFv with those expressing a library of other TNFRSF or Ig receptor members demonstrated specific binding to BCMA. GLP toxicity studies in mice showed no unexpected adverse events. We generated a retroviral construct for clinical use including a truncated epithelial growth factor receptor (EGFRt) elimination gene: EGFRt/hBCMA-41BBz. Clinical investigation of this construct is underway in a dose escalation, single institution trial. Enrollment is completed on 2/4 planned dose levels (DL). On DL1 pts received cyclophosphamide conditioning (3g/m2 x1) and 72x106 mean CAR+ T cells. On DL2 pts received lower dose cyclophosphamide/fludarabine (300/30 mg/m2 x3) and 137x106 mean CAR+ T cells. All pts screened for BCMA expression by IHC were eligible. High risk cytogenetics were present in 4/6 pts. Median prior lines of therapy was 7; all pts had IMiD, PI, high dose melphalan, and CD38 directed therapies. With a data cut off of 7/20/17, 6 pts are evaluable for safety. There were no DLT's. At DL1, grade 1 CRS, not requiring intervention, occurred in 1/3 pts. At DL2, grade 1/2 CRS occurred in 2/3 pts; both received IL6R directed Tocilizumab (Toci) with near immediate resolution. In these 2 pts time to onset of fever was a mean 2d, Tmax was 39.4-41.1 C, peak CRP was 25-27mg/dl, peak IL6 level pre and post Toci were 558-632 and 3375-9071 pg/ml, respectively. Additional serum cytokines increased &gt;10 fold from baseline in both pts include: IFNg, GM CSF, Fractalkine, IL5, IL8, and IP10. Increases in ferritin were limited, and there were no cases of hypofibrinogenemia. There were no grade 3-5 CRS and no neurotoxicities or cerebral edema. No pts received steroids or Cetuximab. Median time to count recovery after neutropenia was 10d (range 6-15d). Objective responses by IMWG criteria after a single dose of CAR T cells were observed across both DLs. At DL1, of 3 pts, responses were 1 VGPR, 1 SD, and 1 pt treated with baseline Mspike 0.46, thus not evaluable by IMWG criteria, had &gt;50% reduction in Mspike, and normalization of K/L ratio. At DL2, 2/2 pts had objective responses with 1 PR and 1 VGPR (baseline 95% marrow involvement); 1 pt is too early to evaluate. As we are employing a human CAR, the study was designed to allow for an optional second dose in pts that do not reach CR. We have treated 2 pts with a second dose, and longer follow up data is pending. Figure 1 Figure 1. Disclosures Smith: Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: BCMA targeted CAR T cells, Research Funding. Almo: Cue Biopharma: Other: Founder, head of SABequity holder; Institute for Protein Innovation: Consultancy; AKIN GUMP STRAUSS HAUER & FELD LLP: Consultancy. Wang: Eureka Therapeutics Inc.: Employment, Equity Ownership. Xu: Eureka Therapeutics, Inc: Employment, Equity Ownership. Park: Amgen: Consultancy. Curran: Juno Therapeutics: Research Funding; Novartis: Consultancy. Dogan: Celgene: Consultancy; Peer Review Institute: Consultancy; Roche Pharmaceuticals: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Liu: Eureka Therpeutics Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Brentjens: Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

scholarly journals Phase 2 Study of the Response and Safety of P-Bcma-101 CAR-T Cells in Patients with Relapsed/Refractory (r/r) Multiple Myeloma (MM) (PRIME)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3184-3184 ◽  
Author(s):  
Caitlin L. Costello ◽  
Tara K. Gregory ◽  
Syed Abbas Ali ◽  
Jesus G. Berdeja ◽  
Krina K. Patel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 2 ◽  
Employment Equity ◽  
Advisory Committees ◽  
Car T Cells ◽  
Car T ◽  
Equity Ownership

P-BCMA-101 is a novel chimeric antigen receptor (CAR)-T cell product targeting B Cell Maturation Antigen (BCMA). P-BCMA-101 is produced using the piggyBac® (PB) DNA Modification System instead of the viral vector that is used with most CAR-T cells, requiring only plasmid DNA and mRNA. This makes it less costly and produces cells with a high percentage of the favorable T stem cell memory phenotype (TSCM). The higher cargo capacity of PB permits the incorporation of multiple genes in addition to CAR(s), including a safety switch allowing for rapid CAR-T cell elimination with a small molecule drug infusion in patients if desired, and a selection gene allowing for enrichment of CAR+ cells. Rather than using a traditional antibody-based binder, P-BCMA-101 has a Centyrin™ fused to a CD3ζ/4-1BB signaling domain. Centyrins are fully human proteins with high specificity and a large range of binding affinities, but are smaller, more stable and potentially less immunogenic than traditional scFv. Cumulatively, these features are predicted to result in a greater therapeutic index. A Phase 1, 3+3 dose escalation from 0.75 to 15 x 106 P-BCMA-101 CAR-T cells/kg (RP2D 6-15 x 106 cells/kg) was conducted in patients with r/r MM (Blood 2018 132:1012) demonstrating excellent efficacy and safety of P-BCMA-101, including notably low rates and grades of CRS and neurotoxicity (maximum Grade 2 without necessitating ICU admission, safety switch activation or other aggressive measures). These results supported FDA RMAT designation and initiation of a pivotal Phase 2 study. A Phase 2 pivotal portion of this study has recently been designed and initiated (PRIME; NCT03288493) in r/r MM patients who have received at least 3 prior lines of therapy. Their therapy must have contained a proteasome inhibitor, an IMiD, and CD38 targeted therapy with at least 2 of the prior lines in the form of triplet combinations. They must also have undergone ≥2 cycles of each line unless PD was the best response, refractory to the most recent line of therapy, and undergone autologous stem cell transplant or not be a candidate. Patients are required to be >=18 years old, have measurable disease by International Myeloma Working Group criteria (IMWG; Kumar 2016), adequate vital organ function and lack significant autoimmune, CNS and infectious diseases. No pre-specified level of BCMA expression is required, as this has not been demonstrated to correlate with clinical outcomes for P-BCMA-101 and other BCMA-targeted CAR-T products. Interestingly, unlike most CAR-T products patients may receive P-BCMA-101 after prior CAR-T cells or BCMA targeted agents, and may be multiply infused with P-BCMA-101. Patients are apheresed to harvest T cells, P-BCMA-101 is then manufactured and administered to patients as a single intravenous (IV) dose (6-15 x 106 P-BCMA-101 CAR-T cells/kg) after a standard 3-day cyclophosphamide (300 mg/m2/day) / fludarabine (30 mg/m2/day) conditioning regimen. One hundred patients are planned to be treated with P-BCMA-101. Uniquely, given the safety profile demonstrated during Phase 1, no hospital admission is required and patients may be administered P-BCMA-101 in an outpatient setting. The primary endpoints are safety and response rate by IMWG criteria. With a 100-subject sample, the Phase 2 part of the trial will have 90% power to detect a 15-percentage point improvement over a 30% response rate (based on that of the recently approved anti-CD38 antibody daratumumab), using an exact test for a binomial proportion with a 1-sided 0.05 significance level. Multiple biomarkers are being assessed including BCMA and cytokine levels, CAR-T cell kinetics, immunogenicity, T cell receptor diversity, CAR-T cell and patient gene expression (e.g. Nanostring) and others. Overall, the PRIME study is the first pivotal study of the unique P-BCMA-101 CAR-T product, and utilizes a number of novel design features. Studies are being initiated in combination with approved therapeutics and earlier lines of therapy with the intent of conducting Phase 3 trials. Funding by Poseida Therapeutics and the California Institute for Regenerative Medicine (CIRM). Disclosures Costello: Takeda: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Gregory:Poseida: Research Funding; Celgene: Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau. Ali:Celgene: Research Funding; Poseida: Research Funding. Berdeja:Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy; AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding; Poseida: Research Funding. Patel:Oncopeptides, Nektar, Precision Biosciences, BMS: Consultancy; Takeda, Celgene, Janssen: Consultancy, Research Funding; Poseida Therapeutics, Cellectis, Abbvie: Research Funding. Shah:University of California, San Francisco: Employment; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Indapta Therapeutics: Equity Ownership; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ostertag:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Martin:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Ghoddusi:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Shedlock:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Spear:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Orlowski:Poseida Therapeutics, Inc.: Research Funding. Cohen:Poseida Therapeutics, Inc.: Research Funding.

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