Phase I Dose-Escalation Trial of CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) T-Cells for the Treatment of Relapsed or Refractory B-Cell Lymphomas and Chronic Lymphocytic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 19-20
Author(s):  
Sanaz Ghafouri ◽  
Christopher Walthers ◽  
Mobina Roshandell ◽  
Brenda Ji ◽  
Jacqueline Trent ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Publicly Traded ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Background: Single-input anti-CD19 CAR T-cells have demonstrated clinical efficacy for relapsed or refractory (R/R) non-Hodgkin B-cell lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Despite excellent response rates, over 50% of CD19 CAR T-cell recipients relapse. Preclinical data show engineering of bispecific anti-CD19/CD20 CAR T-cells via lentiviral transduction effectively targets tumor cells and overcomes antigen escape (Zah E et al., Cancer Immunol Res, 2016). Based on these promising preclinical results and the limitations of single-input anti-CD19 CARs, we investigated the bispecific anti-CD19/CD20 CAR naïve/memory T-cells in a phase I dose-escalation clinical trial for patients with R/R NHL/CLL (NCT04007029). Methods: This trial includes patients who have measurable disease after 2 lines of therapy for diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBCL), and after 3 lines of therapy for mantle cell lymphoma (MCL), follicular lymphoma (FL), CLL and small lymphocytic leukemia (SLL). Eligible participants received lymphodepleting chemotherapy with fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 for three days, followed by anti-CD19/CD20 CAR T-cell infusion. The CAR T-cell infusion will be given with standard "3+3" dose escalation to determine the maximum tolerated dose (MTD), with a dose range of 5 x 107 to 6 x 108 CAR-positive cells per patient. Results: To date, three patients received treatment on cohort 1 with 5 x 107 CD19/CD20 CAR T-cells for R/R MCL, FL and PMBCL, with an average age of 49.3 (range, 29-60) and a mean of 3.7 prior regimens (range, 3-4). All 3 patients' lymphomas were CD19+/CD20+ on tissue biopsy prior to CAR infusion and all 3 received bridging chemotherapy. The infusion was well tolerated and no major infusion reactions occurred. Peak expansion was noted on day 14. No dose limiting toxicities were identified. The maximum grade CRS was 1 and there was no ICANS. At the 6.0-month cutoff date, 2 of the 3 patients remain in ongoing complete remission. Unfortunately, one patient developed progressive disease 0.5 months after CAR infusion, yet remains alive after treatment with immunotherapy. Both of the responders continue to demonstrate ongoing CAR T-cell persistence and B-cell aplasia by 3.0 and 6.0-month follow up, respectively. Conclusions: Here we demonstrate impressive responses in 2 of 3 patients at the 5 x 107 CD19/CD20 CAR T-cell dosages. Bispecific CD19/CD20 CAR T-cell therapy appears to be safe and effective in patients with R/R NHL and CLL and obviates the challenges with the single antigen directed CARs by decreasing risk of target antigen loss and expression downregulation. A longer follow up period is required to determine the impact of modifying naïve/memory T cells and the durability of response. The trial continues to enroll patients and additional clinical and translational data are being collected on the initial patient cohort. Disclosures Timmerman: Corvus: Current equity holder in publicly-traded company; Marker Therapeutics: Current equity holder in publicly-traded company; Bluebird Bio: Current equity holder in publicly-traded company; Immune Design: Honoraria; Celldex Therapeutics: Consultancy; Valor: Research Funding; Merck: Research Funding; Spectrum Pharmaceuticals: Research Funding; BMS: Other: Travel support, Research Funding; Kite, a Gilead Company: Consultancy, Other: Travel support, Research Funding; Genmab: Current equity holder in publicly-traded company. Chen:Kalthera Therapeutics: Other: Co-founder; Notch Therapeutics: Membership on an entity's Board of Directors or advisory committees; Gritstone Oncology: Membership on an entity's Board of Directors or advisory committees. Larson:BMS, Bioline, Celgene, Juno, Janssen: Research Funding; TORL Biotherapeutics: Current equity holder in private company.

scholarly journals Analysis of CAR-T and Immune Cells within the Tumor Micro-Environment of Diffuse Large B-Cell Lymphoma Post CAR-T Treatment By Multiplex Immunofluorescence

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 678-678 ◽  
Author(s):  
Pei-Hsuan Chen ◽  
Mikel Lipschitz ◽  
Kyle Wright ◽  
Philippe Armand ◽  
Caron A. Jacobson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cd8 T Cells ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Abstract BACKGROUND: Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that shows efficacy in patients with refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma and transformed follicular lymphoma after failure of conventional therapy. However, the exact mechanism of anti-tumor immunity is poorly understood, in part due to the dearth of data on the events in the tumor micro-environment (TME) that occur upon exposure to CAR-T cells. We sought to quantify and characterize both CAR-T cells and non-CAR T cells within the TME of DLBCL using tissue biopsy samples collected in the ZUMA-1 multicenter trial of CAR-T cell therapy for patients with refractory DLBCL. METHODS: Tumor samples obtained from patients 5-30 days (median 10 days) after CAR-T infusion ("CAR-treated", n=14) and randomly-selected untreated ("untreated ", n=15) archival DLBCL tissue samples were analyzed by multiplex immunofluorescence using formalin-fixed, paraffin embedded tissue sections, with successive labeling by the primary antibodies KIP-1 and/or KIP-3 (recognizing separate CD19 CAR epitopes), PAX5, PD-1, CD4, and CD8, followed by secondary amplification and tyramide-conjugated fluorophores. For each case, at least 3 representative 20x fields of view were selected and imaged using a multispectral imaging platform. Two specific image analysis algorithms were designed to accurately identify CD4 and CD8 T cells and PAX5+ DLBCL cells simultaneously, then to threshold PD-1 and KIP-1/-3 by relative fluorescent units (RFU) in each phenotype. RESULTS: We identified CAR T-cells within the fixed biopsy samples of CAR-treated DLBCLs by immunostaining with CAR T-cell specific antibody KIP-1; at the timepoints analyzed, CAR T-cells comprised only a small minority of total T- cells (<2%) and included CD4+ and CD8+ T-cells. Immunostaining with a second antibody, KIP-3, validated the presence of CAR T-cells in these cases and confirmed the KIP-1 results. Expression of the T cell activation marker PD-1 was detected among majority of KIP-1+ cells. Further analysis that included KIP1-negative cells revealed that the percentage of CD8+ cells co-expressing PD-1 across all CD8+ cells was higher in the CAR-treated DLBCLs compared to the untreated DLBCLs (mean 50.1% vs 17.5%, p<0.0001 with unpaired t test ), indicating CD8 T cell activation within the tumor environment. In contrast, PD-1 positivity across CD4+ T cells were equivalent between the two groups (mean 21.8% vs 21.6%, ns with unpaired t test). The percentages of total, CD4+, and CD8+ T-cell populations in the TME were similar between the CAR-treated DLBCL and untreated biopsies. CONCLUSIONS: CD4+ and CD8+ CAR-T cells can be detected in CAR-treated DLBCL patient tissue biopsies by multiplex immunofluorescence. At the time points analyzed to date, CAR-T cells comprise only a small percentage of all T-cells (<2%) within the TME. However, the presence of gene marked T cells with downregulated CAR protein expression is also possible. The activation marker PD-1 is preferentially expressed by KIP-1-negative CD8+ T cells compared to CD4+ T cells in CAR-T treated DLBCLs relative to untreated DLBCLs. These data implicate preferential activation of CD8+ non-CAR "by-stander" T-cells in the post CAR-T TME, and the possible benefit of combining PD-1 blockade with CAR-T therapy in DLBCL. *PH.C and M.L share equal contribution. Disclosures Armand: Otsuka: Research Funding; Affimed: Consultancy, Research Funding; Pfizer: Consultancy; Infinity: Consultancy; Adaptive: Research Funding; Merck: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding. Roberts:KITE: Employment. Rossi:KITE: Employment. Bot:KITE: Employment. Go:KITE: Employment. Rodig:Merck: Research Funding; Bristol Myers Squibb: Research Funding; Affimed: Research Funding; KITE: Research Funding.

scholarly journals CD229 CAR T Cell Therapy for the Treatment of Relapsed B Cell Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2800-2800
Author(s):  
Michael Olson ◽  
Tim Luetkens ◽  
Fiorella Iglesias ◽  
Sabarinath Radhakrishnan ◽  
Jennie Y. Law ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract B cell lymphoma is the most common hematologic malignancy in the United States. Although treatment options have greatly improved in the past several decades, outcomes for patients with relapsed B cell lymphoma remain poor. Chimeric antigen receptor (CAR) T cells have recently entered the clinic with promise to address the gap in effective therapies for patients relapsed B cell lymphoma. However, antigen loss and poor CAR T cell persistence has been shown to drive resistance to the widely approved CD19-targeted CAR in some patients, demonstrating the need for additional therapies. Here, we demonstrate CD229-targeted CAR T cell therapy as a promising option for the treatment of relapsed B cell lymphoma, addressing an important group of patients with typically poor outcomes. CD229 is an immune-modulating receptor expressed on the surface of B cells that we recently found to be highly expressed in the plasma cell neoplasm multiple myeloma (Radhakrishnan et al. 2020). We utilized semi-quantitative PCR and flow cytometry to assess whether CD229 is also expressed on malignant B cells earlier in development as found in B cell lymphoma. Expression analysis revealed the presence of CD229 in a panel of 11 B cell lymphoma cell lines and 45 primary B cell lymphoma samples comprising several subsets of disease including aggressive B cell lymphomas such as diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and Burkitt lymphoma as well as indolent subtypes of B cell lymphoma including chronic lymphoblastic leukemia (CLL) and follicular lymphoma. Of note, CD229 was found to be overexpressed on primary B cell lymphoma cells when compared to autologous normal B cells. Given the high levels of CD229 expression throughout all B cell lymphoma subtypes analyzed, we generated CD229 CAR T cells in order to determine whether CAR T cell therapy is an effective way to target CD229 expressing B cell lymphoma cells. CD229 CAR T cells exhibited robust cytotoxicity when cocultured with B cell lymphoma cell lines and primary samples characterized by significant production of TH1 cytokines IL-2, TNF and IFNγ and rapid loss of B cell lymphoma cell viability when compared to control CAR T cells lacking an antigen binding scFv domain (∆scFv CAR T cells). In vivo analysis revealed effective tumor control in NSG mice carrying B cell lymphoma cell lines JeKo-1 (MCL) and DB (DLBCL) when treated with CD229 CAR T cells versus ∆scFv CAR T cells. Finally, we sought to determine the efficacy of CD229 CAR T cells in the context of CD19 CAR T cell therapy relapse. Here, a 71-year-old patient with CLL had an initial response when treated with CD19 CAR T cells but quickly relapsed only 2 months after treatment. Malignant cells from the CLL patient retained CD229 expression as identified by flow cytometry and an ex vivo coculture with CD229 CAR T cells revealed robust killing of CLL cells by CD229 CAR T cells. Transfer of antigen from target cell to CAR T cell by trogocytosis was recently suggested to drive relapse following CAR T cell therapy by decreasing antigen on tumor cells and promoting CAR T cell fratricide (Hamieh et al. 2019). We cocultured CD19 and CD229 CAR T cells with primary CLL cells and assessed CD19 and CD229 expression as well as CAR T cell viability by flow cytometry. In contrast with CD19 CAR T cells, CD229 CARs did not strip their target antigen from the surface of CLL cells. The transfer of CD19 from CLL cells to CD19 CAR T cells resulted in poor CAR T cell viability while CD229 CAR T cell viability remained high following coculture. In summary, we demonstrate that CD229 is a promising therapeutic target in B cell lymphoma due to its high levels of expression throughout many subtypes of disease. CD229 CAR T cells effectively kill B cell lymphoma cells in vitro and control growth of aggressive B cell lymphomas in vivo. Finally, CD229 CAR T cells are effective against primary CLL cells from patients that have relapsed from CD19 CAR T cell therapy and do no exhibit antigen loss by trogocytosis. Taken together, these data suggest that CD229 CAR T cell therapy may be a promising option to address the poor outcomes for patients with relapsed B cell lymphoma. Disclosures No relevant conflicts of interest to declare.

scholarly journals Fatal late-onset CAR T-cell–mediated encephalitis after axicabtagene-ciloleucel in a patient with large B-cell lymphoma

2021 ◽  
Vol 5 (19) ◽  
pp. 3789-3793
Author(s):  
Susanne Jung ◽  
Jochen Greiner ◽  
Stephanie von Harsdorf ◽  
Pavle Popovic ◽  
Roland Moll ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Car T Cells ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T ◽  
Large B Cell

Abstract Treatment with CD19-directed (CAR) T cells has evolved as a standard of care for multiply relapsed or refractory large B-cell lymphoma (r/r LBCL). A common side effect of this treatment is the immune effector cell–associated neurotoxicity syndrome (ICANS). Severe ICANS can occur in up to 30% to 40% of patients treated with axicabtagene-ciloleucel (axi-cel), usually within the first 4 weeks after administration of the dose and usually responding well to steroids. We describe a case of progressive central neurotoxicity occurring 9 months after axi-cel infusion in a patient with r/r LBCL who had undergone a prior allogeneic hematopoietic cell transplant. Despite extensive systemic and intrathecal immunosuppression, neurological deterioration was inexorable and eventually fatal within 5 months. High CAR T-cell DNA copy numbers and elevated levels of interleukin-1 (IL-1) and IL-6 were found in the cerebral spinal fluid as clinical symptoms emerged, and CAR T-cell brain infiltration was observed on autopsy, suggesting that CAR T cells played a major pathogenetic role. This case of unexpected, devastating, late neurotoxicity warrants intensified investigation of neurological off-target effects of CD19-directed CAR T cells and highlights the need for continuous monitoring for late toxicities in this vulnerable patient population.

Long-term follow-up of anti-CD19 CAR T-cell therapy for B-cell lymphoma and chronic lymphocytic leukemia.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3012-3012 ◽  
Author(s):  
Kathryn Cappell ◽  
Richard Mark Sherry ◽  
James C. Yang ◽  
Stephanie L. Goff ◽  
Danielle Vanasse ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Long Term Adverse Effects

3012 Background: T cells expressing anti-CD19 chimeric antigen receptors (CARs) can cause complete remissions of relapsed lymphoma. We conducted the first clinical trial of anti-CD19 CAR T cells to show responses against lymphoma. This CAR was later developed as axicabtagene ciloleucel. Here, we aimed to assess the long-term durability of remissions and the long-term adverse effects after anti-CD19 CAR T-cell therapy. Methods: Between 2009 and 2015, we treated 43 patients with anti-CD19 CAR T cells preceded by conditioning chemotherapy of cyclophosphamide plus fludarabine (NCT00924326). Three patients were re-treated for a total of 46 CAR T-cell treatments. Twenty-eight patients had aggressive lymphoma (diffuse large B-cell lymphoma or primary mediastinal B cell lymphoma), eight patients had low-grade lymphoma (five with follicular lymphoma and 1 each with splenic marginal zone lymphoma, mantle cell lymphoma, and unspecified low-grade non-Hodgkin lymphoma), and seven patients had chronic lymphocytic leukemia (CLL). Patients were treated in three cohorts that differed in the CAR T-cell production process and conditioning chemotherapy dose. Results: Of the 43 treated patients, 63% had chemotherapy-refractory lymphoma. Patients had received a median of 4 previous lines of therapy. The median CAR+ T cell dose per kilogram was 2X10^6. The overall remission rate was 76% with 54% complete remissions (CR) and 22% partial remissions (PR). Patients with CR had higher median peak blood CAR levels (86 CAR+ cells/µL) than those who did not have CR (16 CAR+ cells/µL, P= 0.0041). Long-term adverse effects were rare except for B-cell depletion and hypogammaglobulinemia, which both improved over time. Conclusions: This is the longest follow-up study of patients who received anti-CD19 CAR T cells. Anti-CD19 CAR T cells cause highly durable remissions of relapsed B-cell lymphoma and CLL, and long-term adverse effects of anti-CD19 CAR T cells were rare and usually mild. Clinical trial information: NCT00924326 . [Table: see text]

scholarly journals ZUMA-11: A Phase 1/2 Multicenter Study of Axicabtagene Ciloleucel (Axi-Cel) + Utomilumab Patients with Refractory Large B Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4084-4084 ◽  
Author(s):  
Ran Reshef ◽  
David B. Miklos ◽  
John M. Timmerman ◽  
Caron A. Jacobson ◽  
Nabila N. Bennani ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Phase 2 ◽  
Car T Cells ◽  
Car T

Background: Relapsed/refractory (R/R) large B cell lymphoma (LBCL) is associated with poor outcomes to standard salvage therapy (Crump M, et al. Blood. 2017). In SCHOLAR-1, a large multicenter, patient-level, retrospective study, patients with R/R diffuse LBCL had a 26% objective response rate (ORR) to the next line of therapy, a 7% complete response (CR) rate, and a median overall survival of 6.3 months (Crump M, et al. Blood 2017). Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for patients with R/R LBCL with ≥ 2 prior systemic therapies. With a median follow-up of 27.1 months in ZUMA-1, the ORR with axi-cel was 83% (58% CR rate) in patients with refractory LBCL (Locke FL, et al. Lancet Oncol. 2019). Activation of the costimulatory receptor 4-1BB (CD137) on CAR T cells may enhance axi-cel antitumor activity by enhancing T cell proliferation, function, and survival. Utomilumab (uto), an investigational monoclonal antibody agonist of the 4-1BB pathway, enhanced T cell function and survival in preclinical studies (Fisher TS, et al. Cancer Immunol Immunother. 2012) and had favorable single-agent safety in patients (Segal NH, et al. Clin Cancer Res. 2018). Possible mechanisms of resistance to axi-cel are thought to be suboptimal CAR T cell expansion an exclusionary tumor microenvironment and CD19 target antigen loss (Neelapu SS, et al. Blood 2017, Rossi JM, et al J Immunother Cancer. 2018). Combination strategies that increase proliferation, expansion, and persistence of CAR T cells or prevent activation-induced cell death of CAR T cells may improve clinical outcomes observed with axi-cel. ZUMA-11 is a Phase 1/2 study investigating the efficacy and safety of axi-cel + uto in patients with refractory LBCL. Methods: The primary objectives of this study are to determine the safety, recommended Phase 2 dosing and timing (Phase 1), and efficacy (Phase 2) of axi-cel + uto in adult patients with refractory LBCL. Patients with progressive or stable disease as the best response to second-line chemotherapy or relapse ≤ 12 months after autologous stem cell transplantation, a prior anti-CD20 antibody and anthracycline-containing regimen, and Eastern Cooperative Oncology Group performance status 0-1 are eligible. Patients with histologically proven primary mediastinal B cell lymphoma, history of Richter's transformation or chronic lymphocytic lymphoma, prior CAR T cell therapy, or central nervous system involvement of lymphoma are ineligible. In Phase 1, ≈24 patients in ≤ 3 cohorts will receive a single dose of axi-cel and escalating doses of uto (10, 30, or 100 mg) using a 3 + 3 design in up to 4 of 6 cohorts. The recommended uto dose will be based on dose-limiting toxicities and other factors. Patients will be leukapheresed and may receive optional, nonchemotherapy bridging therapy per investigator decision. After conditioning chemotherapy, patients will receive a single infusion of axi-cel (target dose, 2 × 106 CAR T cells/kg) on Day 0 followed by uto on Day 1 and every 4 weeks for 6 months or until progressive disease. Patients will be treated one at a time during Phase 1, and patients treated with axi-cel will be staggered by ≥ 2 weeks. Day 21 uto administration will be explored if toxicity is unacceptable with Day 1 administration. The primary endpoints are incidence of dose-limiting toxicities in Phase 1 and CR rate in Phase 2. Secondary endpoints include ORR, duration of response, progression-free survival, overall survival, safety, and levels of CAR T cells and cytokines in blood. This study uses a single-arm design to estimate the true CR rate; with a sample size of 27 patients, of which ≤ 3 patients will have been treated in the Phase 1 portion, the maximum half-width of the 95% confidence interval about response will be ≥ 21%. ZUMA-11 is open and accruing patients. Disclosures Reshef: Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Incyte: Consultancy, Research Funding; Shire: Research Funding; BMS: Consultancy; Atara: Consultancy, Research Funding; Magenta: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy, Research Funding. Miklos:Pharmacyclics: Consultancy, Patents & Royalties, Research Funding; Precision Bioscience: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; Miltenyi: Consultancy, Research Funding; Becton Dickinson: Consultancy; Janssen: Consultancy; AlloGene: Consultancy; Novartis: Consultancy; Kite, A Gilead Company: Consultancy, Research Funding; Celgene-Juno: Consultancy. Timmerman:Spectrum Pharmaceuticals: Research Funding; Kite, A Gilead Company: Consultancy, Honoraria, Other: travel support, Research Funding; ImmunGene: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: travel support, Research Funding. Jacobson:Novartis: Consultancy, Honoraria, Other: travel support; Bayer: Consultancy, Other: travel support; Precision Biosciences: Consultancy, Other: travel support; Humanigen: Consultancy, Other: travel support; Celgene: Consultancy, Other: travel support; Pfizer: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: travel support. Bennani:Kite, A Gilead Company: Consultancy, Research Funding. Rossi:Kite, A Gilead Company: Employment. Sherman:Kite, A Gilead Company: Employment. Sun:Kite, A Gilead Company: Employment. Palluconi:Kite, A Gilead Company: Employment. Kim:Kite, A Gilead Company: Employment. Jain:Kite/Gilead: Consultancy.

scholarly journals Low Levels of Neurologic Toxicity with Retained Anti-Lymphoma Activity in a Phase I Clinical Trial of T Cells Expressing a Novel Anti-CD19 CAR

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 697-697 ◽  
Author(s):  
Jennifer Brudno ◽  
Steven Hartman ◽  
Norris Lam ◽  
David F. Stroncek ◽  
John M. Rossi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Antigen Recognition ◽  
Car T Cells ◽  
Car T

Abstract Anti-CD19 chimeric antigen receptor (CAR) T cells have powerful activity against B-cell lymphoma, but improvement is clearly needed. Toxicity, including cytokine-release syndrome (CRS) and neurologic toxicity, occurs after anti-CD19 CAR T cell infusions. Most CAR T-cell toxicity is caused, either directly or indirectly, by cytokines or other proteins that are secreted from CAR T cells. The structure of a CAR is an extracellular antigen-recognition domain connected by hinge and transmembrane (TM) domains to intracellular T-cell signaling moieties. In vitro, T cells expressing CARs with hinge and TM domains from the CD8-alpha molecule released significantly lower levels of cytokines compared with T cells expressing CARs with hinge and TM domains from CD28; however, T cells expressing CARs with hinge and TM domains from CD8-alpha retained sufficient functional capability to eradicate tumors from mice (Alabanza et al. Molecular Therapy. 2017. 25(11) 2452). To reduce cytokine production with a goal of reducing clinical toxicity, we incorporated CD8-alpha hinge and TM domains into an anti-CD19 CAR. The CAR also had a human antigen-recognition domain, a CD28 costimulatory domain, and a CD3-zeta domain. This CAR was designated Hu19-CD828Z and was encoded by a lentiviral vector. Hu19-CD828Z was different from the FMC63-28Z CAR that we used in prior studies. FMC63-28Z had hinge and TM domains from CD28 along with a CD28 costimulatory domain, a CD3-zeta domain, and murine-derived antigen-recognition domains. Twenty patients with B-cell lymphoma were treated on a phase I dose-escalation clinical trial of Hu19-CD828Z T cells (Table). Patients received low-dose cyclophosphamide and fludarabine daily for 3 days on days -5 to -3. Two days later, on day 0, CAR T cells were infused. The overall response rate (ORR) after 1st treatments with Hu19-CD828Z T cells was 70%, and the complete response (CR) rate 55%; the 6-month event-free survival was 55%. The anti-lymphoma activity of Hu19-CD828Z T cells in the current trial was comparable to the anti-lymphoma activity of FMC63-28Z T cells in a similar prior trial that also enrolled patients with advanced B-cell lymphoma. In the prior trial, we observed a 73% ORR, a 55% CR rate, and a 6-month event-free survival of 64% in 22 patients treated with FMC63-28Z T cells (Kochenderfer et al. Journ. Clin. Oncology. 2017 35(16) 1803). In our previous clinical trial of FMC63-28Z T cells, the rate of Grade 3 or 4 neurologic toxicity among 22 patients treated was 55%. Strikingly, in our trial of Hu19-CD828Z T cells, the rate of Grade 3 or 4 neurologic toxicity was only 5% (1/20 patients). In addition, the rate of Grade 2 or greater neurologic toxicity with FMC63-28Z T cells was 77.3% while the rate of Grade 2 or greater neurologic toxicity with Hu19-CD828Z T cells was 15%. To explore the mechanism for the difference in neurologic toxicity in patients receiving FMC63-28Z T cells versus Hu19-CD828Z T cells, we assessed serum levels of 41 proteins in patients treated with these CAR T-cells. This comparison is valid because the same Luminex methodology was used for the serum protein analysis for both trials, and controls of known amounts of each protein were assayed to ensure that protein levels were comparable on the different trials. Lower levels of several serum proteins that might be important in CAR toxicity were found in patients treated with Hu19-CD828Z T cells versus patients treated with FMC63-28Z T cells: Granzyme A (P<0.001), Granzyme B (P<0.001), interferon gamma (P=0.011), interleukin (IL)-15 (P=0.007), IL-2 (P=0.0034), and macrophage inflammatory protein-1A (P<0.001). Median peak patient blood CAR+ cell levels were 44 cells/µL for Hu19-CD828Z and 46.5 cells/µL for FMC63-28Z (P=not significant). We hypothesize that lower levels of potentially neurotoxic proteins in patients receiving Hu19-CD828Z T cells versus FMC63-28Z T cells led to a lower frequency of neurologic toxicity in patients receiving Hu19-CD828Z T cells. The lower levels of immunologically active proteins found in the serum of patients receiving Hu19-CD828Z T cells compared with patients receiving FMC63-28Z T cells is consistent with our in vitro experiments showing lower cytokine production by T cells expressing CARs with CD8 hinge and TM domains versus CD28 hinge and TM domains. Altering CAR hinge and TM domains can affect CAR T-cell function and is a promising approach to improve the efficacy to toxicity ratio of CAR T-cells. Disclosures Rossi: KITE: Employment. Shen:Kite, a Gilead Company: Employment. Xue:Kite, a Gilead Company: Employment. Bot:KITE: Employment. Rosenberg:Kite, a Gilead Company: Research Funding. Kochenderfer:Kite a Gilead Company: Patents & Royalties: CAR technology, Research Funding; Celgene: Research Funding.

scholarly journals Efficacy and Safety of CD19-Targeted CAR-T Cell Therapy for Refractory/Relapsed B-Cell Lymphoma: A Single Center of Real World Data

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4827-4827
Author(s):  
Jing Huang ◽  
Jia Fei ◽  
Ruiming Ou ◽  
Zhi Liu ◽  
Liling Zheng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Disease Progression ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Efficacy And Safety ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Abstract 【Abstract】 Objective To investigate the efficacy and safety of CD19-targeted chimeric antigen receptor T cell (CAR-T cell) for refractory/relapsed B-cell lymphoma. Methods The efficacy and safety of CD19-CAR-T cells(4-1BB costimulatory domain) in treatment of 12 patients with relapsed/refractory B-cell lymphoma from March 2018 to December 2019 in the Department of Hematology of Guangdong Second Province Hospital were collected analyzed retrospectively. There were 9 patients (75%) with diffuse large B cell lymphoma, 1 patient with blastic variant of mantle cell lymphoma, 1 patient(8.3%) with Burkitt lymphoma, 1 patient with B cell non-Hodgkin lymphoma that cannot be classified. 3 patients (25%) with large mass (≥7.5cm) and 9 patients (75%) with ECOG score ≥2. The number of chemotherapy courses received before transfusion was 4-9, the median number of chemotherapy courses was 7. All 12 patients were autogenous mouse CAR-T cells. Fludarabine + Cyclophosphamide (FC) regimen was used for pretreatment before transfusion, and the number of CAR-T cells was 1 ~ 3.69×10 6/kg. Results All 12 patients received CD19-targeted CAR-T cell therapy. There were 9 patients had treatment response, and the total effective rate was 75%. Among them, there were 3 patients with complete response (CR), with CR rate of 25%, and 6 patients with partial response (PR), with PR rate of 50%. Among the 3 patients with CR remained CR at the follow-up date. Among the 6 patients with PR, 4 showed disease progression in the second month after transfusion, and 2 showed disease progression in the third month after transfusion. All the 9 patients with effective treatment had different degrees of cytokine release syndrome (CRS), including 3 level-1 CRS, 4 level-2 CRS, and 2 level-3 CRS. Two of them had grade 2 CRES, and all CRS and CRES were controlled after treatment with IL-6 receptor antagonists and glucocorticoids. None of the 3 patients failed to respond to treatment had CRS. Conclusion CD19-targeted CAR-T cell immunotherapy has been shown to be effective in CD19-antigen positive B-cell lymphoma, and adverse CRS reactions during treatment can be controlled after treatment. Patients who obtained CR seemed to be able to maintain long-term CR status, while patients who failed to obtain CR showed disease progression within a short period of 3 months, suggesting that patients who obtained CR at an early stage could achieve better efficacy. Therefore, how to identify patients who receive CR at an early stage may be a research direction for the clinical application of CAR-T cell immunotherapy in B-cell lymphoma. 【Key words】Chimeric antigen receptor T-cell; Relapsed/refractory B cell lymphoma; Efficacy; Safety; Cytokine release syndrome Disclosures No relevant conflicts of interest to declare.

scholarly journals Ibrutinib before Apheresis May Improve Tisagenlecleucel Manufacturing in Relapsed/Refractory Adult Diffuse Large B-Cell Lymphoma: Initial Results from a Phase 1b Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 3-4
Author(s):  
Julio C. Chavez ◽  
Frederick L. Locke ◽  
Ellen Napier ◽  
Carl Simon ◽  
Andrew Lewandowski ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Biomedical Research ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Background: Tisagenlecleucel (tisa-cel), an autologous anti-CD19 chimeric antigen receptor (CAR)-T cell therapy, has demonstrated durable responses and a manageable safety profile in adult patients (pts) with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). It has previously been suggested that prior therapy with ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, may improve tisa-cel manufacturing, in vivo cellular kinetics, and antitumor efficacy (Fraietta et al. Blood. 2016). Moreover, since BTK signaling is involved in direct pro-inflammatory polarization of macrophages, as well as indirectly by T cells, it is hypothesized that ibrutinib may mitigate CAR-T cell-related toxicities such as cytokine release syndrome (CRS) and neurological events (NE). We report the initial results from a Phase Ib, multicenter, open-label trial evaluating the safety and tolerability of tisa-cel in combination with ibrutinib in adult pts with r/r DLBCL. Methods: Adult pts with r/r DLBCL who received &gt;2 prior lines of systemic therapy, including pts who progressed after or were ineligible for autologous stem cell transplant, were enrolled. The study design has 2 nonrandomized arms. In Arm 1, pts received ibrutinib 560 mg/d for ~4 weeks prior to leukapheresis; in Arm 2, pts were exposed to ibrutinib after leukapheresis. In both arms, ibrutinib was continued throughout lymphodepleting chemotherapy, tisa-cel infusion, and post infusion for up to 24 months. Lymphodepleting chemotherapy, ending at least 2 days before tisa-cel infusion, was either fludarabine (25 mg/m2) and cyclophosphamide (250 mg/m2) daily for 3 days or bendamustine (90 mg/m2) daily for 2 days. Pts received a single infusion of tisa-cel (target dose: 0.6-6.0×108 viable CAR+ T cells). Primary endpoints are incidence and severity of adverse events and ibrutinib dose interruptions/modifications. Secondary endpoints include best overall response (BOR) by Lugano criteria and cellular kinetics of tisa-cel. Results: As of June 9, 2020, 10 pts have been treated and observed through at least the Day 28 assessment: 4 in Arm 1 and 6 in Arm 2. Median age was 59 (range, 32-67) in Arm 1 and 64 (range, 58-76) in Arm 2. Median number of prior therapies was 3.5 (range, 2-5) in Arm 1 and 2 (range, 2-3) in Arm 2. Three of 10 pts (Arm 1, n=1; Arm 2, n=2) had an activated B-cell-like subtype of DLBCL. Six of 10 pts (Arm 1, n=1; Arm 2, n=5) had grade 1 CRS (by Lee scale) and 1 pt had NE (Arm 2, grade 1 by ASTCT criteria; Table). One pt in Arm 2 had grade 3 neutropenia lasting &gt;28 days post tisa-cel infusion. No other pts had grade 3 or 4 neutropenia or thrombocytopenia lasting &gt;28 days. No major bleeding events were observed. Ibrutinib-related bradycardia and atrial fibrillation (both grade 2) were each observed in 1 pt in Arm 1; supraventricular tachycardia (grade 1) related to tisa-cel was observed in 1 pt in Arm 2. No pt required tocilizumab or ICU admission. As of data cutoff, BOR in Arm 1 was complete response (CR) in 2 pts and partial response (PR) in 2 pts, with no relapses. BOR in Arm 2 was CR in 2 pts, PR in 1 pt, and progressive disease in 3 pts (Table). CAR-T cell expansion in vivo by qPCR was in line with data from the pivotal JULIET trial, except for 1 pt in Arm 2 whose transgene levels were below the limit of quantification at all points in time and who progressed at Day 28. Median viability of the leukapheresis material was 96.80% (range, 88.8-97.3) in Arm 1 and 90.95% (range, 88.1-94.7) in Arm 2. A naïve/stem cell-like central memory phenotype (CD45RA+/CCR7+) was observed in 24.05% (median; range, 15.9-37.0) of CD8+ T cells in the leukapheresis material for Arm 1 and in 8.12% (median; range, 1.3-20.4) for Arm 2 (Fig.1A). Fig.1B shows total CAR+ manufactured cells in each arm. The median dose of the final product was 3.9×108 CAR+ T cells in Arm 1 (range, 3.4-4.6×108 CAR+ T cells; median viability 92.25%) and 1.7×108 CAR+ T cells in Arm 2 (range, 1.2-3.0×108 CAR+ T cells; median viability 85.8%; Fig.1C). IFNγ secretion of tisa-cel in vitro in response to CD19+ target cells was similar between the 2 arms, whereas median normalized IL-2 responses were 23.1 fg/CAR+ cell in Arm 1 (range, 16.7-43.8) and 1.1 fg/CAR+ cell in Arm 2 (range, 0-17.3). Conclusions: These results support the feasibility of administering ibrutinib to pts with DLBCL throughout tisa-cel therapy. When given before apheresis, ibrutinib may improve CAR-T cell manufacturing, although further studies are needed to confirm this finding. Disclosures Chavez: AstraZeneca: Speakers Bureau; Morphosys: Consultancy, Speakers Bureau; Merck: Research Funding; Bayer: Consultancy; BeiGene: Speakers Bureau; Karyopharm: Consultancy; Genentech: Speakers Bureau; AbbVie: Consultancy; Epizyme: Speakers Bureau; Gilead: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Speakers Bureau; Verastem: Consultancy; Pfizer: Consultancy. Locke:Kite, a Gilead Company: Consultancy, Research Funding; Calibr: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; GammaDelta Therapeutics: Consultancy; Cellular Biomedicine Group: Other: Consultancy with grant options; Allogene: Consultancy; Wugen: Consultancy. Simon:Novartis: Current Employment. Lewandowski:Novartis Institutes for BioMedical Research: Current Employment. Awasthi:Novartis Institutes for BioMedical Research: Current Employment. Engels:Novartis Institutes for BioMedical Research: Current Employment. Georgala:Novartis Pharmaceuticals Corporation: Current Employment. Bondanza:Novartis Institutes for BioMedical Research: Current Employment. Schuster:AlloGene, AstraZeneca, BeiGene, Genentech, Inc./ F. Hoffmann-La Roche, Juno/Celgene, Loxo Oncology, Nordic Nanovector, Novartis, Tessa Therapeutics: Consultancy, Honoraria; Novartis, Genentech, Inc./ F. Hoffmann-La Roche: Research Funding.

scholarly journals Final Results of a Phase 1 Study of AntiCD19 CAR-T Cells with TNFRSF19 Transmembrane Domain

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3833-3833
Author(s):  
Paolo F. Caimi ◽  
Armin Ghobadi ◽  
Jane Reese ◽  
Benjamin Tomlinson ◽  
Folashade Otegbeye ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Transmembrane Domain ◽  
B Cell Lymphoma ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Abstract Background: AntiCD19 CAR-T cells are effective against chemorefractory B cell lymphoma. Patients (pts) with rapidly progressive disease and urgent need for therapy have very poor prognosis and may not be able to receive CAR-T cells in time. Decreasing the apheresis to infusion time can make CAR-T cells rapidly available. We conducted a dual-center phase I trial using on-site manufacture of CAR-T cells for treatment of relapsed and refractory (r/r) B cell lymphoma. Methods: Adult pts with r/r CD19+ B cell lymphomas who failed ≥ 2 lines of therapy were enrolled. Autologous T cells were transduced with a lentiviral vector (Lentigen Technology, Inc, LTG1563) encoding an antiCD19 binding motif, CD8 linker, TNFRS19 transmembrane region, and 4-lBB/CD3z intracellular signaling domains. GMP-compliant manufacture was done using CliniMACS Prodigy in a 12-day culture, subsequently shortened to 8 days. Dose escalation was done using 3+3 design. Lymphodepletion included cyclophosphamide (60mg/kg x 1) and fludarabine (25mg/m2/d x 3). Cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) were graded using the Lee and CARTOX criteria, respectively. CAR-T persistence was measured with qPCR and flow cytometry. Plasma cytokine concentrations were measured using electrochemiluminescence (MesoScale Diagnostics, Inc). Results: Thirty-one pts were enrolled and treated. Baseline patient and disease characteristics are listed in table 1. Twenty-nine (94%) pts were refractory to the prior line of therapy and 21 (68%) had symptomatic disease at the time of lymphocyte collection. CAR-T cell product manufacture was successful in all pts. Median transduction rate was 45% [range 15-66], median culture expansion was 36-fold [range 3-79]. CAR-T cell doses were 0.5 x 10 6/kg (n = 4), 1 x 10 6/kg (n = 16), and 2 x 10 6/kg (n = 11). Median time from apheresis to lymphodepletion was 7 days (range 2 - 15) and median time from apheresis to CAR-T cell infusion time was 13 days (range 9 - 20). Twenty-eight pts were infused fresh product. Seventeen pts (55%) experienced CRS. Grade 1-2 CRS was observed in 15 pts (48%), grade ≥ 3 was observed in 3 pts (10%). One patient had grade 4 CRS that was later complicated by hemophagocytic syndrome and died on day 21; a second patient had grade 5 CRS in the context of bulky disease and died on day 8. Ten pts (32%) had ICANS and 4 pts had grade 3-4 ICANS. Treatment for CRS / ICANS included tocilizumab (n = 12), siltuximab (n = 4), anakinra (n = 3) and corticosteroids (n = 10). The most common all grade non - hematologic toxicity was fatigue, observed in 19 pts, all grade 1. Hematologic toxicity was common, with grade ≥ 3 neutropenia observed in all subjects. Twenty-five (81%) presented disease response and twenty-two pts (71%) achieved complete response (CR). There were no statistically significant differences in the overall and complete response rates between dose levels. After a median follow up of 18 months (range 1 - 32), 5 pts relapsed, and 7 pts have died. Causes of death include progressive disease (n=5), CRS (n=1) and CRS/HLH (n=1). Two-year estimates of PFS and OS for the whole cohort were 67% (95%CI 52-88%) and 75% (95%CI 60-93%)(fig1), respectively. Two-year estimates for patients achieving disease response (CR or PR) were 82% (95%CI 67-99%) and 90% (95%CI 78-100%), respectively. The median duration of response has not been reached (95% CI 74-100). Among pts achieving CR, 94% (95% CI 61-100%) had sustained remission at 12 months. Median time to peak CAR-T expansion, measured by PCR, was 14 days (IQR 14-19), without differences between dose levels, culture duration or fresh vs. cryopreserved infusion. All evaluable subjects had persistent CAR-Ts on PCR measurements done on days 30, 60 and 90. CAR-T cell dose did not have an impact in the time to peak in vivo CAR-T cell expansion or in the rate of CAR-T cell persistence (fig 2). Cytokine measurements have been conducted in 19 pts, with area under the curve (AUC) analyses showing pts with CRS had higher plasma concentrations of multiple cytokines (fig 3). Patients achieving CR had higher plasma concentrations of MIP3B. Conclusions: Second generation antiCD19 CAR-T cells with TNFRS19 transmembrane domain have potent clinical activity. On-site manufacture was successful in all pts. This strategy, in combination with fresh product infusion, can make CAR-T cell therapy rapidly available for pts with high-risk r/r B cell lymphoma. Figure 1 Figure 1. Disclosures Caimi: Amgen Therapeutics.: Consultancy; TG Therapeutics: Honoraria; XaTek: Patents & Royalties: Royalties from patents (wife); Kite Pharmaceuticals: Consultancy; Genentech: Research Funding; ADC Theraputics: Consultancy, Research Funding; Seattle Genetics: Consultancy; Verastem: Consultancy. Ghobadi: Wugen: Consultancy; Atara: Consultancy; Amgen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Celgene: Consultancy. Schneider: Lentigen Technology: Current Employment. Boughan: Beigene: Speakers Bureau. Metheny: Incyte: Speakers Bureau; Pharmacosmos: Honoraria. Krueger: Lentigen: Current Employment. Kadan: Lentigen: Current Employment. Orentas: Lentigen: Patents & Royalties. Dropulic: Lentigen: Ended employment in the past 24 months, Patents & Royalties. de Lima: Miltenyi Biotec: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: AntiCD19 CAR-T cells with TNFRSF19 transmembrane domain for treatment of relapsed and refractory B cell lymphomas.

scholarly journals Lenalidomide Enhance CAR T-Cells Response in Patients with Refractory/Relapsed Large B Cell Lymphoma Experiencing Progression after Infusion

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 16-17
Author(s):  
Catherine Thieblemont ◽  
Sylvie Chevret ◽  
Vincent Allain ◽  
Roberta Di Blasi ◽  
Florence Morin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Response Rate ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Car T Cells ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T

Background. Anti-CD19 Chimeric Antigen Receptor (CAR) T-cells is a major therapeutic advance in the management of patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). However, some patients will experience progression or relapse after infusion. Treatment of these relapses or progressions is not standardized and is usually based on strategies that will avoid the destruction of the CAR T-cells, such as immuno-oncology drugs. Lenalidomide is reported to activate CD8 T cells, inhibit regulatory T cells and restore T-cell immune synapse. We report here our experience of Lenalidomide in the treatment of progression or relapse after CAR T-cells infusion. Methods. Between June 2018 and July 2020, 111 patients with R/R DBLCL were treated with commercialized anti-CD19 CAR T-cells, axicabtagene ciloleucel (axi-cel yescarta) (n=60) or tisagenlecleucel (Tisa-cel kymriah) (n=51). Relapse and progression after CAR T-cells was defined based on the Cheson 2014 criteria. Efficacy of the treatment proposed at time of relapse post-CAR T-cells was assessed by CT scan and 18FDG-PET after the 1st cycle and at the end of treatment. CAR-T expansion was regularly monitored in blood by flow cytometry. Results. In the whole cohort, the clinical characteristic was a median age at 61.9 (range 23 to 77), male n=73 (66%). Histology subtypes were DLBCL (n=90) (including GC n=39 and non-GC n=37), PMBL (n=6), Tr FL (n=15). 85 (76.6%) patients presented a primary refractory lymphoma. IPI included 30 low risk, 23 low-intermediate, 23 high-intermediate and 14 high risk. The median number of lines of treatment before CAR T cells infusion was 3 (IQR, 2 to 4) ranging from 1 to 9. At time of infusion, median total metabolic tumor volume (TMTV) was 52.4 (IQR, 12.1 to 170.1), ranging from 1.44 to 4247. Fifty-nine patients failed after Tisa-cel (n=33) of Axi-cel (n=26) infusion. Failure occurred after CAR T-cell within a median time of 6 months; 16 (27%) of the failures occurred before day 15 (D15), 27 (45.8%) during the first month after infusion (&lt;M1), and 45 (76.3%) during the first-3 months after infusion (&lt;M3). At failure, the patients received lenalidomide (LEN) (n=41, 69.5%) with (n=30) or without (n= 10) rituximab (R) or Obinutuzumab (O) (n=1); immune-checkpoint inhibitor including Pembrolizumab (n=2); BTK inhibitor (n=1); BET inhibitor (n=1); chemotherapy or immune-chemotherapy (n=3); radiotherapy (n=2). Six (10.2%) patients received palliative care only and three (5.1%) patients died before receiving further treatment. The best overall response rate was observed in 16 (27.1%) of the patients, including best complete response in 9 and best partial response in 7; 35 progressed. The median progression-free survival was 101 days, and the median overall survival 225 days. Considering the cohort of patients who received LEN, the 11 patients who started LEN+/-R or O before D15 post-CAR T-cell infusion (group ≤D15) experienced a higher ORR (7/11, 63.6% vs 9/48, 18.8%, p=0.006), and a higher CR rate (4/11, 36.4% vs 5/48, 10.4%, p=0.05). In univariate analysis, the 6 evaluable patients with early LEN (≤D15) had a higher CART expansion in blood during the first 28 days (median AUC D0-D28=1363 days*CART Cells number/µL of total blood) than other relapsing patients (median=97, p=0.042), including those treated with LEN after D15 (median=56, p=0.033), or even than patients without relapse (median=277, p=0.069). Conclusion. LEN used at time of relapse post-CAR T-cell may provide high response rate, particularly in patients receiving LEN early after infusion. Comprehensive analyses of the anti-tumoral effect, but also an immunomodulatory effect mechanisms using tumor transcriptomic and single cell analyses will be presented. Disclosures Thieblemont: Cellectis: Speakers Bureau; Roche, Amgen, Kyte Gilead, Celgene, Abbvie, Novartis, Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche, Hospita: Research Funding. Roulland:Celgene/BMS: Research Funding; Roche: Honoraria.

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