Allogeneic Hematopoietic Stem Cell Transplantation with Conditioning Including Donor Humanized CAR-T Cells for Refractory/Relapsed B-Cell Non-Hodgkin Lymphoma and Multiple Myeloma

Abstract Background: The prognosis of refractory/relapsed aggressive B-cell non-Hodgkin lymphoma (r/r B-NHL) and multiple myeloma (r/r MM) is extremely poor, especially for the patients who failed to CAR-T cells therapy and/or ASCT. Aims: Forr/r B-NHLand r/r MM, a clinical trial using Allo-HSCT with conditioning including donor humanized CAR-T cells from the same donor (allo-CAR-T) has been registered, and the safety and efficacy will be evaluated. Methods: From September 2020 to May 2021, 11 patients were enrolled.The median age was 41 (26-64) years old. The diagnosis included high grade B-cell lymphoma (n=9) and Multiple myeloma (n=2). Seven cases were with TP53 mutations.All patients was progressive disease (PD) who failed to multi-line therapies, including chemotherapy (n=11), ASCT (n=4), autologous CAR-T (n=11).In order to further reduce the tumor burden, all patients were treated with combination therapy before transplantation. Before the trial, the expression of CD19 and/or CD22 or CD20 antigen in tumor tissue of r/r B-NHL and BCMA antigen in r/r MM patients was positive confirmed by immunohistochemistry.There were matched sibling identical donor in 1 case,matched unrelated donor in 1 case and haploidentical donor in 9 cases；Conditioning with busulfan, fludarabine-based regimen combined with allo-CAR-T was applied. Tacrolimus, mycophenolate mofetil, a short-term methotrexate and antithymocyte globulin were used for GVHD prophylaxis. The kinetics and function of CAR-T cells was monitored by quantitative PCR and flow cytometry. The efficacy was evaluated by PET-CT in r/r NHL as well as bone marrow puncture and immunofixation electrophoresis in r/r MM every 2 month after CAR-T infusion. Results: The median allo-CAR-T cells infused were 4 (range,0.78-4.88)×10 6/kg. CRS occurred in all cases with 6 cases in grade I, 1 case in grade II and 4 cases in grade III.The peak of cytokine IFN-γ and IL-6 in grade III CRS were significantly higher than those with grade I-II.No ICANS was noted. Four cases with grade III CRS were relieved with methylprednisolone. G-CSF-mobilized PBSC were infused 7 days after allo-CAR-T with the median CD34 + cells 6 (range,3-8.19)×10 6/kg. The neutrophil and platelets engraftment was achieved in all cases on median days 13 (range,11-24) and 16 (range,14-85) respectively post-transplant .All cases were donor type by STR analysis.Three cases of grade II acute GVHD were seen. CMV viremia occurred in 7 cases.For allo-CAR-T cell expansion,the peak time in vivo was on median 14(range,7-28) days after infusion.The median peak lever was 221 (range,0.191-1502)×10 6/L, which positively correlated with the number of allo-CAR-T infused. The tumor burden before transplantation was not significantly associated with allo-CAR-T expansion.Levels of allo-CAR-T cells were very low after the first 2 months of HSCT which detected persistently in 9/11(81.8%) patients, and the longest lasting time was 239 days post-transplant so far. B-cell aplasia was documented in 8/9 cases of r/r B-NHL during the follow-up. With the median follow-up 171 (range,100-295) days, 7/11(63.6%) patients survived,five cases(5/11,45.5%) achieved CR,one cases(1/11,9.1%) obtained PR, and 1 case(1/11,9.1%) of MM achieved SD and survival with tumor .Three cases(3/11,27.3%) with DLBCL died of PD whose disease status before transplantation were SD or PD, one patient(1/11,9.1%) died of infection.Significantly lower levels of Cumulative CAR T cell levels (AUC) during the first 2 month post transplantation were observed in patients who relapsed compared with those who had durable responses (P=0.0001).aGVHD were not associated directly with in vivo CAR T-cell expansion(P=0.193). Conclusion: Our preliminary results have shown that CRS is manageable and has no influence on hematopoiesis reconstitution. Allo-CAR-T cells still exist persistently post-transplant in majority of patients, which may contribute a long-term anti-lymphoma effect.With current protocol, aGVHD and viral reactivation was mild. Allo-HSCT with conditioning including allo-CAR-T cells is a safe and effective strategy for r/r B-NHL and MM. The Poor clinical efficacy was associated with high tumor burden before transplantation. [Key words] refractory/relapsed B-cell non-Hodgkin lymphoma; refractory/relapsed multiple myeloma;allogeneic CAR-T cell; allogeneic hematopoietic stem cell transplantation Disclosures No relevant conflicts of interest to declare.

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Efficacy and Safety of JWCAR029 in Adult Patients with Relapsed and Refractory B-Cell Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood-2018-99-115769 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4187-4187 ◽

Cited By ~ 2

Author(s):

Zixun Yan ◽

Wen Wang ◽

Zhong Zheng ◽

Ming Hao ◽

Su Yang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Hodgkin Lymphoma ◽

Dose Level ◽

Car T Cells ◽

Car T Cell ◽

Non Hodgkin Lymphoma ◽

Car T

Abstract Introduction JWCAR029 is a novel CD19-directed 4-1BB stimulated chimeric antigen receptor T (CAR-T) cell type, which is different from JWCAR017 with independent production of CD4 and CD8 T cells and transfusion in non-fixed ratio. We conducted a single arm, open-label, dose escalation Phase I trial of JWCAR029 in relapsed and refractory B-cell non-Hodgkin lymphoma (NCT03355859). Methods From January to July 2018, 10 patients have been enrolled in this trial, including eight diffused large B cell lymphoma (DLBCL) and two MALT lymphoma, with median age of 47 years (range 32 to 59 years). All the patients received immunochemotherapy as induction and more than two lines of salvage treatment. Two patients received bridging chemotherapy after T-cell collection due to rapid tumor progression, followed by re-evaluation before CAR-T cell infusion. Lymphodepletion preconditioning was accomplished by fludarabine 25mg/m2/d and cyclophosphamide 250mg/m2/d on Day-4 to D-2, followed by CAR-T cell infusion on Day0. JWCAR029 was administrated as a single infusion in escalation dose levels, from 2.5×107 CAR-T cells (dose level 1, DL1) to 5.0×107 CAR-T cells (dose level 2, DL2) and to 1.0×108 CAR-T cells (dose level 3, DL3) according to mTPI-2 algorithm. Circulating blood count, serum biochemistry, and coagulation status were follow-up after infusion. Cytokines were assessed on a Luminex platform. Tumor evaluation was performed on Day 29 by PET-CT. PK data were detected by flow cytometry and real-time quantitative polymerase chain reaction system. All the adverse events were recorded. The study was approved by the Shanghai Rui Jin Hospital Review Board with informed consent obtained in accordance with the Declaration of Helsinki. Results The demographic characteristics of the patients were demonstrated in Table 1. Among six evaluable patients (3 of DL1 and 3 of DL2), the ORR was 100% on Day 29, including four complete remission and 2 partial remission. Cytokine release syndrome (CRS) was 100% in Gr 1, with main symptoms as fever (<39.0 degrees), fatigue, and muscle soreness. No neurotoxicity was observed. Four of the six patients with fever >38.0 degrees used prophylactic IL-6 Inhibitor (8mg/kg, ACTEMRA, two patients administered twice). No patients received steroids. The CRS showed no difference between dose level groups (p>0.99). Adverse effects included leukopenia (Gr 3-4: 83.3%, Gr 1-2: 16.7%), hypofibrinogenemia (Gr 1: 16.7%, Gr 2-4: 0%), liver dysfunction (Gr 1: 33.3%, Gr 2-4: 0%), elevated CRP (Gr 1: 83.3%, Gr 2-4: 0%), ferritin (Gr 1-2: 83.3%, Gr 2-4: 0%), or IL-6 (Gr 1-2:100%, Gr 3-4: 0%, Table 2). Conclusion Although long-term follow-up was needed, the preliminary data of six patients in this trial have demonstrated high response rates and safety of JWCAR029 in treating relapsed and refractory B-cell non-Hodgkin lymphoma. Disclosures Hao: JW Therapeutics: Employment, Equity Ownership.

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Chimeric Antigen Receptor T Cell Targeting to CD19 and CD22 Combined with Anti-PD-1 Antibody Induce High Response in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood-2021-146293 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1730-1730

Author(s):

Ying Zhang ◽

Jiaqi Li ◽

Xiangping Zong ◽

Jin Zhou ◽

Sixun Jia ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Hodgkin Lymphoma ◽

Chimeric Antigen Receptor ◽

Car T Cells ◽

Car T Cell ◽

Non Hodgkin Lymphoma ◽

Car T

Abstract Objective: Despite the remarkable success of chimeric antigen receptor modified T (CAR-T) cell therapy for refractory or relapsed B cell non-Hodgkin lymphoma (R/R B-NHL), high rates of treatment failure and relapse after CAR-T cell therapy are considerable obstacles to overcome. Preclinical models have demonstrated that anti-PD-1 antibody is an attractive option following CAR-T therapy to reverse T cell exhaustion. Thus, we investigated their combination in R/R B-NHL. Methods: We performed a prospective, single-arm study of CAR-T cell combined with anti-PD-1 antibody treatment in R/R B-NHL (NCT04539444). Anti-PD-1 antibody was administrated on day 1 after patients received sequential infusion of anti-CD19 and anti-CD22 second-generation CAR-T cells, and the efficacy and safety of the combination treatment were evaluated. Results: From August 1, 2020 to June 30, 2021, a total of 11 patients were enrolled and completed at least 3 months follow-up. The median follow-up time is 5.8 months. Overall response was achieved in 9 of 11 patients (81.8%), and the complete response (CR) was achieved in 8 of 11 patients (72.7%). All 8 patients achieving CR still sustained remission at the last follow-up. The progression-free survival (PFS) and overall survival (OS) rates at 6 months were 80.8% and 100.0%, respectively. Cytokine release syndrome (CRS) occurred in only 4 patients (all were grade 1), and no neurotoxicity were observed. Conclusion: This study suggests that CAR-T cells combined with anti-PD-1 antibody elicit a safe and durable response in R/R B-NHL. Keywords: chimeric antigen receptor modified T cell, anti-PD-1 antibody, CD19/CD22, refractory or relapsed B cell non-Hodgkin lymphoma Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: We use the T cells were transduced with a lentivirus encoding the CD19-4-1BB-CD3 z and CD22-4-1BB-CD3 ztransgene to produce CAR-T cells. The main purpose of our study is to improve the response rate in patients with R/R B-NHL.

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CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma

Blood ◽

10.1182/blood.2018883421 ◽

2019 ◽

Vol 134 (7) ◽

pp. 626-635 ◽

Cited By ~ 17

Author(s):

Craig S. Sauter ◽

Brigitte Senechal ◽

Isabelle Rivière ◽

Ai Ni ◽

Yvette Bernal ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Hodgkin Lymphoma ◽

B Cell Lymphoma ◽

Car T Cells ◽

Poor Risk ◽

Car T Cell ◽

Non Hodgkin Lymphoma ◽

Car T

Abstract High-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT) is the standard of care for relapsed or primary refractory (rel/ref) chemorefractory diffuse large B-cell lymphoma. Only 50% of patients are cured with this approach. We investigated safety and efficacy of CD19-specific chimeric antigen receptor (CAR) T cells administered following HDT-ASCT. Eligibility for this study includes poor-risk rel/ref aggressive B-cell non-Hodgkin lymphoma chemosensitive to salvage therapy with: (1) positron emission tomography–positive disease or (2) bone marrow involvement. Patients underwent standard HDT-ASCT followed by 19-28z CAR T cells on days +2 and +3. Of 15 subjects treated on study, dose-limiting toxicity was observed at both dose levels (5 × 106 and 1 × 107 19-28z CAR T per kilogram). Ten of 15 subjects experienced CAR T-cell–induced neurotoxicity and/or cytokine release syndrome (CRS), which were associated with greater CAR T-cell persistence (P = .05) but not peak CAR T-cell expansion. Serum interferon-γ elevation (P < .001) and possibly interleukin-10 (P = .07) were associated with toxicity. The 2-year progression-free survival (PFS) is 30% (95% confidence interval, 20% to 70%). Subjects given decreased naive-like (CD45RA+CCR7+) CD4+ and CD8+ CAR T cells experienced superior PFS (P = .02 and .04, respectively). There was no association between CAR T-cell peak expansion, persistence, or cytokine changes and PFS. 19-28z CAR T cells following HDT-ASCT were associated with a high incidence of reversible neurotoxicity and CRS. Following HDT-ASCT, effector CD4+ and CD8+ immunophenotypes may improve disease control. This trial was registered at www.clinicaltrials.gov as #NCT01840566.

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Early Response Observed in Pediatric Patients with Refractory/Relapsed B-Cell Non-Hodgkin Lymphoma Treated with Sequential Chimeric Antigen Receptor T Cells

Blood ◽

10.1182/blood-2019-125753 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1945-1945 ◽

Cited By ~ 3

Author(s):

Wenqun Zhang ◽

Bo Hu ◽

Ling Jing ◽

Jing Yang ◽

Shan Wang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Hodgkin Lymphoma ◽

Pediatric Patients ◽

Response Rate ◽

Car T Cell ◽

Non Hodgkin Lymphoma ◽

Car T ◽

To Receive

Background:Outcomes for pediatric patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL) are poor despite use of high-intensity chemotherapy. CAR-T has shown efficacy in treating refractory/relapsed leukemia in pediatric patients and non-Hodgkin lymphoma in adult patients. Objectives:To assess the safety and efficacy of sequential CAR-T in the treatment of refractory/ relapsed B-NHL in pediatric patients. Design/Methods:In our ongoing clinical trial (ChiCTR1800014457), we enrolled and treated 17 pediatric patients with refractory/relapsed B-NHL. Following leukapheresis, T cells were activated with CD3 and CD28 antibodies for 24h, then transduced with lentivirus encoding anti-CD19-CD3zeta-4-1BB CAR and cultured for 5-6 days in serum-free media containing IL2, IL7, IL15, IL21. Meanwhile, all patients briefly received lympho-depleting chemotherapies consisting of fludarabine (30 mg/m2/day) and cyclophosphamide (250 mg/m2/day) on days −5, −4 and −3 according to tumor burden and patient state. On day 0, all patients received a single-dose infusion of CAR-T cells. CAR-T cell dose ranged from 0.5 to 3 million/kg. CAR-T cell numbers and cytokines were measured weekly. Tumor responses were evaluated at day 30 and day 60 post infusion and every two months thereafter. Adverse events were graded according to CTCAEv4 except cytokine release syndrome (CRS) was graded according to Lee et al. Results:Treated patients had relapsed/refractory Burkitt lymphoma (BL) (13/17), diffuse large B cell lymphoma (DLBCL) (2/17), B-lymphoblastic lymphoma (B-LBL) (2/17), and ranged from 4.5-18.0 years old. By St Jude's staging, 9 cases (46.7%) were in stage III, 8 cases (53.3%) were in stage IV. There were 3 cases with CNS involvement (17.6%) and 7 cases with bone marrow involvement (41.2%). They all failed at prior treatment including an average of 8.9 (6-15) courses of chemotherapy. They were then treated with sequential CAR-T cell therapy. A total of 26 courses of CAR-T cell infusion were administered. The overall complete response rate (CRR) was 41.7% (7/17) when first course of CAR-T therapy was conducted, which were all CD19 targeted. Among the 10 patients who did not achieve CR, 2 patients achieved PR with ongoing response, 1 patient died of severe CRS and progression at day 6 and another patient refused to continue the following therapy when tumor progressed at day 99, and he died 1 week later, the other 6 continued to receive second course of CAR-T therapy targeting CD20 or CD22, and 3 of them achieved CR. Thus the overall CRR increased to 58.8% (10/17). The 3 patients, who still did not achieve CR, continued to receive third course of CAR-T therapy targeting CD20 or CD22. Two of them finally achieved CR and the other failed to get CR and is now retreated with chemotherapy and oral Olaparib and Venclexta. Thus, with a median follow-up of 6.2 months (1-18 months), the overall response rate of sequential CAR-T therapy was 94.1% (16/17) and the overall CRR was 70.6% (12/17). Toxicity information through day 30 revealed the occurrence of mild CRS in 8 subjects (47.1%, grade I n=8, grade II n=0), severe CRS in 9 subjects (52.9%, grade III n=8, grade IV n=1). Neurotoxicity was observed in 7 cases (41.2%, seizure in 3 cases, tremor in 4 cases, headache in 1 cases). One case who died rapidly at day 6 of therapy suffered severe CRS (high fever, Capillary leak syndrome, severe pleural effusion, respiratory failure, shock, cardiopulmonary arrest) and neurotoxicity besides disease progression. Other patients with severe CRS and neurotoxicity recovered fully after glucocorticoid use and symptomatic treatment including anti-epilepsy, fluid, dehydrating agent. No case used tocilizumab. Response assessments were performed at day 15, 30, 45, 60. Updated enrollment, toxicity and response assessments will be presented. Conclusion: CD19/CD20/CD22-CAR-T therapy showed promising efficacy for pediatric patients with r/r B-NHL and the toxicities are tolerable with proper symptomatic and supportive treatment. Sequential CAR-T therapy can improve the efficacy compared with a single course of CAR-T infusion. Disclosures No relevant conflicts of interest to declare.

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Beyond Chemotherapy: Checkpoint Inhibition and Cell-Based Therapy in Non-Hodgkin Lymphoma

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_200549 ◽

2018 ◽

pp. 592-603 ◽

Cited By ~ 4

Author(s):

Paolo Strati ◽

Shabnum Patel ◽

Loretta Nastoupil ◽

Michelle A. Fanale ◽

Catherine M. Bollard ◽

...

Keyword(s):

Clinical Trials ◽

T Cells ◽

T Cell ◽

B Cell ◽

Hodgkin Lymphoma ◽

Checkpoint Inhibition ◽

Cell Therapies ◽

Car T Cells ◽

Car T Cell ◽

Car T

Immune-based treatment strategies, such as checkpoint inhibition and chimeric antigen receptor (CAR) T cells, have started a new frontier for treatment in non-Hodgkin lymphoma (NHL). Checkpoint inhibition has been most successful in Hodgkin lymphoma, where higher expression of PD-L1 is correlated with better overall response rate. Combinations of checkpoint inhibition with various chemotherapy or biologics are in clinical trials, with initially promising results and manageable safety profiles. CAR T-cell therapies that target CD19 are a promising and attractive therapy for B-cell NHLs, with a product approved by the US Food and Drug Administration in 2017. Changes in the target, hinge, or costimulatory domain can dramatically alter the persistence and efficacy of the CAR T cells. The ZUMA trials from Kite used CD19-(CD28z) CAR T cells, whereas the TRANSCEND studies from Juno and the JULIET studies from Novartis used CD19-(4-1BBz) CARs. Despite the recent successes with CAR T-cell clinical trials, major concerns associated with this therapy include cytokine release syndrome, potential neurotoxicities, B-cell aplasia, loss of tumor antigen leading to relapse, and cost and accessibility of the treatment. Although first-generation CAR T-cell therapies have failed in solid malignancies, newer second- and third-generation CAR T cells that target antigens other than CD19 (such as mesothelin or B-cell maturation antigen) are being studied in clinical trials for treatment of lung cancer or multiple myeloma. Overall, immune-based treatment strategies have given oncologists and patients hope when there used to be none, as well as a new basket of tools yet to come with further research and development.

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

Blood ◽

10.1182/blood.v128.22.4192.4192 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4192-4192 ◽

Cited By ~ 12

Author(s):

Jeremy S. Abramson ◽

Lia Palomba ◽

Leo I Gordon ◽

Matthew Lunning ◽

Jon Arnason ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Research Funding ◽

Employment Equity ◽

Car T Cells ◽

Car T Cell ◽

Non Hodgkin Lymphoma ◽

Car T ◽

Equity Ownership

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

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CAR T-Cell Therapy in Hematologic Malignancies: Clinical Role, Toxicity, and Unanswered Questions

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_320085 ◽

2021 ◽

pp. 1-20

Author(s):

Saar Gill ◽

Jennifer N. Brudno

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Hodgkin Lymphoma ◽

Lymphoblastic Leukemia ◽

Hematologic Malignancies ◽

Lymphocytic Leukemia ◽

Car T Cells ◽

Car T Cell ◽

Car T

At the time of writing, five anti-CD19 CAR T-cell products are approved by the U.S. Food and Drug Administration for seven different indications in lymphoid malignancies, including B-cell non-Hodgkin lymphoma, pediatric B-cell acute lymphoblastic leukemia, and multiple myeloma. CAR T cells for chronic lymphocytic leukemia, acute myeloid leukemia, and less common malignancies such as T-cell lymphomas and Hodgkin lymphoma are being tested in early-phase clinical trials worldwide. The purpose of this overview is to describe the current landscape of CAR T cells in hematologic malignancies, outline their outcomes and toxicities, and explain the outstanding questions that remain to be addressed.

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Clinical Response in Relapsed/Refractory (R/R) B-NHL Treated with the CD19-Directed CAR T-Cell Product JWCAR029

Blood ◽

10.1182/blood-2019-127751 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2876-2876 ◽

Cited By ~ 2

Author(s):

Zhitao Ying ◽

Pengpeng Xu ◽

Li Wang ◽

Shu Cheng ◽

Wen Wu ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Dose Level ◽

Employment Equity ◽

Car T Cells ◽

Car T Cell ◽

Non Hodgkin Lymphoma ◽

Car T ◽

Equity Ownership

Introduction JWCAR029 is a CD19-directed 4-1BB chimeric antigen receptor (CAR) T cell product with a 4-1BB costimulatory domain, of which CD4 and CD8 CAR T cells are produced together and transfused in non-fixed ratio. We conducted a single arm, open-label, dose escalation Phase I trial of JWCAR029 in relapsed and refractory B-cell non-Hodgkin lymphoma (NCT03344367 and NCT03355859). Methods Eligible pts had confirmed B-cell NHL with R/R disease after ≥2 prior lines of therapy. All subjects received lymphodepleting chemotherapy prior to receiving JWCAR029. After lymphodepleting chemotherapy, JWCAR029 was administrated as a single infusion in escalating dose levels, from 25×106 CAR T cells (dose level 1, DL1), 50×106 CAR T cells (dose level 2, DL2), 100×106 CAR T cells (dose level 3, DL3) to 150×106 CAR T cells (dose level 4, DL4) according to mTPI-2 algorithm. Circulating blood counts, serum biochemistry, coagulation status, and cytokines were followed up after infusion. Cytokines were assessed on a Luminex platform. Tumor evaluation was evaluated per the Lugano criteria by PET-CT (Cheson, 2014) and safety and disease status was followed at approximately 1, 3, 6, 9, 12, 18 and 24 months after receiving JWCAR029. PK was measured by flow cytometry and real-time quantitative polymerase chain reaction system. All the adverse events were recorded for 24 months after infusion. The study was approved by Beijing Cancer Hospital and Shanghai Rui Jin Hospital Review Board with informed consent obtained in accordance with the Declaration of Helsinki. Results As of July 5, 2019, 44 patients were screened and 32 patients were enrolled and received treatment in two study sites in China. Twenty nine patients are evaluable and have been followed for at least 6 months: 20 diffuse large B cell lymphoma (DLBCL) and 9 follicular lymphoma, mantle cell lymphoma and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue lymphoma. Median age was 52 years (range 29 to 68 years). The demographic characteristics of the patients are shown in Table 1. All patients received immunochemotherapy as induction and a median of four lines of salvage treatment (range 2 to 7). Eleven (34%) patients received bridging chemotherapy after T cell collection due to rapid tumor progression, followed by re-evaluation before CAR T cell infusion. Lymphodepletion consisted of fludarabine 25mg/m2/d and cyclophosphamide 250mg/m2/d on Day -4 to Day -2, followed by CAR T cell infusion on Day 0. Median time to peak CAR+ T cell expansion was 11 (8-15) days. No DLTs were reported. There were no treatment-related deaths. Seventeen patients (53.1%) reported cytokine release syndrome (CRS) with 16 grade 1 or 2 (50%) and 1 (3.1%) grade 3. No grade 4 or 5 CRS was observed. Main symptoms were fever (>39.0 degrees), fatigue, and muscle soreness. The rate of CRS was similar across dose level groups. Grade 1 and 2 neurotoxicity was observed in 5 patients (15.6%). No grade ≥3 neurotoxicity was reported. Most common adverse events (frequency >20%) included leukopenia (Gr 3-4: 21.9%, Gr 1-2: 43.8%), lymphopenia (Gr 1-2: 21.9%, Gr 3-4: 21.9%), neutropenia (Gr 1-2: 37.5%, Gr 3-4: 28.2%), thrombocytopenia (Gr 1-2: 21.9%, Gr 3-4: 3.1%), pyrexia (Gr 1-2: 21.9%) and immunoglobulins decreased (Gr 1: 28.1%). Among all 29 efficacy-evaluable patients (6 of DL1, 6 of DL2, 8 of DL3 and 9 of DL4), the best ORR was 89.7%; 85% for DLBCL patients. ORR/CRR of all evaluable patients at 1, 3 and 6 months were 86.2%/65.5%, 69%/62.1% and 58.6%/55.2%, respectively, and for the 20 DLBCL patients the ORR/CRR was 80%/60%, 55%/55%, and 45%/45%, respectively (Table 2). Conclusion Although longer follow-up is needed, the data from 29 evaluable patients in this Phase I trial have demonstrated high response rates and a favorable safety profile of JWCAR029 in relapsed and refractory B-cell non-Hodgkin lymphoma. A Ph II trial that further assess safety and efficacy of JWCAR029 in DLBCL and FL patients has been initiated and is open for enrollment. Disclosures Wang: JW therapeutics (Shanghai) Co., Ltd: Employment, Equity Ownership. Hao:JW therapeutics (Shanghai) Co., Ltd: Employment, Equity Ownership. Yang:JW therapeutics (Shanghai) Co., Ltd: Employment, Equity Ownership. Lam:JW therapeutics (Shanghai) Co., Ltd: Employment, Equity Ownership. Li:JW therapeutics (Shanghai) Co., Ltd: Employment, Equity Ownership. Zheng:JW therapeutics (Shanghai) Co., Ltd: Employment, Equity Ownership.

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Systematically optimized BCMA/CS1 bispecific CAR-T cells robustly control heterogeneous multiple myeloma

10.1101/2020.03.12.989491 ◽

2020 ◽

Author(s):

Eugenia Zah ◽

Eunwoo Nam ◽

Vinya Bhuvan ◽

Uyen Tran ◽

Brenda Y. Ji ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

T Cell ◽

Cell Therapy ◽

B Cell ◽

T Cell Therapy ◽

Car T Cells ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

ABSTRACTChimeric antigen receptor (CAR)-T cell therapy has shown remarkable clinical efficacy against B-cell malignancies but also demonstrated marked vulnerability to antigen escape and tumor relapse. Here, we report the rational design and systematic optimization of bispecific CAR-T cells with robust activity against multiple myeloma (MM), including heterogeneous MM that is resistant to conventional CAR-T cell therapy targeting B-cell maturation antigen (BCMA). We demonstrate that BCMA/CS1 bispecific CAR-T cells exhibit significantly higher CAR expression levels and greater antigen-stimulated proliferation compared to T cells that co-express individual BCMA and CS1 CARs. Compared to single-input BCMA- or CS1-targeting CAR-T cells, BCMA/CS1 bispecific CAR-T cells significantly prolong the survival of animals bearing heterogeneous MM tumors. Combination therapy with anti–PD-1 antibody further accelerates the rate of initial tumor clearance in vivo, but CAR-T cell treatment alone was able to achieve durable tumor-free survival even upon tumor re-challenge. Taken together, the BCMA/CS1 bispecific CAR presents a promising treatment approach to prevent antigen escape in CAR-T cell therapy against MM, and the vertically integrated optimization process can be used to develop robust cell-based therapy against novel disease targets.

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Antigen Glycosylation Is a Central Regulator of CAR T Cell Efficacy

Blood ◽

10.1182/blood-2021-146651 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1721-1721

Author(s):

Amanda Heard ◽

Mehmet Emrah Selli ◽

John Lattin ◽

Jack Landmann ◽

Jufang Chang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Hodgkin Lymphoma ◽

Stock Options ◽

Research Funding ◽

Car T Cell ◽

Non Hodgkin Lymphoma ◽

Car T ◽

Complex Glycans

Abstract Chimeric antigen receptor-engineered T cells targeting CD19 (CART19) have revolutionized the management of relapsed and refractory B cell malignancies. Despite high initial response rates, many patients with acute lymphoblastic leukemia (ALL) ultimately relapse after CART19. In contrast, most patients with non-Hodgkin lymphoma experience only partial or no responses. Collectively, <50% of patients treated with CART19 achieve durable disease remission. Identification of the biology responsible for these failures is central to improving CAR T cell efficacy. Several clinical reports have demonstrated that a common cause of resistance to CART19 is antigen escape, in which ALL clones emerge that have lost surface expression of CD19. The mechanisms of antigen escape that have been recognized to date all rely on disruption of CD19 genomic loci or transcribed CD19 mRNA; alterations of fully-translated CD19 protein that lead to CART19 failure have not been described. To identify pathways responsible for enabling tumor-intrinsic resistance to CART19 we performed a genome-wide loss-of-function screen in the Nalm6 ALL cell line. The second-most enriched gene in this screen was SPPL3 (Figure 1a), encoding a Golgi-resident aspartyl protease. Previous studies have determined that SPPL3 functions to broadly limit protein glycosylation by cleaving glycosyltransferases from the Golgi membrane, impairing their ability to add complex glycans to proteins as they pass through the Golgi (Voss M. et al. EMBO, 2014). Using targeted genomic disruption, we confirmed that loss of SPPL3 results in resistance to CART19 in human ALL and non-Hodgkin lymphoma models (Figures 1b-c). CART19 cells exposed to SPPL3KO ALL demonstrated significantly lower expression of CD69, PD1, Tim3 and CD107a, as well as less activation of the central T cell transcription factors NFAT and NFκB, indicating a global suppression of T cell stimulation. Consistent with its known function, loss of SPPL3 resulted in increased addition of complex glycans to CD19. Surface staining of SPPL3KO cells revealed that CD19 antibodies were less capable of binding this hyperglycosylated CD19. This included decreased binding of the antibody used to construct the anti-CD19 CAR (clone FMC63). Protein modeling revealed that an asparagine residue known to be normally glycosylated on CD19 (N125) is in close physical proximity to the FMC63 binding site (Figure 1d), suggesting that the addition of complex glycans at this site may be responsible for disruption of CAR binding that led to impaired T cell activation. We next turned our attention to CD22, another B cell antigen that is normally glycosylated and the target of CAR therapy. In contrast to CD19, loss of SPPL3 had no impact on CD22 glycosylation or antibody binding. Similarly, loss of SPPL3 did not enable resistance to CD22-targeted CAR T cells. These findings substantiated our hypothesis loss of SPPL3 lead to CART19 failure directly via modifying CD19 glycosylation, and not through another CD19-independent mechanism. To further validate the impact of CD19 glycosylation in regulating CART19 efficacy, we over-expressed SPPL3 in ALL cells, previously shown to promote global hypoglycosylation. We confirmed decreased glycosylation of CD19 (Figure 1e), and found that this resulted in loss of FMC63 binding to CD19 and complete resistance to CART19 activity (Figure 1f). In summary, our findings identify that changes to CD19 glycosylation, either enhanced or decreased, impair the ability of CARs to bind and initiate T cell effector function against malignant B cells. Further, these data identify post-translational protein modification as a novel mechanism of antigen escape from CAR-based T cell immunotherapy. Figure 1 Figure 1. Disclosures Ruella: AbClon: Consultancy, Research Funding; viTToria biotherapeutics: Research Funding; BMS, BAYER, GSK: Consultancy; Novartis: Patents & Royalties; Tmunity: Patents & Royalties. Gill: Interius Biotherapeutics: Current holder of stock options in a privately-held company, Research Funding; Novartis: Other: licensed intellectual property, Research Funding; Carisma Therapeutics: Current holder of stock options in a privately-held company, Research Funding.

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