scholarly journals Phase I Study of AUTO3, a Bicistronic Chimeric Antigen Receptor (CAR) T-Cell Therapy Targeting CD19 and CD22, in Pediatric Patients with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia (r/r B-ALL): Amelia Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2620-2620 ◽  
Author(s):  
Persis J Amrolia ◽  
Robert Wynn ◽  
Rachael E Hough ◽  
Ajay Vora ◽  
Denise Bonney ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Employment Equity ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Equity Ownership

Introduction CAR T-cell therapies directed against CD19 or CD22 have shown remarkable activity in r/r B-ALL but relapse due to target antigen down-regulation/loss has been the major cause of treatment failure. To address this, we developed AUTO3, a CAR T-cell therapy designed to target CD19 and CD22 simultaneously. Preliminary results of this study showed an acceptable safety profile and encouraging efficacy in pediatric r/r B-ALL (all 6 patients treated in active doses ≥3 x 106 CAR T-cells/ Kg achieved complete remission (CR) with negative minimal residual disease (MRD) (Amrolia et al, Blood 2018 132:279). Here we present the updated results of CAR naïve patients treated at the active doses. Methods & Patients We constructed a bicistronic retroviral vector encoding both an anti-CD19 CAR and an anti-CD22 CAR. This second-generation CAR incorporated an OX40 co-stimulatory domain for the CD19 CAR and a 41BB for the CD22 CAR. The cell product was manufactured on a semi-automated/closed process. Patients (aged 1‒24 years) with high risk relapsed (IBFM criteria) or refractory B-ALL, adequate performance score/organ function, an absolute lymphocyte count ≥0.5 x 109/L are eligible. Patients with CNS Grade 3 disease, active graft versus host disease are excluded. Patients receive lymphodepletion with 30 mg/m2/day fludarabine x 4 days and 500 mg/m2/day cyclophosphamide x 2 days prior to AUTO3 infusion. Three dose levels were explored (1 x 106, 3 x 106, and 5 x 106 cells/kg), CAR T cells are infused as a single (for <25% blasts) or split (for ≥25% blasts) dose based on leukemia burden. Bridging therapy is allowed during the manufacturing period. The primary endpoint is the frequency of dose-limiting toxicities (DLTs) and key secondary endpoints include morphological/MRD negative CR rate, disease-free survival, overall survival, as well as AUTO3 levels and persistence in blood and bone marrow. Results As of the data cut-off date (June 17, 2019), 10 patients received AUTO3 at 3 x 106 cells/Kg (n= 5, of whom 1 received split dose) or 5 x 106 CAR T-cells/Kg (n= 5, all of them received single infusion). The median transduction efficiency was 15.5% (range 8.6‒39.3%). Median age was 8.5 years (range 5‒16 years) and 5 (50%) patients had prior haemopoietic stem cell transplant (HSCT). One patient (10%) had prior anti-CD19 CAR-T cells. The disease burden at Day ‒7 ranged from 0 to 38% (median 7.5%) blasts. Among the 10 treated patients, 2 have not completed the 30 days post-infusion DLT observation period as of the cut-off date. No deaths or DLTs were observed. MTD has not yet been reached. The most common grade (Gr) ≥3 adverse events were neutropenia (60%), anaemia (50%), pyrexia (40%), febrile neutropenia (40%) and thrombocytopenia (30%). Eight patients (80%) had Gr 1 cytokine release syndrome (CRS), one (10%) had Gr 2 CRS; no ≥Gr 3 CRS was observed. Only one patient was treated with tocilizumab and none required admission to ICU due to CRS. One patient (10%) experienced Gr 1 neurotoxicity; no ≥ Gr 2 neurotoxicity was reported. Among the 9 CAR naïve patients, 7 (4 in the 3 x 106 cells/Kg dose cohort, 3 in the 5 x 106 cells/Kg dose cohort) had a minimum of 8 weeks' follow up and were evaluable for efficacy analysis. All 7 patients achieved CR/CRi (100%) following AUTO3 infusion as well as molecular negative remission (100%). After a median follow-up of 8 months (range 2-12), emergence of MRD by PCR occurred in four patients, lack of persistence of circulating CAR T-cells was observed in 3 of the 4 patients. Three relapses were reported including one with CD19 negative/CD22 low expression at 1 year after treatment. One patient in ongoing molecular remission proceeded to HSCT. All the remaining 4 patients in ongoing CR/CRi maintain B-cell aplasia. The median CAR T-cell expansion (expressed as vector copy number per microgram of DNA) at peak was 102K (range 56-128). The median persistence of CAR-T cells in blood was 180 days (range 21-330). Updated data with longer follow up and additional patient data will be presented. Conclusion This interim data analysis demonstrates that AUTO3 at ≥3 x 106 cells dose achieved 100% molecular remission rate with a favourable safety profile, no ≥ Gr 3 CRS or ≥ Gr 2 neurotoxicity was reported. The most common cause of relapse was antigen positive relapse due to lack of CAR T cell persistence. Evaluation of patients with a modified manufacturing process is planned. Disclosures Amrolia: UCLB: Patents & Royalties. Clark:Autolus Ltd: Employment, Equity Ownership. Al-Hajj:Autolus Therapeutics: Employment, Equity Ownership. Cordoba:Autolus: Employment, Equity Ownership. Kotsopoulou:Autolus Therapeutics: Employment, Equity Ownership. Khokhar:Autolus Therapeutics: Employment, Equity Ownership. Pule:Autolus: Employment, Equity Ownership, Patents & Royalties. Peddareddigari:Autolus Therapeutics: Employment, Equity Ownership.

scholarly journals Preclinical Evaluation of ALLO-819, an Allogeneic CAR T Cell Therapy Targeting FLT3 for the Treatment of Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3921-3921 ◽  
Author(s):  
Cesar Sommer ◽  
Hsin-Yuan Cheng ◽  
Yik Andy Yeung ◽  
Duy Nguyen ◽  
Janette Sutton ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Target Cells ◽  
Employment Equity ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Equity Ownership

Autologous chimeric antigen receptor (CAR) T cells have achieved unprecedented clinical responses in patients with B-cell leukemias, lymphomas and multiple myeloma, raising interest in using CAR T cell therapies in AML. These therapies are produced using a patient's own T cells, an approach that has inherent challenges, including requiring significant time for production, complex supply chain logistics, separate GMP manufacturing for each patient, and variability in performance of patient-derived cells. Given the rapid pace of disease progression combined with limitations associated with the autologous approach and treatment-induced lymphopenia, many patients with AML may not receive treatment. Allogeneic CAR T (AlloCAR T) cell therapies, which utilize cells from healthy donors, may provide greater convenience with readily available off-the-shelf CAR T cells on-demand, reliable product consistency, and accessibility at greater scale for more patients. To create an allogeneic product, the TRAC and CD52 genes are inactivated in CAR T cells using Transcription Activator-Like Effector Nuclease (TALEN®) technology. These genetic modifications are intended to minimize the risk of graft-versus-host disease and to confer resistance to ALLO-647, an anti-CD52 antibody that can be used as part of the conditioning regimen to deplete host alloreactive immune cells potentially leading to increased persistence and efficacy of the infused allogeneic cells. We have previously described the functional screening of a library of anti-FLT3 single-chain variable fragments (scFvs) and the identification of a lead FLT3 CAR with optimal activity against AML cells and featuring an off-switch activated by rituximab. Here we characterize ALLO-819, an allogeneic FLT3 CAR T cell product, for its antitumor efficacy and expansion in orthotopic models of human AML, cytotoxicity in the presence of soluble FLT3 (sFLT3), performance compared with previously described anti-FLT3 CARs and potential for off-target binding of the scFv to normal human tissues. To produce ALLO-819, T cells derived from healthy donors were activated and transduced with a lentiviral construct for expression of the lead anti-FLT3 CAR followed by efficient knockout of TRAC and CD52. ALLO-819 manufactured from multiple donors was insensitive to ALLO-647 (100 µg/mL) in in vitro assays, suggesting that it would avoid elimination by the lymphodepletion regimen. In orthotopic models of AML (MV4-11 and EOL-1), ALLO-819 exhibited dose-dependent expansion and cytotoxic activity, with peak CAR T cell levels corresponding to maximal antitumor efficacy. Intriguingly, ALLO-819 showed earlier and more robust peak expansion in mice engrafted with MV4-11 target cells, which express lower levels of the antigen relative to EOL-1 cells (n=2 donors). To further assess the potency of ALLO-819, multiple anti-FLT3 scFvs that had been described in previous reports were cloned into lentiviral constructs that were used to generate CAR T cells following the standard protocol. In these comparative studies, the ALLO-819 CAR displayed high transduction efficiency and superior performance across different donors. Furthermore, the effector function of ALLO-819 was equivalent to that observed in FLT3 CAR T cells with normal expression of TCR and CD52, indicating no effects of TALEN® treatment on CAR T cell activity. Plasma levels of sFLT3 are frequently increased in patients with AML and correlate with tumor burden, raising the possibility that sFLT3 may act as a decoy for FLT3 CAR T cells. To rule out an inhibitory effect of sFLT3 on ALLO-819, effector and target cells were cultured overnight in the presence of increasing concentrations of recombinant sFLT3. We found that ALLO-819 retained its killing properties even in the presence of supraphysiological concentrations of sFLT3 (1 µg/mL). To investigate the potential for off-target binding of the ALLO-819 CAR to human tissues, tissue cross-reactivity studies were conducted using a recombinant protein consisting of the extracellular domain of the CAR fused to human IgG Fc. Consistent with the limited expression pattern of FLT3 and indicative of the high specificity of the lead scFv, no appreciable membrane staining was detected in any of the 36 normal tissues tested (n=3 donors). Taken together, our results support clinical development of ALLO-819 as a novel and effective CAR T cell therapy for the treatment of AML. Disclosures Sommer: Allogene Therapeutics, Inc.: Employment, Equity Ownership. Cheng:Allogene Therapeutics, Inc.: Employment, Equity Ownership. Yeung:Pfizer Inc.: Employment, Equity Ownership. Nguyen:Allogene Therapeutics, Inc.: Employment, Equity Ownership. Sutton:Allogene Therapeutics, Inc.: Employment, Equity Ownership. Melton:Allogene Therapeutics, Inc.: Employment, Equity Ownership. Valton:Cellectis, Inc.: Employment, Equity Ownership. Poulsen:Allogene Therapeutics, Inc.: Employment, Equity Ownership. Djuretic:Pfizer, Inc.: Employment, Equity Ownership. Van Blarcom:Allogene Therapeutics, Inc.: Employment, Equity Ownership. Chaparro-Riggers:Pfizer, Inc.: Employment, Equity Ownership. Sasu:Allogene Therapeutics, Inc.: Employment, Equity Ownership.

scholarly journals Feasibility, and Efficacy of Donor-Derived cd19-Targeted Car t-Cell Therapy in Refractory/Relapsed(r/r)b-Cell Acute Lymphoblastic Leukemia (b-all) Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-6
Author(s):  
Xian Zhang ◽  
Junfang Yang ◽  
Wenqian Li ◽  
Gailing Zhang ◽  
Yunchao Su ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Backgrounds As CAR T-cell therapy is a highly personalized therapy, process of generating autologous CAR-T cells for each patient is complex and can still be problematic, particularly for heavily pre-treated patients and patients with significant leukemia burden. Here, we analyzed the feasibility and efficacy in 37 patients with refractory/relapsed (R/R) B-ALL who received CAR T-cells derived from related donors. Patients and Methods From April 2017 to May 2020, 37 R/R B-ALL patients with a median age of 19 years (3-61 years), were treated with second-generation CD19 CAR-T cells derived from donors. The data was aggregated from three clinical trials (www.clinicaltrials.gov NCT03173417; NCT02546739; and www.chictr.org.cn ChiCTR-ONC-17012829). Of the 37 patients, 28 were relapsed following allogenic hematopoietic stem cell transplant (allo-HSCT) and whose lymphocytes were collected from their transplant donors (3 HLA matched sibling and 25 haploidentical). For the remaining 9 patients without prior transplant, the lymphocytes were collected from HLA identical sibling donors (n=5) or haploidentical donors (n=4) because CAR-T cells manufacture from patient samples either failed (n=5) or blasts in peripheral blood were too high (&gt;40%) to collect quality T-cells. The median CAR-T cell dose infused was 3×105/kg (1-30×105/kg). Results For the 28 patients who relapsed after prior allo-HSCT, 27 (96.4%) achieved CR within 30 days post CAR T-cell infusion, of which 25 (89.3%) were minimal residual disease (MRD) negative. Within one month following CAR T-cell therapy, graft-versus-host disease (GVHD) occurred in 3 patients including 1 with rash and 2 with diarrhea. A total of 19 of the 28 (67.9%) patients had cytokine release syndrome (CRS), including two patients (7.1%) with Grade 3-4 CRS. Four patients had CAR T-cell related neurotoxicity including 3 with Grade 3-4 events. With a medium follow up of 103 days (1-669days), the median overall survival (OS) was 169 days (1-668 days), and the median leukemia-free survival (LFS) was 158 days (1-438 days). After CAR T-cell therapy, 15 patients bridged into a second allo-HSCT and one of 15 patients (6.7%) relapsed following transplant, and two died from infection. There were 11 patients that did not receive a second transplantation, of which three patients (27.3%) relapsed, and four parents died (one due to relapse, one from arrhythmia and two from GVHD/infection). Two patients were lost to follow-up. The remaining nine patients had no prior transplantation. At the time of T-cell collection, the median bone marrow blasts were 90% (range: 18.5%-98.5%), and the median peripheral blood blasts were 10% (range: 0-70%). CR rate within 30 days post CAR-T was 44.4% (4/9 cases). Six patients developed CRS, including four with Grade 3 CRS. Only one patient had Grade 3 neurotoxicity. No GVHD occurred following CAR T-cell therapy. Among the nine patients, five were treated with CAR T-cells derived from HLA-identical sibling donors and three of those five patients achieved CR. One patient who achieved a CR died from disseminated intravascular coagulation (DIC) on day 16. Two patients who achieved a CR bridged into allo-HSCT, including one patient who relapsed and died. One of two patients who did not response to CAR T-cell therapy died from leukemia. Four of the nine patients were treated with CAR T-cells derived from haploidentical related donors. One of the four cases achieved a CR but died from infection on day 90. The other three patients who had no response to CAR T-cell therapy died from disease progression within 3 months (7-90 days). Altogether, seven of the nine patients died with a median time of 19 days (7-505 days). Conclusions We find that manufacturing CD19+ CAR-T cells derived from donors is feasible. For patients who relapse following allo-HSCT, the transplant donor derived CAR-T cells are safe and effective with a CR rate as high as 96.4%. If a patient did not have GVHD prior to CAR T-cell therapy, the incidence of GVHD following CAR T-cell was low. Among patients without a history of transplantation, an inability to collect autologous lymphocytes signaled that the patient's condition had already reached a very advanced stage. However, CAR T-cells derived from HLA identical siblings can still be considered in our experience, no GVHD occurred in these patients. But the efficacy of CAR T-cells from haploidentical donors was very poor. Disclosures No relevant conflicts of interest to declare.

scholarly journals Allogeneic Hematopoietic Cell Transplantation Is Critical to Maintain Remissions after CD19-CAR T-Cell Therapy for Pediatric ALL: A Single Center Experience

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Aimee C Talleur ◽  
Renee M. Madden ◽  
Amr Qudeimat ◽  
Ewelina Mamcarz ◽  
Akshay Sharma ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Allogeneic Hct ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

CD19-CAR T-cell therapy has shown remarkable efficacy in pediatric patients with relapsed and/or refractory B-cell acute lymphoblastic leukemia (r/r ALL). Despite high short-term remission rates, many responses are not durable and the best management of patients who achieve a complete response (CR) post-CAR T-cell therapy remains controversial. In particular, it is unclear if these patients should be observed or proceed to consolidative allogeneic hematopoietic cell transplantation (HCT). To address this question, we reviewed the clinical course of all patients (n=22) who received either an investigational CAR T-cell product (Phase I study: SJCAR19 [NCT03573700]; n=12) or tisagenlecleucel (n=10) at our institution. The investigational CD19-CAR T cells were generated by a standard cGMP-compliant procedure using a lentiviral vector encoding a 2nd generation CD19-CAR with a FMC63-based CD19 binding domain, CD8a stalk and transmembrane domain, and 41BB.ζ signaling domain. Patients received therapy between 8/2018 and 3/2020. All products met manufacturing release specifications. Within the entire cohort, median age at time of infusion was 12.3 years old (range: 1.8-23.5) and median pre-infusion marrow burden using flow-cytometry minimal residual disease (MRD) testing was 6.8% (range: 0.003-100%; 1 patient detectable by next-generation sequencing [NGS] only). All patients received lymphodepleting chemotherapy (fludarabine, 25mg/m2 daily x3, and cyclophosphamide, 900mg/m2 daily x1), followed by a single infusion of CAR T-cells. Phase I product dosing included 1x106 CAR+ T-cells/kg (n=6) or 3x106 CAR+ T-cells/kg (n=6). Therapy was well tolerated, with a low incidence of cytokine release syndrome (any grade: n=10; Grade 3-4: n=4) and neurotoxicity (any grade: n=8; Grade 3-4: n=3). At 4-weeks post-infusion, 15/22 (68.2%) patients achieved a CR in the marrow, of which 13 were MRDneg (MRDneg defined as no detectable leukemia by flow-cytometry, RT-PCR and/or NGS, when available). Among the 2 MRDpos patients, 1 (detectable by NGS only) relapsed 50 days after CAR T-cell infusion and 1 died secondary to invasive fungal infection 35 days after infusion. Within the MRDneg cohort, 6/13 patients proceeded to allogeneic HCT while in MRDneg/CR (time to HCT, range: 1.8-2.9 months post-CAR T-cell infusion). All 6 HCT recipients remain in remission with a median length of follow-up post-HCT of 238.5 days (range 19-441). In contrast, only 1 (14.3%) patient out of 7 MRDneg/CR patients who did not receive allogeneic HCT, remains in remission with a follow up of greater 1 year post-CAR T-cell infusion (HCT vs. no HCT: p&lt;0.01). The remaining 6 patients developed recurrent detectable leukemia within 2 to 9 months post-CAR T-cell infusion (1 patient detectable by NGS only). Notably, recurring leukemia remained CD19+ in 4 of 5 evaluable patients. All 4 patients with CD19+ relapse received a 2nd CAR T-cell infusion (one in combination with pembrolizumab) and 2 achieved MRDneg/CR. There were no significant differences in outcome between SJCAR19 study participants and patients who received tisagenlecleucel. With a median follow up of one year, the 12 month event free survival (EFS) of all 22 patients is 25% (median EFS: 3.5 months) and the 12 month overall survival (OS) 70% (median OS not yet reached). In conclusion, infusion of investigational and FDA-approved autologous CD19-CAR T cells induced high CR rates in pediatric patients with r/r ALL. However, our current experience shows that sustained remission without consolidative allogeneic HCT is not seen in most patients. Our single center experience highlights not only the need to explore maintenance therapies other than HCT for MRDneg/CR patients, but also the need to improve the in vivo persistence of currently available CD19-CAR T-cell products. Disclosures Sharma: Spotlight Therapeutics: Consultancy; Magenta Therapeutics: Other: Research Collaboration; CRISPR Therapeutics, Vertex Pharmaceuticals, Novartis: Other: Clinical Trial PI. Velasquez:St. Jude: Patents & Royalties; Rally! Foundation: Membership on an entity's Board of Directors or advisory committees. Gottschalk:Patents and patent applications in the fields of T-cell & Gene therapy for cancer: Patents & Royalties; TESSA Therapeutics: Other: research collaboration; Inmatics and Tidal: Membership on an entity's Board of Directors or advisory committees; Merck and ViraCyte: Consultancy.

Update of CARTITUDE-1: A phase Ib/II study of JNJ-4528, a B-cell maturation antigen (BCMA)-directed CAR-T-cell therapy, in relapsed/refractory multiple myeloma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8505-8505 ◽  
Author(s):  
Jesus G. Berdeja ◽  
Deepu Madduri ◽  
Saad Zafar Usmani ◽  
Indrajeet Singh ◽  
Enrique Zudaire ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Phase 1B

8505 Background: JNJ-68284528 (JNJ-4528) is a chimeric antigen receptor T (CAR-T) cell therapy containing 2 BCMA-targeting single-domain antibodies. Here we present updated CARTITUDE-1 (NCT03548207) phase 1b results with longer follow-up. Methods: Pts had MM per IMWG criteria, measurable disease, received ≥3 prior regimens or were double refractory to a PI and IMiD, and received anti-CD38 antibody. Cyclophosphamide 300 mg/m2+ fludarabine 30 mg/m2 over 3 days were used for lymphodepletion. JNJ-4528 (median, 0.73x106 CAR+ viable T cells/kg) was given as a single infusion. Cytokine release syndrome (CRS) was graded by Lee et al2014 and neurotoxicity by CTCAE, v5.0 and ASTCT grading. Response was assessed per IMWG criteria. Results: As of 17 Jan 2020, median follow-up is 9 mo (3–17). Phase 1b enrollment is complete (N = 29 treated; median 5 (3–18) prior lines, 76% penta-exposed, 86% triple-refractory, 31% penta-refractory, 97% refractory to last line of therapy). Most frequent adverse events (AEs) were neutropenia (100%), CRS (93%), and thrombocytopenia (93%). Grade (Gr) ≥3 hematologic AEs were neutropenia (100%), thrombocytopenia (69%), and leukopenia (59%). 27 (93%) pts had CRS; 25 Gr 1–2, 1 Gr 3, and 1 Gr 5 (day 99 subsequent to dose-limiting toxicity of prolonged Gr 4 CRS). Median time to onset of CRS was 7 days (2–12). 4 pts had treatment-related neurotoxicity: 3 Gr 1–2 and 1 Gr 3. ORR was 100%, with 22 (76%) stringent complete responses (sCRs), 6 (21%) very good partial responses (VGPRs), and 1 (3%) PR. Median time to ≥CR was 2 mo (1–9). 26/29 pts are progression-free, with 6-mo progression-free survival rate of 93% and longest response ongoing at 15 mo. 1 death due to CRS and 1 to acute myeloid leukemia (not treatment-related) occurred during the study. All 16 pts (14 sCR, 2 VGPR) evaluable at 6 mo were minimal residual disease negative at 10−5 or 10−6. JNJ-4528 CAR+ T cell expansion peaked between day 10–14. At 6-mo individual follow-up, 22/28 pts had JNJ-4528 CAR+ T cells below the level of quantification (2 cells/µL) in peripheral blood, suggesting CAR-T persistence in peripheral blood did not seem to correlate with deepening of response. At peak expansion, preferential expansion of CD8+ CAR-T cells with a central memory phenotype was observed in peripheral blood. Conclusions: JNJ-4528 treatment led to responses in all pts. These responses were early, deep, and durable at a low dose of CAR-T cells with 26/29 (90%) pts progression free at median 9-mo follow-up. CRS was manageable in most pts, supporting outpatient dosing. Clinical trial information: NCT03548207 .

Long-Term Follow-Up of CD19-CAR T-Cell Therapy in Children and Young Adults With B-ALL

2021 ◽  
pp. JCO.20.02262
Author(s):  
Nirali N. Shah ◽  
Daniel W. Lee ◽  
Bonnie Yates ◽  
Constance M. Yuan ◽  
Haneen Shalabi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

PURPOSE CD19 chimeric antigen receptor (CD19-CAR) T cells induce high response rates in children and young adults (CAYAs) with B-cell acute lymphoblastic leukemia (B-ALL), but relapse rates are high. The role for allogeneic hematopoietic stem-cell transplant (alloHSCT) following CD19-CAR T-cell therapy to improve long-term outcomes in CAYAs has not been examined. METHODS We conducted a phase I trial of autologous CD19.28ζ-CAR T cells in CAYAs with relapsed or refractory B-ALL. Response and long-term clinical outcomes were assessed in relation to disease and treatment variables. RESULTS Fifty CAYAs with B-ALL were treated (median age, 13.5 years; range, 4.3-30.4). Thirty-one (62.0%) patients achieved a complete remission (CR), 28 (90.3%) of whom were minimal residual disease−negative by flow cytometry. Utilization of fludarabine/cyclophosphamide–based lymphodepletion was associated with improved CR rates (29/42, 69%) compared with non–fludarabine/cyclophosphamide–based lymphodepletion (2/8, 25%; P = .041). With median follow-up of 4.8 years, median overall survival was 10.5 months (95% CI, 6.3 to 29.2 months). Twenty-one of 28 (75.0%) patients achieving a minimal residual disease−negative CR proceeded to alloHSCT. For those proceeding to alloHSCT, median overall survival was 70.2 months (95% CI, 10.4 months to not estimable). The cumulative incidence of relapse after alloHSCT was 9.5% (95% CI, 1.5 to 26.8) at 24 months; 5-year EFS following alloHSCT was 61.9% (95% CI, 38.1 to 78.8). CONCLUSION We provide the longest follow-up in CAYAs with B-ALL after CD19-CAR T-cell therapy reported to date and demonstrate that sequential therapy with CD19.28ζ-CAR T cells followed by alloHSCT can mediate durable disease control in a sizable fraction of CAYAs with relapsed or refractory B-ALL (ClinicalTrials.gov identifier: NCT01593696 ).

scholarly journals Cyclophosphamide and Fludarabine Conditioning Chemotherapy Induces a Key Homeostatic Cytokine Profile in Patients Prior to CAR T Cell Therapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4426-4426 ◽  
Author(s):  
Adrian Bot ◽  
John M. Rossi ◽  
Yizhou Jiang ◽  
Lynn Navale ◽  
Yueh-wei Shen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Fold Increase ◽  
Employment Equity ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Equity Ownership

Abstract This study is supported in part by funding from the Cooperative Research and Development Agreement (CRADA) between the National Cancer Institute and Kite Pharma Introduction: CAR-engineered autologous T-cell therapy has shown promising activity in relapsed/refractory B-cell malignancies in an ongoing phase 1 study (Kochenderfer et al. J Clin Oncol 2014). Lymphodepleting conditioning chemotherapy is critical for optimal CAR T-cell activity in animal models. We evaluated the effects of conditioning chemotherapy on cytokine and chemokine levels in patients dosed with anti-CD19 CAR T cells. Methods: In this National Cancer Institute clinical trial (NCT00924326), patients with relapsed/refractory B-cell malignancies received conditioning with cyclophosphamide and fludarabine daily for 3 days starting on day -5; followed by anti-CD19 CAR T cells engineered with a CAR comprising CD28 and CD3-zeta signaling domains. Forty one cytokines, chemokines and immune response related markers were measured in the blood of patients pre (day -5) and post conditioning (day 0) by using EMD Millipore Luminex® xMAP® multiplex assays. Data acquisition and analysis were performed using a Luminex 200™ instrument and xPONENT® 3.1 data analysis software. Increases in cytokine and chemokine levels were analyzed pre- and post- conditioning, and the fold-changes in cytokine and chemokine levels were analyzed relative to clinical outcome subsequent to infusion with anti-CD19 CAR T cells. Analyses were performed with the Wilcoxon rank sum test adjusted for multiplicity with a Bonferroni correction, using a nominal level of 0.006 for significance. Results: Samples from 15patients have been evaluated. There were significant increases pre- to post-conditioning in the levels of interleukin 15 (IL-15; p=0.001), interleukin 7 (IL-7; p=0.0002), and monocyte chemoattractant protein-1 (MCP-1; p<0.0025) in blood, five days after the initiation of conditioning chemotherapy. Levels of interferon-gamma induced protein 10 (IP-10) were elevated post-conditioning, but did not meet the threshold for significance (p=0.048). Compared with baseline, levels of IL-15 increased on average 13 fold and levels of IL-7, IP-10 and MCP-1, about 2 fold. Comparison of the fold-increases in IL-15 upon conditioning between responders and non-responders approached significance (p=0.01), but did not meet the threshold after multiplicity adjustment. Larger fold-change increases for responders versus non-responders were also observed with placental growth factor (PLGF) (median fold increase 2.6 v. 1.6, average fold increase 32 v 4.2), C-reactive protein (CRP) (median fold increase 3.5 v 2.4, average fold increase 6.6 v. 2.0), IP-10 (median fold increase 2.1 v. 0.7, average fold increase 2.6 v. 2.8), and interleukin 10 (IL-10) (median fold increase 1.8 v. 0.4, average fold increase 3.1 v. 2.0), but did not meet the threshold for significance. In addition to ongoing analysis of conditioning-mediated cytokine induction and clinical response, we are evaluating the impact of conditioning chemotherapy dose on cytokine levels, as well as the relationship between conditioning-related cytokines and CAR T-cell expansion and persistence. Conclusions: The data obtained to date support the hypothesis that cytokines such as IL-15 play a key role in the clinical outcomes to anti-CD19 CAR T-cell therapy. Our results demonstrate that conditioning chemotherapy significantly increases the levels of homeostatic cytokines known to regulate T-cell expansion, as well as specific pro-inflammatory cytokines and chemokines. Optimization of conditioning chemotherapy is critical to the activity of CAR T-cell therapies. Disclosures Bot: Kite Pharma: Employment, Equity Ownership. Rossi:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership. Jiang:Kite Pharma: Employment, Equity Ownership. Navale:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership. Shen:Kite Pharma: Employment, Equity Ownership. Sherman:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership. Mardiros:Kite Pharma: Employment, Equity Ownership. Yoder:Kite Pharma: Employment, Equity Ownership. Go:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership. Rosenberg:Kite Pharma: Other: CRADA between Surgery Branch-NCI and Kite Pharma. Wiezorek:Kite Pharma: Employment, Equity Ownership, Other: Officer of Kite Pharma. Chang:Kite Pharma: Employment, Equity Ownership, Other: Officer of Kite Pharma. Roberts:Kite Pharma: Employment, Equity Ownership, Other: Officer of Kite Pharma.

CD19-Targeted 19-28z CAR Modified Autologous T Cells Induce High Rates of Complete Remission and Durable Responses in Adult Patients with Relapsed, Refractory B-Cell ALL

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 382-382 ◽  
Author(s):  
Jae H Park ◽  
Isabelle Riviere ◽  
Xiuyan Wang ◽  
Yvette J Bernal ◽  
Sarah Yoo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Adult Patients ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Background: Relapsed adult acute lymphoblastic leukemia (ALL) is associated with high reinduction mortality, chemotherapy resistance, and dismal prognosis with a median overall survival (OS) < 6 months and 5-year OS ≤10%. We have previously reported a high anti-tumor activity of autologous T cells genetically modified to express 19-28z chimeric antigen receptor (19-28z CAR) targeting CD19 in adult patients with CLL and ALL (Brentjens R et al. Blood 2011; Davila M et al. Sci Transl Med2014). Herein, for the first time, we further report the long-term outcome of our phase I clinical trial in adults with relapsed/refractory (R/R) ALL (NCT01044069) with analysis on potential predictive markers of response and neurological toxicities. Patients and Methods: Adult patients with R/R B-ALL were enrolled. Eligible patients underwent leukapheresis, and T cells were transduced with a retrovirus encoding a CAR construct composed of anti-CD19 scFV linked to CD28 and CD3ζ signaling domains (19-28z). All patients received lymphodepleting chemotherapy followed 2 days later by 1x106 – 3x10619-28z CAR T cells/kg. The primary objective of the study was to evaluate the safety and anti-tumor activity of 19-28z CAR T cells in ALL. Post-treatment minimal residual disease (MRD) was assessed at day 14-28 by multiparameter flow cytometry and deep sequencing in the bone marrow (BM) samples (Adaptive Biotech Corp.) Results: 24 patients have been treated. The median age was 56 years (range, 23-74). 6 patients (25%) had Ph+ B-ALL (T315I mutation in 2 patients), 6 patients (25%) had prior allogeneic hematopoietic stem cell transplant (allo-HSCT), and 11 patients (46%) had 3 or more prior lines of ALL therapy before receiving the 19-28z CAR T cell therapy. Of the 24 patients, 22 patients were evaluable for response. At the time of 19-28z CAR T cell infusion, 12 of 22 patients had morphologic disease (6 to 97% blasts in the BM) and the remaining 10 patients had MRD. Twenty out of 22 patients (91%) were in complete remission (CR) after 19-28z CAR T-cell infusion, and 18 of these 20 patients (90%) achieved an MRD-negative CR. Ten of the 13 transplant eligible patients (77%) successfully underwent allo-HSCT following the 19-28z CAR T cell therapy. As of July 1, 2014, the median follow-up was 7.4 months (range 1-34), with 13 patients having at least 6 months of follow-up. Responses appear durable with 6 patients remaining disease-free beyond 1 year (range 12.6 – 34 months). Median overall survial (OS) is 9 months. 5 patients relapsed during the follow-up, including 1 patient with CD19 negative relapse. Three of the relapsed patients were treated again with the 19-28z CAR T cells, and two patients achieved a second CR. Comparing responders to non-responders, no association was observed between response and age (<60 vs. ≥60), prior allo-HSCT, number of prior therapies, or pre-treatment blast percentage. While none of the 10 patients with MRD at the time of T cell infusion developed cytokine release syndrome (CRS), 9 of 13 patients with morphologic disease at the time of the T cell infusion developed CRS with or without neurological symptoms that required intervention with an IL-6R antagonist or corticosteroid. A detailed analysis of serum cytokines demonstrated a consistent peak of IL-6 (22.2 to 553-fold increase) immediately prior to the development of neurological toxicities. Based on these data, we have developed a multi-disciplinary CRS management algorithm for patients at high risk in order to reduce the severity of CRS and improve safety of the 19-28z CAR T cell therapy. Conclusions: While longer follow-up is needed to confirm the durability of the observed responses, the potent induction of MRD-negative responses and successful long-term outcomes, including subsequent allo-HSCT without apparent additional post-transplant toxicities, strongly support the use of 19-28z CAR T cells in adult patients with B-ALL. A temporal relationship between serum IL-6 levels and neurological toxicities indicates that early intervention with IL-6 directed therapy may be more effective in ameliorating neurological toxicities in patients with morphologic disease at the time of T-cell infusion. These findings will need to be evaluated systematically and confirmed in a larger phase 2 trial. Disclosures Park: Juno Therapeutics: Research Funding. Riviere:Juno Therapeutics: Consultancy, scientific co-founders Other. Sadelain:Juno Therapeutics: Consultancy, Scientific co-founder and Stock holder Other. Brentjens:Juno Therapeutics: Consultancy, Scientific co-founder and Stock holder Other.

scholarly journals Feasibility of Outpatient CAR T Cell Therapy: Experience of a Single Institution

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4828-4828
Author(s):  
Yusra F Shao ◽  
Dipenkumar Modi ◽  
Andrew Kin ◽  
Asif Alavi ◽  
Lois Ayash ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Abstract Background Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a promising therapeutic option for relapsed/refractory non-Hodgkin lymphoma. However, access to CAR T cell therapy remains limited as CAR T cells are routinely administered in the hospital setting. Hence, there's a growing interest in standardizing outpatient administration of CAR T cells to increase patient access and minimize costs. Here, we describe our institution's experience with outpatient administration of CAR T cells. Methods In this retrospective study, we reviewed who received CAR T cell therapy in the outpatient setting at Karmanos Cancer Center between June 2019 and June 2021.Charts were reviewed for age, disease pathology, prior lines of therapy, need for hospitalization within 30 days, development of CRS and/or neurotoxicity, need for ICU admission, need for steroids and/or tocilizumab, length of admission, and disease state at last follow up. All patients received fludarabine and cyclophosphamide as lymphodepletion (LD) therapy day -5 to -3. CAR T cells were infused on day 0. Patients subsequently followed up in clinic daily for 2 weeks and were started on allopurinol, ciprofloxacin, fluconazole, acyclovir and levetiracetam. First response was assessed by FDG PET scan 4 weeks after CAR T cell . Results A total of 12 patients received CAR T cells during the study period. All patients had a diagnosis of DLBCL and received Tisagenlecleucel. Median age at CAR T cell therapy was 69.5 years (40-78 years). Median number of prior lines of therapy was (2-3) while 2 patients had received prior stem cell transplantation. Table 1 describes patient characteristics and lines of therapy. Two patients received bridging therapy prior to LD. Overall response rate was 58.3% (complete response-3, partial response-4). Median duration of follow up was 6.7 (0.6-13.8 months). Four patients required subsequent therapy after CAR T cell for disease progression while 9 patients were alive at the time of data cut off. Figure 1 summarizes disease response and follow . Table 2 summarizes complications during follow up. Nine (75%) patients developed anemia (grade 3-4 n=4, 33.3%), 8 (66.7%) developed thrombocytopenia (grade 3-4 n= 3, 37.5%), and 8 (66.7%) developed neutropenia (grade 3-4 n=8, 66.7%). Median time to platelet recovery to &gt;,000 and neutrophil recovery to &gt;500 was 66 days (44-81 days) and 11.5 days (6-65 days), respectively. Three (25%) patients required platelet and red blood cell transfusion support. Six (50%) patients developed cytokine release syndrome (CRS) with median grade 2 (range 1-3, grade 3-4 n=1). Five (5/6) patients required hospitalization, five (5/6) required tocilizumab, and one (1/6) required steroids. One (8.3%) patient developed neurotoxicity of grade 1 severity improved without systemic therapy. Six patients required hospitalization within 30 days of CAR T cell infusion. Median day of admission from CAR T cell infusion was 4 days (range 2-12 days (range 2-12 days, admission within 3 days n=2, admission under observation n=1). Patient characteristics at admission are summarized in table 3. Of these, 5 patients were diagnosed with CRS,1 patient with colitis and none with blood stream infection. Two patients required ICU admission. Median length of hospital admission was 5.5 days (2-9 days). All patients were alive at discharge while 1 patient required subsequent admission within 30 . Conclusion Outpatient administration of Tisagenlecleucel is feasible with low risk of hospital admission within 3 days of infusion. Adoption of outpatient CAR T cell therapy may increase patient access for treatment of DLBCL and diseases such as multiple myeloma while reducing administration costs for this novel therapy. Figure 1 Figure 1. Disclosures Modi: Genentech: Research Funding; Seagen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees. Deol: Kite, a Gilead Company: Consultancy.

scholarly journals Biomarkers of Cytokine Release Syndrome and Neurotoxicity after CD19 CAR-T Cells and Mitigation of Toxicity By Cell Dose

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1852-1852 ◽  
Author(s):  
Cameron J Turtle ◽  
Kevin A Hay ◽  
Gust Juliane ◽  
Laila-Aicha Hanafi ◽  
Daniel Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Cell Dose ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Equity Ownership

Abstract BACKGROUND: Lymphodepletion chemotherapy with infusion of CD19-specific chimeric antigen receptor (CAR)-modified T cells has produced impressive antitumor responses in CD19+ malignancies in phase 1 clinical trials, but can be associated with cytokine release syndrome (CRS) and neurotoxicity (NT). Our understanding of CRS and NT continues to evolve, and identification of predictive biomarkers and strategies to mitigate these toxicities will facilitate management of patients (pts) undergoing CD19 CAR-T cell therapy in multicenter phase 2 trials. METHODS: We treated 127 adults with ALL, NHL or CLL with anti-CD19 CAR-T cells manufactured from defined CD4+ and CD8+ T cell subsets, formulated in a 1:1 ratio of CD8+:CD4+ CAR+ T cells, and infused at 1 of 3 dose levels (2x105, 2x106 or 2x107 CAR-T cells/kg) following lymphodepletion chemotherapy. The incidence and grade (gr) of CRS and NT, and correlative biomarkers were analyzed through 28 days after infusion. RESULTS: One hundred and nine pts (45 ALL, 47 NHL, 17 CLL) have completed toxicity and response assessment. CRS was graded according to Lee et al (Blood, 2014) and developed in 71% of pts (44% gr 1-2, 22% gr 3-4, 5% gr 5). Pressors were only required in 21% of the pts who developed gr 3-4 CRS. Gr ³3 NT (CTCAE v 4.03) developed in 25% of pts, all of whom developed fever before NT. The median duration of all-cause hospitalization from the start of lymphodepletion was 7, 6, and 10 days for ALL, NHL and CLL pts, respectively. Because we observed short CAR-T cell persistence and an anti-CAR transgene immune response in an initial cohort of pts who received cyclophosphamide (Cy) lymphodepletion, fludarabine (Flu) was added to Cy. This regimen abrogated immune CAR-T cell rejection and dramatically increased early CAR-T cell expansion. We found that infusion of 2x107 CAR-T cells/kg after Cy/Flu was excessively toxic (5/9 developed gr 4-5 CRS), and identified 2x106 CAR-T cells/kg as the maximum tolerated dose in NHL and CLL. Of 26 NHL pts (22 with aggressive histology) treated with Cy/Flu and 2x106 CAR-T cells/kg, the ORR was 73% and the CR rate 46%. No pts had gr 5 CRS or required pressors, and only 12% of pts experienced either gr 3-4 CRS and/or gr ³3 NT. Of 13 CLL pts treated with Cy/Flu and ²2x106 CAR-T cells/kg, the ORR (CT+/-PET) was 85%. In 85%, of pts no marrow disease was detected by flow cytometry. Overall, 38% of pts achieved CR, including 1 pt with residual CLL after the first infusion who achieved CR after a second CAR-T cell infusion. No pts had gr 4-5 CRS or required pressors, and 23% had either gr 3 CRS and/or gr 3 NT. In ALL pts, the incidence of CRS and NT correlated with the percentage of marrow blasts and CAR-T cell dose, and further dose modification was required for pts with ³ 5% marrow blasts, in whom 2x106 CAR-T cells/kg was excessively toxic (56% gr 4-5 CRS; 56% gr 4-5 NT; n=9). CRS and NT was mitigated in pts with ³ 5% blasts by administering 2x105 CAR-T cells/kg resulting in 6% gr 4 CRS, 17% gr 3; and 17% gr 3-4 NT; n=18). Efficacy was not compromised with the T cell dose reduction for the high tumor burden cohort with 89% of pts achieving a bone marrow CR by high-resolution flow cytometry. Detailed characterization of early biomarkers of CRS and NT may provide an opportunity to develop data-driven toxicity grading to facilitate mitigation strategies that could be applied across different centers. Compared to pts with gr 0-2 CRS, those with gr 3-5 CRS had significantly higher peak levels of IL-15, IL-6, IL-2, IFN-g, C-reactive protein, and ferritin in both ALL and NHL cohorts. Importantly, in univariate analysis, the levels of IL-15, IL-6, IL-8, IL-10, soluble TNF receptor type 1, and IFN-g were significantly higher on day 1 after CAR-T cells in pts that developed gr 3-5 CRS, and might be used to identify pts to test early intervention strategies to reduce later severe toxicity. We made similar observations in pts with and without NT. Multivariate analysis of biomarkers including clinical and laboratory parameters (Figure 1) is ongoing. CONCLUSION: CD19 CAR-T cell immunotherapy can be associated with severe CRS and NT. The use of CAR-T cell products with a prescribed 1:1 CD4/CD8 composition identified CAR-T cell doses associated with a reduced incidence and severity of these complications without impairing efficacy. Additional study of correlative biomarkers to inform rational strategies for early intervention will facilitate the safe and effective clinical application of CAR-T cell therapy. Disclosures Turtle: Seattle Genetics: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Research Funding. Li:Juno Therapeutics: Employment, Equity Ownership. Riddell:Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding; Cell Medica: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria. Maloney:Juno Therapeutics: Research Funding; Genentech/Roche: Consultancy, Honoraria.

scholarly journals Updated Phase 1 Results of C-CAR088, an Anti-BCMA CAR T-Cell Therapy in Relapsed or Refractory Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1830-1830
Author(s):  
Xiaoyan Qu ◽  
Gang An ◽  
Weiwei Sui ◽  
Tingyu Wang ◽  
Xian Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Overall Response Rate ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Background: C-CAR088, an anti-BCMA CAR T-cell therapy, is a novel 2nd generation 4-1BB chimeric antigen receptor T (CAR-T) cell therapy targeting BCMA. Previously presented results from an ongoing study of C-CAR088 in R/R MM (NCT03751293, NCT03815383, NCT04322292, NCT04295018) included a 95.7% overall response rate (ORR) for the dose of 1.0~6.0x10 6 CAR-T cells/kg with a favorable safety profile (Lu, 2020 ASH Oral Presentation #182). Here we present the updated results of the study, with more patients and longer follow up time. Methods: Dose escalation and expansion studies were conducted at four medical centers in China to evaluate the safety and efficacy of C-CAR088 in patients with R/R MM who were previously treated with at least 2 lines of therapy, including proteasome inhibitors (PIs) and IMiDs. C-CAR088 was administered to patients as a single infusion after lymphodepletion with fludarabine (30 mg/m 2) and cyclophosphamide (300 mg/m 2) daily for 3 days. The primary endpoint was the incidence of adverse events (AEs), including dose-limiting toxicities (DLTs), and the secondary endpoints included overall response rate(ORR), duration of response (DOR), and progression-free survival (PFS) by IMWG Uniform Response Criteria. Results: As of July 2nd, 2021, 31 patients had been infused with C-CAR088. The median vein-to-vein time was 18 days. The manufacturing success rate was 100%. 4, 13 and 14 patients were infused with 1.0, 3.0 and 4.5~6.0 x10 6 CAR+ T cells/kg respectively. The median follow-up time for all patients was 8.0 months (0.1-24.2). The median age of patients was 61 years (45-74). The median number of prior lines of therapy was 4 (2-13). There were 25 (80.6%) patients with at least one high risk cytogenetic abnormality and 17 (54.8%) patients with at least two high risk cytogenetic abnormalities. 7 patients (22.6%) received bridging therapy before C-CAR088 therapy. Cytokine release syndrome (CRS) developed in 29/31 (93.5%) patients, grade 1 in 18/31 (58.1%), grade 2 in 8/31 (25.8%) and grade 3 in 3/31 (9.7%) respectively. The median time to the first onset of CRS was 6 days (1-11) and the median duration of CRS was 5 days (2-14). 9/31 (29%) patients used tocilizumab and 6/31 (19.4%) patients used corticosteroids to manage CRS. Only one patient developed a grade 1 neurotoxicity. No DLTs were observed and all adverse events were reversible. One patient died of septic shock on day 2 after receiving C-CAR088. Clinical efficacy was assessed in 28 patients with ≥ 1 month of follow up. Among the 28 patients, 3, 11 and 14 patients were infused with the dose of 1.0 x 10 6 CAR+ T cells/kg 3 x10 6 CAR+ T cells/kg, and 4.5~6x10 6 CAR+ T cells/kg respectively. The ORR was 27/28 (96.4%): 4 (14.3%) achieved CR, 12 (42.9%) achieved sCR and 9 (32.1%) achieved very good partial response (VGPR). At the dose level of 1.0 x10 6 CAR+ T cells/kg, 3(100%) patients achieved VGPR. The median DOR was 3.7 months (1.8-5.8), and the median PFS was 4.6 months (2.7-6.2). The CR rate was 54.5% (6/11) and 71.4% (10/14) in the 3.0 and 4.5~6.0 x10 6 CAR+ T cells/kg cohorts respectively. The median time to CR was 2.0 (0.5-9.5) months. Minimal residual disease (MRD) was testedbyEuroFlow-based flow cytometric analysis in 16 patients who had CR, 15/16 (93.7%) patients were MRD negative with the sensitivity of 10 -5. With a median follow-up of 9.5 months (1.9-24.2) in ≥ 3.0x10 6 CAR+ T cells/kg cohorts, the median DOR and PFS had not been reached. The Kaplan-Meier estimation of PFS at 6 and 12 months was 81.1% (95% CI:65.9% ~99.8%) and 69.5 % (95% CI:51.6 % ~93.6%) respectively. 8 patients in the ≥ 3.0x10 6 CAR+ T cells/kg cohorts discontinued the study. 7 discontinued due to disease progression (PD), and 1 discontinued for other anticancer therapy. 4 progressed within 6 months, 2 progressed within 6-12 months, and 1 progressed within 12-24 months. C-CAR088 proliferated and expanded well in patients' blood. The median C max was 734,868 copies/μg gDNA. The median AUC 0~28day was 7,468,779 day·copies/μg gDNA. The median T max was 14 days. The median T last was 84 days. 71% (95% CI: 42%~92%) of patients with C max equal to or greater than the median C max achieved CR/sCR. Conclusion: C-CAR088 has a manageable safety profile, which includes low neurotoxicity rates (with no gr ≥3 events). Deep and durable responses were observed in ≥ 3.0x10 6 CAR-T cells/kg cohorts. Doses of 3.0 and 6.0×10 6 CAR T cells/kg were selected for further study. Figure 1 Figure 1. Disclosures Zhu: CBMG: Current Employment. Huang: CBMG: Current Employment. Li: CBMG: Current Employment. Lan: CBMG: Current Employment. Chen: CBMG: Current Employment. Humphries: CBMG Ltd: Current Employment. Yao: CBMG: Current Employment, Current holder of stock options in a privately-held company.

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