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B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapies have shown efficacy in relapsed/refractory multiple myeloma (RRMM). Because the non-human originated antigen-targeting domain may limit clinical efficacy, we developed a fully human BCMA-specific CAR, CT103A, and report its safety and efficacy in a phase 1 trial. Eighteen consecutive patients with RRMM, including 4 with prior murine BCMA CAR exposures, were enrolled. CT103A was administered at 1, 3, and 6 × 106 CAR-positive T cells/kg in the dose-escalation phase, and 1 × 106 CAR-positive T cells/kg in the expansion cohort. The overall response rate was 100%, with 72.2% of the patients achieving complete response or stringent complete response. For the 4 murine BCMA CAR-exposed patients, 3 achieved stringent complete response, and 1 achieved a very good partial response. At 1 year, the progression-free survival rate was 58.3% for all cohorts and 79.1% for the patients without extramedullary myeloma. Hematologic toxicities were the most common adverse events; 70.6% of the patients experienced grade 1 or 2 cytokine release syndromes. No immune effector cell-associated neurotoxicity syndrome was observed. To the cutoff date, CAR transgenes were detectable in 77.8% of the patients. The median CAR transgene persistence was 307.5 days. Only 1 patient was positive for the anti-drug antibody. Altogether, CT103A is safe and highly active in patients with RRMM and can be developed as a promising therapy for RRMM. Patients who relapsed from prior murine BCMA CAR T-cell therapy may still benefit from CT103A. This trial was registered at http://www.chictr.org.cn as #ChiCTR1800018137.

B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapies have shown efficacy in relapsed/refractory multiple myeloma (RRMM). Because the non-human originated antigen-targeting domain may limit clinical efficacy, we developed a fully human BCMA-specific CAR, CT103A, and report its safety and efficacy in a phase 1 trial. Eighteen consecutive patients with RRMM, including 4 with prior murine BCMA CAR exposures, were enrolled. CT103A was administered at 1, 3, and 6 × 106 CAR-positive T cells/kg in the dose-escalation phase, and 1 × 106 CAR-positive T cells/kg in the expansion cohort. The overall response rate was 100%, with 72.2% of the patients achieving complete response or stringent complete response. For the 4 murine BCMA CAR-exposed patients, 3 achieved stringent complete response, and 1 achieved a very good partial response. At 1 year, the progression-free survival rate was 58.3% for all cohorts and 79.1% for the patients without extramedullary myeloma. Hematologic toxicities were the most common adverse events; 70.6% of the patients experienced grade 1 or 2 cytokine release syndromes. No immune effector cell-associated neurotoxicity syndrome was observed. To the cutoff date, CAR transgenes were detectable in 77.8% of the patients. The median CAR transgene persistence was 307.5 days. Only 1 patient was positive for the anti-drug antibody. Altogether, CT103A is safe and highly active in patients with RRMM and can be developed as a promising therapy for RRMM. Patients who relapsed from prior murine BCMA CAR T-cell therapy may still benefit from CT103A. This trial was registered at http://www.chictr.org.cn as #ChiCTR1800018137.

Background: Management of CML with TKIs is constrained by treatment resistance, which portends a poor prognosis particularly in pts failing 2 nd-generation TKIs. Cells with BCR-ABL1 T315I mutations are insensitive to 1 st- and 2 nd -generation TKIs, and compound BCR-ABL1 mutations complicate management with all TKIs (including 3 rd-generation ponatinib). Olverembatinib is a novel, potent, 3 rd-generation, orally active BCR-ABL1 TKI with promising activity against CML , largely irrespective of genotype and has a preliminary favorable safety profile. Methods: HQP1351-CC201 and HQP1351-CC202 are Chinese open, single-arm, multicenter phase 2 trials evaluating the safety and efficacy of olverembatinib in adults with TKI-resistant (BCR-ABL1 T351-mutated) CML-CP and CML-CP, respectively. Olverembatinib was administered at 40 mg orally on alternate days for 28-day cycles. The primary outcome measure is major cytogenetic response (MCyR) and major hematologic response (MaHR) by the end of Cycle 12 in CML-CP and CML-AP, respectively. Secondary study endpoints include : complete CyR (CCyR), complete hematologic response (CHR), major molecular response (MMR), progression-free survival (PFS), overall survival (OS), and safety, including treatment-related adverse events (TRAEs) and serious AEs (SAEs). Results: Baseline characteristics Study CC201 （CML-CP ） On the study cutoff date of August 25,2020, 41 pts were enrolled, of whom 32 (78%) completed ≥ 12 cycles and 21 (51.2%) were male. The median (range) follow-up was 13 (3.1-16.3) months, age was 47 (22-70) years, and interval from CML diagnosis to first olverembatinib dose was 5.31 (0.6-23.2) years. In all, 32 (78.1%) pts had received ≥ 2 prior TKIs and 9 pts withdrew because of progressive disease (PD), intolerance, or consent withdrawal before Cycle 12. Study CC202 （CML-AP ） On the cut-off date of July 27, 2020, 23 pts were enrolled, of whom 14 (61%) had completed ≥ 12 cycles and 18 (78.3%) were male. The median (range) follow-up was 13.5 (1.4-15.2) months, age was 41 (21-74) years, and interval from CML diagnosis to first olverembatinib dose was 4.96 (0.4-10.2) years. In all, 18 (78.3%) pts had received ≥ 2 prior TKIs, and 11 pts withdrew because of PD or intolerance before Cycle 12. Efficacy Study CC201 （CML-CP ） After ≥ 12 treatment cycles in pts without responses at baseline, all 31 (100%) experienced CHR (10 other pts had CHR at baseline); 31/41 (75.6%) MCyR; 28/41 (68.3%) CCyR; and 23/41 (56.1%) MMR (Figure 1). The median time to CHR was 1 (95% CI = 1.0-1.9) month, the median time to MCyR was 2.8 (95% CI = 2.8-5.6) months, and the median time to MMR was 6.5 (95% CI = 2.8 to not reached [NR]) months. At 12 months, the PFS rate was 89.3% (95% CI = 73.9%-95.8%), and the OS was 100% (95% CI = 100%-100%). Study CC202 （CML-AP ） After ≥ 12 treatment cycles in pts without responses at baseline, 17/23 (73.9%) experienced MaHR (65.2% CHR and 8.7% no evidence of leukemia [NEL]); 12/23 (52.2%) MCyR; 11/23 (47.8%) CCyR; and 9/23 (39.1%) MMR (Figure 1). The median time to MaHR was 2.8 (95% CI = 1.0-4.7) months, the median time to MCyR was 5.6 (95% CI = 2.00-NR) months, and the median time to MMR was 13.1 (95% CI = 5.6-NR) months. At 12 months, the PFS rate was 74.1% (95% CI = 48.2%-88.4%), and the OS was 91.3% (95% CI = 69.5%-97.8%). Safety Study CC201 （CML-CP ） Frequent TRAEs (all grades; grade 3-4; SAEs) included thrombocytopenia (70.7%; 48.8%; 7.3%), followed by anemia (61%; 26.8%; 2.4%), leukopenia (43.9%; 17.1%; 0), and neutropenia (36.6%; 19.5%; 0). Common nonhematologic TRAEs (all grades; G3-4) included skin pigmentation (56.1%, 0%) and elevations in creatine kinase (51.2%, 14.6%), ALT (39%, 2.4%) and AST (34.1%, 0) (Table 1). No deaths occurred. Study CC202 （CML-AP ） Common TRAEs (all grades; G3-4; SAEs) included thrombocytopenia (73.9%; 56.5%; 17.4%), anemia (60.9%; 34.8%; 13.0%), leukopenia (56.5%; 30.4%; 0), and neutropenia (26.1%; 21.7%; 0). Common nonhematologic AEs included skin pigmentation (69.6%), hypocalcemia (52.2%), proteinuria (47.8%), hypertriglyceridemia (56.5%), hyperphosphatemia (47.8%), hyperuricemia (21.7%), and arthralgia (34.8%), of which most were grade 1-2 (Table 2). Conclusions: Olverembatinib was efficacious and well tolerated when administered as monotherapy in pts with TKI-resistant CP-CML and AP-CML and the BCR-ABL1 T315Imutation. Internal study identifiers: HQP1351-CC201-CC202. ClinicalTrials.gov identifiers: NCT03883087 and NCT03883100. Figure 1 Figure 1. Disclosures Chen: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Niu: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Men: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Yang: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding. Zhai: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding; Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding.

INTRODUCTION HQP1351 (olverembatinib) is an orally active third-generation BCR-ABL TKI designed for treatment of the patients with CML, harboring T315I mutation, which confers resistance against all first- and second-generation TKIs. METHODS The TKI resistant CML patients harboring T315I mutations either in chronic-phase (CP), or in accelerated-phase (AP), were enrolled into two single-arm, multicenter, open-label pivotal studies: HQP1351-CC201 in and HQP1351-CC202, respectively. The HQP1351 was administered at 40 mg once every other day (QOD) for 28 consecutive days per cycle over 24 months. The primary objective was to evaluate efficacy by major cytogenetic response (MCyR) in patients with CML-CP and major hematologic response (MaHR) in CML-AP. Secondary objectives included safety, tolerability, and pharmacokinetics (PK). RESULTS Baseline characteristics Study CC201 (CML-CP) As of the study cut-off date of March 23, 2020, total 41 patients were enrolled, of whom 38 (92.7%) completed ≥ 6 cycles and 21 (51.2%) were male. Median (range) follow-up was 7.9 (3.1-11.1) months, median age was 47 (22-70) years old. Median (range) interval from CML diagnosis to first HQP1351 treatment was 5.31 (0.6-23.2) years, and 32 (78.1%) patients received ≥ 2 prior lines of TKI. Three patients withdrew from the study-due to progressive disease (PD), intolerance, or consent withdrawal. Study CC202 (CML-AP) As of the cut-off date of February 11, 2020, total 23 patients were enrolled, of whom 18 (78.3%) completed ≥ 6 cycles and 18 (78.3%) were male. Follow-up duration was 8.2 (1.4-9.6) months, median age was 41 (21-74) years old. Median interval from CML diagnosis to first dose of HQP1351 was 4.96 (0.4-10.2) years, and 18 (78.3%) patients received ≥ 2 prior TKIs. Five patients withdrew because of PD or intolerance before Cycle 6. Efficacy Study CC201 (CML-CP) Across a median follow-up of 7.9 months, the mean (95% CI) 3-month progression-free survival (PFS) was 100% (100-100%) and 6-month PFS 96.7% (78.6-99.5%) because of 1 PD. In 31 evaluable patients who did not have a complete hematologic response (CHR) at baseline, 30 (96.8%) achieved CHR. In 41 evaluable patients who did not have a complete CyR (CCyR) at baseline, 31 (75.6%) achieved MCyR, including 27 (65.9%) CCyR and 4 (9.8%) partial CyR (PCyR). Total 20 out of 41 (48.8%) evaluable patients achieved major molecular response (MMR; Figure 1). Study CC202 (CML-AP) Across a median follow-up of 8.2 months, the 3-month PFS was 100% (100-100%) and the 6- month PFS 95.5% (71.9-99.3%) because of 2 PDs. A total of 18 (78.3%) of 23 evaluable patients without MaHR at baseline achieved MaHR, including 14 (60.9%) with CHR. In the 23 evaluable patients without MCyR at baseline, 12 (52.2%) patients achieved MCyR, including 9 (39.1%) CCyR and 3 (13.1%) PCyR. A total of 6 out of 23 (26.1%) evaluable patients achieved MMR (Figure 1). HQP1351 was highly and durably efficacious in the CML patients with T315I mutation; the probability and depth of clinical response may increase with prolonged treatment period. Safety/tolerability Study CC201 Frequent treatment-related adverse events (TRAEs; all grades; G3-4) included thrombocytopenia (65.9%; 48.8%), followed by anemia (48.8%; 24.4%), leukopenia (46.3%; 12.2%), and neutropenia (36.6%; 19.5%). Common non-hematologic TRAEs of any grade included skin pigmentation (53.7%) as well as elevations in creatine kinase (48.8%), ALT (31.7%) and AST (26.8% which most were grade 1 - 2. No death occurred. Study CC202 Common TRAEs (all grades; G3-4; serious AE [SAE]) included thrombocytopenia (73.9%; 52.2%; 17.4%), anemia (65.2%; 39.1%; 13.0%), leukopenia (56.5%; 30.4%; 0%), and neutropenia (26.1%; 21.7%; 0%;). Common non-hematologic AEs included skin pigmentation (69.6%), hypocalcemia (52.2%), proteinuria (52.2%), hypertriglyceridemia (47.8%), hyperphosphatemia (43.5%), arthralgia (34.8%), and fatigue (26.1%), of which most were grade 1- 2. CONCLUSIONS HQP1351 has been shown highly efficacious in heavily TKI-pretreated patients with T315I-mutated CML-CP or CML-AP and was well tolerated. Registration: Clinicaltrials.gov identifier NCT03883087 (Study HQP1351-CC201) NCT03883100 (Study HQP1351-CC202). Disclosures Chen: Ascentage Pharma Group: Current Employment. Niu:Ascentage Pharma Group: Current Employment. Zeng:Ascentage Pharma Group: Current Employment. Men:Ascentage Pharma Group: Current Employment. Lu:Ascentage Pharma Group: Current Employment, Current equity holder in publicly-traded company. Wang:Ascentage Pharma Group: Current Employment. JI:Ascentage Pharma Group: Current Employment. Yue:Ascentage Pharma Group: Current Employment. Yang:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests. Zhai:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests.

Introduction HMPL-689 is a potent and highly selective small molecule inhibitor of phosphoinositide 3-kinase-delta (PI3Kδ). Despite available agents targeting the B-cell receptor (BCR) pathway, there remains a need for alternative therapies in the relapsed/refractory (R/R) setting due to agent-specific toxicities and suboptimal efficacy among lymphoma subtypes. This study (NCT03128164) is a phase 1, open-label, dose escalation and expansion study in China to assess the safety, pharmacokinetics (PK), and preliminary efficacy of HMPL-689 as a monotherapy in patients with R/R lymphomas. Here we present the preliminary results of the dose-escalation phase of the study. Methods In this dose escalation phase, patients with R/R lymphoma failed of standard therapy, at least 1 prior therapy, were eligible. The dose-escalation study consisted of cohort A (BID) and cohort B (QD), in which HMPL-689 was orally administered continuously on a 28-day cycle. The modified toxicity probability interval scheme-2 (mTPI-2) design was applied for the dose escalation and maximum tolerated dose (MTD) determination. Blood samples for PK and pharmacodynamics (PD) analyses were collected during Cycle 1 and Day 1 of each subsequent cycle. Results A total of 56 patients were enrolled, with 5 chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), 23 follicular lymphoma (FL), 7 marginal zone lymphoma (MZL), 9 mantle cell lymphoma (MCL), 9 diffuse large B cell lymphoma (DLBCL), and 3 Hodgkin's lymphoma (HL) patients (Table 1). The median age was 56 years (range 26-73). The median number of prior therapies was 3 (range 1-8), of which 39 patients had prior exposure to rituximab. 29 patients received HMPL-689 in cohort A (BID): 2.5 mg (n=3), 5 mg (n=9), 7.5 mg (n=8), and 10 mg (n=9), while 27 patients were in cohort B (QD): 5 mg (n=3), 10 mg (n=3), 20 mg (n=9), 30 mg (n=9), and 40 mg (n=3). Median duration of HMPL-689 therapy was 7.6 months (range 0.4 -Not reached [NR]). The most common Grade ≥3 non-hematologic treatment emergent adverse events (TEAEs) were pneumonia and hypertension. Grade ≥3 hematologic TEAEs were neutropenia (Table 2). No Grade 5 TEAE was reported. In cohort A, 4 dose limited toxicities (DLTs) were observed, including Grade 3 asymptomatic amylase (2 pts, 5 mg), Grade 4 hypercalcemia (1 pt, 10 mg), Grade 3 lipase increased (1 pt, 10 mg). In cohort B, 5 DLTs including Grade 3 skin maculopapular (1 pt, 20 mg), hypertriglyceridemia (1 pt, 30 mg), QT interval prolongation (1 pt, 30 mg) and rash (2 pts, 40 mg) were reported. Plasma PK data for the 5-30 mg QD and 2.5-10 mg BID multiple-dose regimens were determined. HMPL-689 drug exposures increased in a dose proportional fashion up to 30mg QD, as reflected in AUC and Cmax. The geometric mean AUCtau and Cmax at 30 mg QD in patients were approximately 2150 h•ng/mL and 260 ng/mL, respectively at steady state. The median Tmax was around 2 h and the arithmetic mean t1/2 was within the range of 5-10 hours, consistent across all dose levels. 51 out of the 56 patients had post-baseline tumor assessment, with 6 complete response (CR) (2 CLL/SLL, 4 FL), 21 partial responses (PR) (2 CLL/SLL, 5 MZL, 7 FL, 4 MCL, 3 DLBCL) and 18 stable disease (SD) (2 MZL, 9 FL, 4 MCL, 1 DLBCL, 2 HL). This resulted in 52.9% (27/51) objective response rate (ORR) in efficacy evaluable patients. The median time to response (TTR) and duration of response (DOR) were 3.5 months (1.8-8.4) and 6.4 months (0.7-NR), respectively (Table 3). One patient with FL who achieved CR (per post hoc independent radiologic review) was on treatment > 586 days. Final data quality control/verification is ongoing. As a result, 30 mg QD of HMPL-689 has been selected as recommended phase 2 dose (RP2D) based on overall safety and tolerability, PK/PD and preliminary efficacy data. Conclusions: HMPL-689 was well tolerated and the RP2D was determined to be 30 mg QD orally. It exhibited dose-proportional pharmacokinetics, a manageable toxicity profile, and promising single-agent clinical activity in R/R B-cell lymphoma patients. The dose expansion study is ongoing, evaluating the safety and efficacy of HMPL-689 in patients with R/R B-cell lymphoma. Acknowledgement 1. We would like to thank all patients and their families who participated in this trial; 2. We would like to thank all investigators, study coordinators and the entire project team. Disclosures Duan: Hutchison MediPharma Limitied: Current Employment. Yu:Hutchison MediPharma Limitied: Current Employment. Cai:Hutchison MediPharma Limitied: Current Employment. Su:Hutchison MediPharma Limited: Current Employment.

Background: Previous studies indicate that patients with relapsed/refractory multiple myeloma (RRMM) who receive BCMA-targeting CAR-T cells may achieve better remission but have a higher relapse rate. Persistence of CAR T cells post-infusion may be one determinant of the duration of response. Moreover, once the disease progresses again, the re-infusion of CAR-T cells is not effective. To solve this dilemma, we have developed a novel BCMA-targeting CAR-T (CT103A) with a lentiviral vector containing a CAR structure with a fully human scFv, CD8a hinger, and transmembrane, 4-1BB co-stimulatory and CD3z activation domains. Methods: ChiCTR1800018137 is a single-center and single-arm trial of CT103A in patients with RRMM (≥ 3 prior lines, including a proteasome inhibitor and an IMiD, or double refractory). The primary objectives are the incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). The secondary objectives are the duration of clinical response, evaluation of minimal residual disease (MRD), progression-free and overall survival, and CAR-T cell persistence in blood. Between September 21, 2018, and August 1st, 2019, sixteen patients (including 4 patients having relapsed after being given a murine BCMA CAR-T and 5 patients having extramedullary disease and/or plasma cell leukemia) received CT103A in 3+3 dose-escalation trial (four doses at 1, 3, 6, 8 ×106/kg) after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. Median follow-up after CT103A infusion was 195 days (23 to 314 days) and all 16 patients were evaluable for initial (14 days) clinical response. Results: As of August 1st, 2019, the objective response rate was 100%, 6/16 patients achieved CR/sCR within two weeks post-infusion and all 8 patients surpassing 6 months achieved VGPR/CR/sCR. CR/sCR was 75%, and VGPR was 25% for these 8 patients, according to the IMWG Uniform Response Criteria for MM. In 4 patients who have participated in a prior CAR-T trial, three have achieved sCR, and 1 achieved VGPR. All 15 patients who could be evaluated for minimal residual disease (MRD) had MRD-negative status (≤10-4 nucleated cells by flow). The circulating CT103A cells were detected in the blood by flow and digital polymerase chain reaction, peaking at 14 days (ranging from 9 to 25), and remaining detectable in 12/16 patients, at the time of their last evaluation. Patient #1 (the first patient treated) has now exceeded 314 days of CART persistence, post-infusion. All sixteen patients developed cytokine release syndrome (according to ASBMT Consensus Grading for Cytokine Release Syndrome and Neurological Toxicity Associated with Immune Effector Cells: 10 Grade 1-2, 5 Grade 3,1 Grade 4). A grade 4 CRS appeared at the 6×106 /kg dose level and was considered as a dose-limiting toxicity DLT. No neurotoxicity was observed in all dose groups. One patient died of a lung infection 19 days post-infusion. Conclusions: Data from this early-stage clinical study showed the unparalleled safety and efficacy of CT103A in heavily pretreated R/R multiple myeloma patients. Highly active (ORR 100%) and rapid response within two weeks, suggests CT103A could be developed as a competitive therapy to treat patients with RRMM. Disclosures Hu: Nanjing Iaso Biotherapeutics Co. Ltd..: Employment. Yang:Nanjing Iaso Biotherapeutics Co.: Employment. Zhou:Nanjing Iaso Biotherapeutics Co. Ltd.: Other: Chairman of Advisory Committee of Science and Medicine .

CD19 CAR T-cell (CAR-19) therapy have elicited great clinical responses in B-cell malignancies. However, CD19-negative relapse has emerged as a major challenge for the long-term disease control post CAR-19 therapy and conferred a dismal outcome to these pts. Recently, co-targeting of CD19/CD20, CD19/CD22 or CD19/CD123 has been proposed as a strategic approach to overcome antigen loss relapse after CAR-19 therapy. However, the infusion scheme has not yet been defined, the efficacy to avoid antigen escape has not been tested, and its toxicity remains to be assessed. Furthermore, the impact of genetic abnormalities on the outcome post CAR T-cell therapy has not been fully elucidated. We conducted an open-label, single-center and single-arm pilot study of sequential infusion of third generation CAR T-cell "cocktail" comprising both anti-CD22 and anti-CD19 CAR T-cells, which was registered with Chinese Clinical Trial Registry (ChiCTR, number ChiCTR-OPN-16008526). Between March 2016 and January 2018, a total of 89 eligibility pts completed CAR-22/19 "cocktail" infusion and were included for analysis. Of 89 pts (median age 36 years; range, 9-71), 51 had refractory/relapsed (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and 38 had R/R B-cell non-Hodgkin lymphoma (B-NHL). The cutoff date for data collection was April 30, 2018, with a median follow-up of 7.6 months (mos) for B-ALL and 5.4 mos for B-NHL. CAR-22 and CAR-19 cells were given separately in 2 divided doses (range, 1 to 4 for CAR-22, and 1 to 5 for CAR-19) with a dose-escalation infusion. Eighty-one pts firstly received CAR-22 infusion, and then CAR-19 infusion, while 8 pts received CAR-19 first and CAR-22 later. B-ALL pts received 2.73±1.19×106/kg CAR-22 and 2.61±1.45×106/kg CAR-19; B-NHL pts received instead higher doses, i.e. 5.28±2.44 ×106/kg CAR-22 and 5.14±2.06 ×106/kg CAR-19. Of the 50 evaluable B-ALL pts, 48 (96.0%) achieved complete remission (CR)/or CR with incomplete count recovery (CRi) at the day 30 assessment. By sensitive multi-parameter flow cytometry (MFC) assay, 47 (94.0%) achieved MRD-negative CR/CRi. At a median follow-up of 7.6 mos (range, 1.3 to 22.2), the progression-free survival (PFS) of all B-ALL pts was 12.0 mos and the overall survival (OS) was not reached. Of the 13 pts with Ph+ B-ALL, 6 of whom had T315I mutation, 11 (84.6%) achieved MRD-negative CR/CRi. The PFS was 15.4 months, and the OS was not reached at a median follow-up of 13.5 months (range, 3 to 22.5). Of the 6 pts with MLL translocations (mainly MLL-AF6), 66.7% were progression-free and the median PFS was not reached. However, among pts with Ph-like ALL, the PFS was only 4.6 months. A total of 23 pts relapsed, however, antigen loss of CD19 and CD22 was not detected by MFC. Forty-Seven pts (92.2%) experienced cytokine release syndrome (CRS) and 11 (21.6%) had severe CRS (≥ grade 3). Except for 1 pt, all the severe cases were reversible. Seven pts (13.7%) developed neurotoxicity. At a minimum follow-up of 3 months, the overall response rate (ORR) and CR rate in 36 evaluable B-NHL pts was 72.2% and 50%, respectively. At the cutoff date for data collection, 50.5% of all pts remained progression-free. A total of 8 pts (26.7%) had relapsed with a median PFS of 2.6 months. Re-biopsy and immunophenotyping was performed in 3 relapsed pts and antigen loss of CD19 or CD22 was not detected. At a median follow-up of 5.4 months (range, 3.0 to 16.2), both PFS and OS of all pts were not reached. Of the 9 pts with MYC translocation, 8 had a response and 7 maintained their responses with a median follow-up of 10.1 months, including all the 4 pts with "double-hit" lymphoma (concurrently carrying MYC and BCL2 or BCL6 translocations). Of the 10 pts with del(17p) or TP53 mutation, 8 (80.0%) had a clinical response. With a median follow-up of 5.3 months, the PFS was 3.3 months, and 45.0% of these pts were progression-free. All the B-NHL pts experienced CRS, but only 21.1% had severe (grade 3 or 4), but reversible CRS and 13.2% developed reversible neurotoxicity. In summary, our results indicated that infusion of third generation CD22/19 CAR T-cell "cocktail" is feasible and safe for pts with B-cell malignancies. Co-targeting to CD19/CD22 is a promising approach for overcoming antigen escape relapse of CAR-19 therapy, but this remain to be fully tested. The treatment response predictive value of distinct genetic subtypes for CAR T-cell therapy should be considered for selection of pts for personalized immunotherapy. Disclosures No relevant conflicts of interest to declare.

Inhibitors of histone deacetylases (HDACIs) are a new generation of anticancer agents that selectively kill tumor cells. However, the molecular basis for their tumor selectivity is not well understood. we employed a genetic technique, named suppression of mortality by antisense rescue technique(SMART), to understand the molecular mechanism of apoptosis induced by HDACI and identify the genes that participate in this process. We identified several novel genes and demonstrated that HDACIs promote apoptosis through activation ubiquitin/proteasome by inducing ubiquitin B not ubiquitin C gene expression. According to degrading the mitochondria membrane protein Mcl-1 by activated ubiquitin/proteasome system, the mitochondria potential collapse and cell apoptosis. Further observation demonstrated that depletion of MCL-1 by RNA interference (RNAi) sensitizes Hela cells to TSA mediated mitochondria membrane potential collapse and apoptosis, and overexpression of MCL-1 confers apoptosis resistance.