ALBERT

Description: This paper investigates impulsive synchronization of multilinks delayed coupled complex networks with perturb effects. Based on the comparison theory of impulsive differential system, a novel synchronization criterion is derived and an impulsive controller is designed simultaneously. Finally, numerical simulations demonstrate the effectiveness of the proposed synchronization criteria.

Description: Background: Chimeric antigen receptor-modified T cells (CARTs) targeting CD19 has illustrated therapeutic efficacy in diffuse large B cell lymphoma (DLBCL). However, severe cytokine release syndrome (sCRS) reaction and CAR-T-cell-related encephalopathy syndrome (CRES) are the main adverse reactions of CART therapy. Because of the concern of severe CRES which is associated with potential mortality, patients with primary central nervous system Lymphoma(PCNSL) are excluded in most of CART clinical trials. CD70 is a promising therapeutic target due to the restricted expression pattern in normal tissues and overexpression in some lymphoma tissues, so CD70 specific CARTs maybe avoid CD19-negative relapse .Here we report a case with refractory and relapsed PCNSL who achieved long-term disease-free survival by combination therapy of CD19 and CD70 specific CARTs without inducing CRS or CRES. Methods: CD3+ cells were selected from the apheresis PBMC and activated before lentiviral 4SCAR infection. The cells were transduced with a caspase 9-inducible, safety-engineered lentivector CAR containing anti-CD19 or -CD70 scFv fused with multiple intracellular signaling domains: CD28/CD27/CD3z-iCasp9 (4SCAR19 or 4SCAR70). The quality of apheresis cells, gene transfer and T cell proliferation efficiencies, and effective CAR T infusion dose were quantitatively scored and documented. Tumor sections were immunohistochemically stained with different antibodies including anti-CD19 and anti-CD70 antibodies to confirm antigen expression. The patient received cyclophosphamide and fludarabine conditioning regimen before the dual CARTs cell infusions. Case presentation: A 67-year-old male who was diagnosed as PCNSL of DLBCL in 2011.The patient received 6 cycles of temozolomide and high does methotrexate, and achieved CR. In December 2016 he relapsed and was treated with right frontal lobe space-occupying resection and multi-course chemotherapy including 2 course of rituximab, high dose methotrexate and temozolomide ,and 6 courses of rituximab, high dose methotrexate and ibrutinib,and he achieved remission again.However, He relapsed again in August 2017, with the clinical symptoms of dizziness , fatigue, left corners of the mouth askew and occlusal difficulties.MRI presented a residual mass on the right side of the postoperative cavity of 26mm*35mm*30mm and stale hemorrhage in left basal ganglia. After confirmation for CD19 and CD70 expression in his tumor specimens, the pt enrolled in the clinicaltrail :"Combination CART cell therapy targeting hematological malignancies"(clinicaltrail.gov registry NCT03125577).He received 4SCAR19 and 4SCAR70 T cells targeting CD19 and CD70 following lymphodepletion chemotherapy with FC regimen conditioning (FLU 30mg/m2, d1-3; CTX 300mg/m2, d1-3) in October 2017. Brain MRI 1 month later showed complete remission and the pt had symptomatic improvement. To date, after more than 8 months of follow-up, the pt remains in CR (figure1) and CART cells still can be detected . There was no CRS or CRES during the treatment and in follow-up period. Conclusions: The study results demonstrate that CARTs are able to pass through the blood-brain barrier without inducing CRS or CRES, suggesting that CNS tumor is not an absolute contraindication to 4sCART therapy. In addition, the combination of CD19 and CD70 specific 4sCARTs could effectively target PCNSL and achieves long-term disease-free survival without sCRS or CRES. Disclosures No relevant conflicts of interest to declare.

Description: BACKGROUND: Earlier studies based on the 4thgeneration CD19 chimeric antigen receptor-modified T cells (4SCAR19) targeting CD19-positive lymphomas have demonstrated improved partial or complete remission responses (PR or CR) even in very late-stage relapsed or refractory B cell lymphoma patients (pts). Nevertheless, many pts experienced relapses and became CD19 CART-resistant. To improve the long term efficacy, we have develop a CAR2.0 strategy to evaluate the safety and efficacy of sequential infusions of multi-target CARTs against lymphomas. METHODS: Lymphoma pts who have exhausted all available treatment options with progressive or stable disease and life expectancy 〉2 months were enrolled in the study. Pts' lymphoma biopsies were immunostained for various target antigens including CD19, CD20, CD22, CD30, CD38, CD70 and PSMA. The choice of CART targets was based on strong positive staining results. Autologous T cells were apheresis collected and transduced with an apoptosis-inducible, safety-engineered lentiviral CAR with the following intracellular signaling domains: CD28/CD27/CD3ζ-iCasp9 (4SCAR). Pts received cyclophosphamide/fludarabine chemotherapy conditioning 1-2 days before infusions of 1.12-2.8x106 CART cells/kg per infusion. The quality of apheresis cells, efficiencies of gene transfer and T cell proliferation, CAR T infusion dose and blood CAR copies were quantitatively documented. RESULTS: Total 36 pts (male and female, 1:1) were evaluated at three month follow-up time, including 25 pts with diffuse large B cell lymphoma (DLBCL), 6 with primary mediastinal B cell lymphoma (PMBL), 3 with follicular lymphoma (FL), 1 with mantle cell lymphoma (MCL), and 1 with gastric mucosal associated lymphoid tissue lymphoma (MALT). Pt characteristics include 10 pts with stage IV disease (28%), 2 after allo-transplantation (6%), 4 with bone marrow involvement (11%), 3 with CNS involvement (9%), and 3 received prior PD-1 antibody treatment (9%), and LDH was increased in 18 pts (50%). There were two treatment cohorts: 18 pts received single 4SCAR19 cells, and 18 pts received multi-CARTs targeting CD19 and an additional target, CD20, CD22, CD30, CD38, CD70 or PSMA. The choice for the additional CART was determined by individual pt's tumor antigen staining results. In the DLBCL cohort, 14 pts received single target 4SCAR19 cell infusion, at an average dose of 1.12x10e6 CART cells/kg, and resulted in 4 CR, 3 PR and 7 PD; the other 11 DLBCL pts received dual target CART infusions (CD19 plus CD20, CD22, CD38 or CD70) at an average dose of 1.32x106 CART cells/kg, and resulted in 6 CR, 4 PR and 1 PD. The three FL pts received dual target CD19+CD22 CART infusions, at an average dose of 2.55x106 CART cells/kg, and resulted in 2 CR, and 1 PR. The 6 PMBL pts, 3 received single target 4SCAR19 cell infusions, at average dose of 2.14x10e6 CART cells/kg, and resulted in 1 PR and 2 PD; the other 3 PMBL pts received dual target CART infusions (CD19+CD22, CD19+CD30), at an average dose of 2.82x106 CART cells/kg, and resulted in 1 CR, 1 PR and 1 PD. The one MCL pt received single target 4SCAR19 cell infusion, at a dose of 1.56x106 CART cells/kg, and resulted in PR. The MALT pt received double CART infusions, 2.8x106 4SCAR19 cells/kg and 2x106 4SCAR-PSMA cells/kg, and achieved PR. None of these pts developed greater than grade 2 CRS response, except for 1 DLBCL pt, who achieved CR following a grade 3 CRS. The toxicity profile of the 4SCARTs is consistent with our previous experiences with B cell acute lymphoblastic leukemia. In summary, CAR2.0 strategy has included a second CART based on immunostaining and confirmation of additional tumor specific antigen. The comparison between single CART versus double CART clearly illustrates an increased response rate for the double CART cohorts, either in DLBCL pts or in all lymphoma pts, as shown in the summary pie graphs below. CONCLUSIONS: These early results of the multi-target 4SCAR2.0 therapy for the treatment of highly resistant lymphomas have demonstrated increased safety and improved response rate. There is clear overall clinical benefit with the multi-target CART regimen as compared with the single CD19 CART treatment. Continued follow-up will determine whether the 4SCAR2.0 therapy can obtain long term overall survival in these pts. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Description: Emerging evidence indicate the concentration of circulating heme in patients who have sickle cell disease (SCD) is sufficient to contribute to vasculopathies such as pulmonary hypertension. Despite this significance, the identity of specific molecules and pathways responsible for heme-induced pulmonary complications in SCD remains poorly understood. This study was conceived with the idea that whole-genome expression profiling offered a rigorous approach to identify specific molecules involved in both pathological and vasculoprotective mechanisms of sickle chronic lung disease. Human pulmonary artery endothelial cells (PAECs) and pulmonary microvascular endothelial cells (PMVECs) were exposed to a concentration (0–25 mM) range of hemin for seven days and total RNA isolated and interrogated with Affymetrix U133 plus 2.0 Genechips. Microarray data from 24 independent experiments was analyzed using the Bioconductor in the R framework and GeneSpring to generate two unique lists of genes regulated by hemin in PAECs and PMVECs. Multiple genes widely known to be influenced by heme including heme oxygenase-1 (HO-1), ferritin, transferrin receptor, and delta-aminolevulinate synthase were altered as expected thus validating the experimental, statistical and bio-informatics approaches used in this study. The microarray expression data was validated for 26 transcripts in PAECs and 14 transcripts in PMVECs using low-density array multiplex quantitative RT-PCR. Our findings indicate that the cytoprotective response to hemin is markedly more enhanced in PMVECs than in PAECs as determined by the number and the magnitude of differential expression of genes in the oxidative stress response and glutathione metabolism pathways. This finding is supported by a higher basal expression of nuclear factor erythroid 2-related factor 2 (Nrf2) in PMVECs than in PAECs. Heterogeneity of these anti-oxidant phenotypes was confirmed at the protein level in a concentration-dependent manner for multiple enzymes regulated by Nrf2 including NAD(P)H:quinone oxidoreductase 1 (NQO1), which is critical for preventing participation of quinones in redox cycling and generation of reactive oxygen species. Moreover, while NQO1 expression increased 3-fold in PMVECs exposed to hemin for seven days no significant increase in NQO1 expression occurred following shorter periods of hemin treatment. The clinicopathological and pathophysiological relevance of these findings were investigated in post-mortem lung tissues of cases of sickle chronic lung disease and in transgenic mice with SCD. Compared to normal human lung tissues, NQO1 expression increased 3-to 5-fold in the endothelium of small caliber size vessels as well as in both large and small airway epithelium in severe cases of sickle chronic lung disease with extensive pulmonary vascular remodeling. On the contrary, no significant difference in NQO1 expression was detected in the lungs of wild-type mice and transgenic hemizygous or homozygous SCD mice lacking pulmonary vascular remodeling. We conclude that different pulmonary segments and specific anti-oxidant molecules respond uniquely to heme. Unraveling this complex heterogeneity is critical to improving understanding of the pathogenesis and treatment of lung complications in SCD. Induction of NQO1 or its upstream regulator Nrf2 offers a potentially attractive strategy to augment the anti-oxidant phenotype of PAECs to slow the progression of pulmonary vasculopathies in SCD.

Description: BACKGROUND: The prognosis of patients with relapsed B-lineage acute lymphocyte leukemia (B-ALL) after allogeneic hematopoietic stem cells transplantation(HSCT) is poor. It is difficult to obtain disease-free remission and long-term survival in these patients based on chemotherapy, donor leukocyte infusion (DLI) or molecular targeted therapy. Donor-derived anti-CD19 CAR-T(CAR 19) cells may obtain remission in these patients, but many still encounter relapse, especially CD19-negative relapse. CD123 is a surface marker not only associated with the progenitors of acute myeloid leukemia, but also found in progenitors of acute lymphoblastic leukemia. Recent studies have shown that CD123 is highly expressed in the patients with CD19-negative relapsed after CAR19 cells therapy. we developed a novel therapeutic strategy for to administer pooled donor-derived fourth generation CART cells targeting CD19 and CD123 respectively, to patients who relapsed following allogeneic HSCT to avoid CD19-negative relapse. In this study, we report three patients who received combination CARTs therapy achieved disease-free survival that at least more than 6 months (www.clinicaltrials.gov; #NCT03125577). PATIENTS AND METHODS: Three patients with relapsed B-ALL after HLA-matched sibling HSCT have been enrolled in the study to date, and all of their leukemia cells highly expressed CD19 and CD123 antigens. The first and second patients experienced relapse 6 months and one year after all-HSCT respectively; their B-ALLs were p190-positive and carried T315I mutation, and resisted to bonatinib, chemotherapy and DLI. The third patient was also refractory to chemotherapy and DLI. All patients received fludarabine (FLU) and cyclophosphamide (CTX) conditioning chemotherapy (FLU 30mg/m2, d1-3; CTX 300mg/m2, d1-3) before CART infusions. Donor T cells were apheresis collected and transduced with an apoptosis-inducible, safety-engineered lentiviral CD19 or CD123 scFv CAR fused with intracellular signaling domains: CD28/CD27/CD3ζ-iCasp9 (4SCAR19 and 4SCAR123). CAR-T cells were infused at dose range of 0.26-1.38x106 cells/kg. The quality of apheresis cells, gene transfer and T cell proliferation efficiencies, and effective CAR T infusion dose were quantitatively scored and documented. RESULTS: All three patients achieved minimal residual disease (MRD) negative remission within 1 month after CAR-T infusions. Monthly follow-ups of the first and second patients indicated that they achieved stable MRD-negative and p190-negative remission, and remained disease-free for 7 months and 11 months, respectively. The third patient was MRD-positive but achieved bone marrow morphological remission at 7 month follow-up time. Flow cytometry analysis of the MRD cells detected CD19 positive and CD123 partial positive ALL clones, and note that the third patient received the lowest dose of CART infusion, 0.26x10e6/kg. The first patient developed grade 1 cytokine release syndrome (CRS) after CAR-T cell infusions. The second patient developed grade 1 oral acute graft-versus-host disease (aGVHD) and pulmonary infection. The third patient developed grade 2 CRS, with hypoxemia and unilateral massive pleural effusion. We detected high IL-6 in his pleural fluid 〉5000 IU/L, but serum level IL-6 is normal. There was no significant absorption of pleural effusion after treatment with anti-interleukin 6 receptor monoclonal antibody. The patient improved after 5 days of treatment with chest drainage and dexamethasone 10mg/qd. None of the three patients developed central nervous system toxicity, and there was no greater than grade 2 CRS and severe myelosuppression, consistent with the safety profile of the 4SCAR design. CONCLUSIONS: We have successfully treated three relapsed allo-HSCT B-ALL patients using donor-derived 4SCAR19 and 4SCAR123 T cells. All three patients achieved long-term disease-free survival without severe CRS and GVHD. Thus, the administration of double 4SCAR19/4SCAR123 T cells may overcome CD19 escape and prolong disease-free survival. Disclosures No relevant conflicts of interest to declare.

Description: Background: CD19 targeting chimeric antigen receptor T cells(CART19) therapy have shown great therapeutic potential in relapsed and refractory B cell acute lymphoblastic leukemia (ALL), but associated with risk of life-threatening adverse effects as severe cytokine release syndrome (sCRS) and CAR-T-cell-related encephalopathy syndrome (CRES).It's been reported that high leukemia burden before CART therapy, and high does infused CART cells are associated with severity of CRS and CRES. To decrease the risk of severe adverse effect, we applied integrated therapeutic strategy of using fourth generation CART cells , reducing leukemia blasts burden in bone marrow, and decreasing the dose of infused CART cells (www.clinicaltrials.gov; #NCT03407859 and #NCT03125577 ). Methods: Between May 23, 2016 and July 2, 2018,the trial enrolled 20 patients (pts) who were exhausted with all available treatment options, life expectancy 〉2 months,CD19-positive and diagnosis of B lineage ALL.T cells were apheresis collected and transduced with an apoptosis-inducible, safety-engineered lentivector CAR with the following intracellular signaling domains: CD28/CD27/CD3ζ-iCasp9 (4SCAR). In vitro amplication of CART was not performed. In pts with bone marrow blasts exceeding 50.0%, VDCP or similar chemotherapy was given to reduce the tumor burden, and then received FC conditioning regimen (FLU 30mg/m2, d1-3; CTX 300mg/m2, d1-3), while FC regimen was directly carried out in pts with bone marrow blasts less than 50.0%.In this trial, Pts received single CD19-targeted CARTs or multi-CARTs targeting CD19 and an additional antigen of CD22 or CD123.The level of CAR-T cells and cytokines in peripheral blood, as well as tumor burden was measured after infusion. Results: 20 pts were enrolled and infused with CAR-T cells. The median age is 37.5 (16-67) years old. Of these pts, 5 had prior HSCT and 14 had adverse genetic abnormalities, including 4 pts (20%) who were Philadelphia chromosome-positive(Ph+). All pts were previously treated with 2-22 courses of cytotoxic chemotherapy regimens. The overall objective response rate was 85%(17/20), and the complete response(CR) rate was 80%(16/20). The complete remission rate of 12 pts receiving single CD19-targeted CART therapy was 83 %(10/12), while 33%(4/12) of them had disease relapse at 6 months after infusion. Of the 7 people who received multi-CARTs infusion, 71%(5/7) achieved complete remission, with relapse rate of 29%(2/7) at 6 months after infusion. 3 pts who relapsed post transplantation received combination therapy of anti-CD19 CART and anti-CD123 CART, and all achieved minimal residual disease-negative CR within 1 month after CART infusion, 2 of whom maintained disease-free survival for 7 months and 11 months to date, respectively. Among the 7 people who underwent HSCT after achieving CR, 6 of them maintained disease-free survival for 3 months to 9 months. At a median follow-up of 115.5 days (ranging from14 to 384), the median overall survival was 269 days and the median event-free survival was 232 days. During treatment and follow-up, the most common adverse events were grade 1-2 cytokine release syndrome (CRS), with an incidence of 55%.No grade 3 or higher CRS was observed.12 pts were infused with a dose equal to or exceeding 5*10^5/kg, 10 of whom had CRS response. While only 2 of the 8 pts who received the infusion dose of less than 5*10^5/kg had CRS reaction and both of them were grade 1 CRS, suggesting low CAR-T cell doses decrease the risk of CRS (P=0.009). Interestingly, the objective response rate did not differ significantly between the low dose and high dose group. Conclusions: Based on fourth generation CART system, a therapeutic strategy of low tumor burden and low CART infusion dose shows a safer profiling while remaining potent efficacy against leukemia. Disclosures No relevant conflicts of interest to declare.

Description: BACKGROUND: Allogeneic haematopoietic stem cell transplantation (allo-HCT) is a standard treatment for relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). However ~30-40% of patients (pts) still relapse after HCT. We report a cohort of 20 r/rB-ALL pts, who relapsed after HCT, and enrolled in the CAR2.0 study receiving one or two types of CAR-T cells targeting various B-ALL antigens. METHOD: Pts with r/r B-ALL who relapsed after allo-HCT and did not have significant active comorbiditeis, were enrolled in the study. The target antigens were determined based on immunostaining of each pt's leukemia cells, and CAR-T infusions included a single, or a combination of CAR-Ts targeting the following antigens: CD19, CD22, CD123 and CD38. T cells were collected from pts (N=4) or their allogeneic donors (N=16) and transduced with an apoptosis-inducible, safety-engineered lentiviral CAR with the following intracellular signaling domains: CD28/CD27/CD3ζ-iCasp9 (4SCAR). Pts received cyclophosphamide/fludarabine lymphodepleting therapy before infusion of 0.2-5.8x106 CAR-T/kg per infusion. In addition to disease response, we carefully monitored the quality of apheresis cells, efficiency of gene transfer, T cell proliferation rate, CAR-T infusion dose, and the CAR-T copy number in peripheral blood. RESULTS: Among the 20 enrolled pts, 11 were 10% blasts in bone marrow, 8 pts had 1 year. None of these 20 pts received a second HCT after CAR-T infusion. GVHD developed in 5/16 (31%) pts after donor source CAR-T cell infusion within one month, but all responded well to treatment. CONCLUSION: This study focuses on CAR-T cell therapy following relapse after HCT. While the expanded study is ongoing, we present results of the first 20 pts. Use of donor-derived or recipient-derived CAR-T products in pts who relapsed after allo-HCT is well tolerated and it may prolong life expectancy of these pts while maintaining good quality of life. Table Disclosures No relevant conflicts of interest to declare.

Description: Osteocytes are the most abundant (90-95%) cells in bone and have emerged as an important regulator of hematopoiesis, but their role in neutrophil development and the underlying mechanisms remain unclear. Interleukin (IL)-19 produced predominantly by osteocytes stimulated granulopoiesis and neutrophil formation, which stimulated IL-19 receptor (IL-20Rb)/Stat3 signaling in neutrophil progenitors to promote their expansion and neutrophil formation. Mice with constitutive activation of the mechanistic target of rapamycin complex (mTORC1) signaling in osteocytes (Dmp1-Cre) exhibited a dramatic increase in IL-19 production and promyelocytes/myelocytic expansion, while mTORC1 inactivation in osteocytes reduced IL-19 production and neutrophil number in mice. We showed that IL-19 administration stimulated neutrophil development, while neutralizing endogenous IL-19 or depletion of its receptor inhibited the process. Importantly, low dose IL-19 reversed chemotherapy, irradiation, or chloramphenicol-induced neutropenia in mice more efficiently than G-CSF. These evidence indicated that IL-19 was an essential regulator of neutrophil development and a potent cytokine for neutropenia treatment.

Description: BACKGROUND: Chimeric antigen receptor-modified T cell (CART) therapy holds great promise as a novel cancer therapy approach. Although CART cell therapy has revolutionized the treatment of B-cell non-Hodgkin lymphomas (NHLs), relapsed/refractory NHLs including diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), and follicular lymphoma (FL) have not responded well to the currently approved CART cell products. The existing limitations include antigen escape, toxicities of currently approved CART cells, and the high cost of manufacture of a product which is only used for a single patient (pt). The development of an innovative multi-CART therapy using a safety improved CAR design may overcome the above limitations. METHODS: Lymphoma pts who have exhausted all available treatments with progressive or stable disease and life expectancy 〉2 months were enrolled in the study. Lymphoma biopsies were immunostained for various target antigens including CD19, CD20, CD22, CD30, CD38, CD70 and PSMA. An advanced CART therapy regimen, CAR 2.0, has been developed, which involves a primary and a booster CAR-T cell infusions targeting multiple antigens identified on each pt's tumor. Autologous T cells were apheresis collected and transduced with an apoptosis-inducible, safety-engineered lentiviral CAR with the following intracellular signaling domains: CD28/CD27/CD3ζ-iCasp9 (4SCAR). Pts received cyclophosphamide/fludarabine chemotherapy conditioning 1-2 days before infusion of 1.21- 4.87x106 CART cells/kg per infusion. The quality of apheresis cells, efficiencies of gene transfer and T cell proliferation, CAR T infusion dose and blood CAR copies were quantitatively documented. RESULTS: Total 60 pts were evaluated at three months follow-up time, including 42 pts with DLBCL, 10 with PMBCL, 7 with FL and 1 with gastric mucosal associated lymphoid tissue lymphoma (MALT). The median age was 47 years (range, 2-77), including 31 males and 29 females. Pt characteristics include 16 pts with stage IV disease (27%), 2 after allo-transplantation (3.3%), 4 with bone marrow involvement (6.7%), 8 with CNS involvement (13%), and 7 received prior PD-1 antibody treatment (12%). The performance status of 52 of the 60 patients (87%) was Eastern Co-operative Oncology Group score 0 at time of infusion. The study included two treatment cohorts: 30 pts received single 4SCAR19 cells, and 30 pts received CAR2.0 targeting CD19 plus an additional target, depending on the individual pt's tumor antigen staining results. In the DLBCL cohort, 25 pts received single target 4SCAR19 cell infusion, at an average dose of 1.42x106 CART cells/kg, and resulted in 7 complete response (CR), 9 partial response (PR), 3 stable disease (SD) and 6 progressive disease (PD). The other 17 DLBCL pts received dual target CART infusions (CD19 plus CD20, CD22, CD38 or CD70) at an average dose of 2.32x106 CART cells/kg, and resulted in 7 CR, 8 PR ,1 SD and 1 PD. The 5 FL pts received dual target CD19+CD22 CART infusions, at an average dose of 4.64x106 CAR-T cells/kg, and resulted in 4 CR, and 1 PR. The 10 PMBCL pts, 3 received single target 4SCAR19 cell infusions, at an average dose of 2.85x106 CART cells/kg, and resulted in 1 PR and 2 PD; the other 7 PMBCL pts received dual target CART infusions (CD19+CD22, CD30, or CD20), at an average dose of 4.87x106 CART cells/kg, and resulted in 4 CR, 2 PR and 1 PD. The MALT pt received double CART cell infusions, 2.8x106 4SCAR19 cells/kg and 2x106 4SCAR-PSMA cells/kg, and achieved PR. None of these pts developed greater than grade 2 CRS response, except for 1 DLBCL pt, who achieved CR following a grade 3 CRS. The toxicity profile of the 4SCART is consistent with our previous experience with B cell acute lymphoblastic leukemia. In summary, the comparison between single versus double CART cell infusions clearly illustrates an increased response rate for the double CART cohorts, either in DLBCL pts or in all lymphoma pts, as illustrated in the summary pie graphs below. CONCLUSIONS: The results of the multi-target 4SCAR2.0 therapy for the treatment of highly resistant lymphomas have demonstrated increased safety and improved response rate with this novel approach. There is clear overall clinical benefit with the multi-target CART regimen as compared with the single CD19 CART treatment. Continued follow-up will verify whether the 4SCAR2.0 therapy regimen can achieve long term overall survival. Figure Disclosures No relevant conflicts of interest to declare.