Chimeric Antigen Receptor-Engineered T-Cells - A New Way and Era for Lymphoma Treatment

2020 ◽  
Vol 14 (4) ◽  
pp. 312-323
Author(s):  
Romeo G. Mihăilă
Keyword(s):  
T Cells ◽  
T Cell ◽  
Response Rate ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Car T Cells ◽  
Future Developments ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T

Background: Patients with refractory or relapsed diffuse large B-cell lymphoma have a poor prognosis with the current standard of care. Objective: Chimeric Antigen Receptor T-cells (CAR T-cells) are functionally reprogrammed lymphocytes, which are able to recognize and kill tumor cells. The aim of this study is to make progress in this area. Method: A mini-review was achieved using the articles published in Web of Science and PubMed in the last year and the new patents were made in this field. Results: The responses to CAR T-cell products axicabtagene ciloleucel and tisagenlecleucel are promising; the objective response rate can reach up to 83%, and the complete response rate ranges between 40 and 58%. About half of the patients may have serious side effects, such as cytokine release syndrome and neurotoxicity. Current and future developments include the improvement of CAR T-cell expansion and polyfunctionality, the combined use of CAR T-cells with a fusion protein between interferon and an anti-CD20 monoclonal antibody, with checkpoint inhibitors or small molecule sensitizers that have apoptotic-regulatory effects. Furthermore, the use of IL-12-expressing CAR T-cells, an improved technology for the production of CAR T-cells based on targeted nucleases, the widespread use of allogeneic CAR T-cells or universal CAR T-cells obtained from genetically engineered healthy donor T-cells are future developments actively considered. Conclusion: CAR T-cell therapy significantly improved the outcome of patients with relapsed or refractory diffuse large B-cell lymphoma. The advances in CAR T-cells production technology will improve the results and enable the expansion of this new immunotherapy.

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 (<M1), and 45 (76.3%) during the first-3 months after infusion (<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.

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.

scholarly journals CAR T cells or allogeneic transplantation as standard of care for advanced large B-cell lymphoma: an intent-to-treat comparison

2020 ◽  
Vol 4 (24) ◽  
pp. 6157-6168
Author(s):  
Peter Dreger ◽  
Sascha Dietrich ◽  
Maria-Luisa Schubert ◽  
Lorenz Selberg ◽  
Andrea Bondong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Standard Of Care ◽  
Car T Cells ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T ◽  
Large B Cell

Abstract CD19-directed chimeric antigen receptor (CAR) T-cell treatment has evolved as standard of care (SOC) for multiply relapsed/refractory (R/R) large B-cell lymphoma (LBCL). However, its potential benefit over allogeneic hematopoietic cell transplantation (alloHCT) remains unclear. We compared outcomes with both types of cellular immunotherapy (CI) by intention to treat (ITT). Eligble were all patients with R/R LBCL and institutional tumor board decision recommending SOC CAR T-cell treatment between July 2018 and February 2020, or alloHCT between January 2004 and February 2020. Primary end point was overall survival (OS) from indication. Altogether, 41 and 60 patients for whom CAR T cells and alloHCT were intended, respectively, were included. In both cohorts, virtually all patients had active disease at indication. CI was recommended as part of second-line therapy for 21 alloHCT patients but no CAR T-cell patients. Median OS from indication was 475 days with CAR T cells vs 285 days with alloHCT (P = .88) and 222 days for 39 patients for whom alloHCT beyond second line was recommended (P = .08). Of CAR T-cell and alloHCT patients, 73% and 65%, respectively, proceeded to CI. After CI, 12-month estimates for nonrelapse mortality, relapse incidence, progression-free survival, and OS for CAR T cells vs alloHCT were 3% vs 21% (P = .04), 59% vs 44% (P = .12), 39% vs 33% (P = .97), and 68% vs 54% (P = .32), respectively. In conclusion, CAR T-cell outcomes were not inferior to alloHCT outcomes, whether measured by ITT or from CI administration, supporting strategies preferring CAR T cells over alloHCT as first CI for multiply R/R LBCL.

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.

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 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 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 Axicabtagene ciloleucel in vivo expansion and treatment outcome in aggressive B-cell lymphoma in a real-world setting

2021 ◽  
Vol 5 (11) ◽  
pp. 2523-2527
Author(s):  
Francis A. Ayuk ◽  
Carolina Berger ◽  
Anita Badbaran ◽  
Tatjana Zabelina ◽  
Tanja Sonntag ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Platelet Counts ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Peak Car ◽  
Aggressive B Cell Lymphoma

Abstract Data on the association between chimeric antigen receptor (CAR)-T-cell kinetics and patient outcome in the nontrial setting are missing, mainly due to the lack of broadly available CAR-T-cell diagnostic quantification tools. We performed prospective quantification of axicabtagene ciloleucel (axi-cel) in 21 patients treated for aggressive B-cell lymphoma at our clinic. Median peak CAR-T-cell count was 16.14 CAR-T cells/µL. Patients with 16.14/μL or higher peak CAR-T cells (strong expanders) had more day-30 objective responses (91% vs 40%, P = .02). In univariate analysis, peak CAR-T cell ≥ 16.14 (P &lt; .001), normal platelet counts at start of lymphodepletion (P &lt; .001), no prior stem cell transplant (P = .04), and peak CAR-T cells as continuous variable (P = .03) were associated with better progression-free survival (PFS). After adjusting for platelet counts and prior stem cell transplantation, peak CAR-T cells below median was still associated with shorter PFS (relative risk, 0.15, 95% confidence interval, 0.04-0.59, P = .007). Low platelet counts also maintained significant impact on PFS. Our data demonstrate association of axi-cel levels and outcome in a nontrial setting and for the first time use a cutoff to segregate weak and strong expanders with respective outcomes.

scholarly journals Development of Novel CAR Therapies for Diffuse Large B-Cell Lymphoma Using Genome-Wide Overexpression Screens

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1726-1726
Author(s):  
Mat Legut ◽  
Zoran Gajic ◽  
Maria Guarino ◽  
Eleni Mimitou ◽  
Stephanie Hao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T ◽  
Large B Cell

Abstract Despite recent therapeutic advances in the management of non-Hodgkin lymphoma (NHL), up to 50% of patients with diffuse large B-cell lymphoma (DLBCL) relapse after first line therapy, and for DLBCL patients who relapse within 12 months after subsequent stem cell transplant (SCT), the median overall survival (OS) is 6.3 months. Recently, chimeric antigen receptor (CAR) T-cell therapy has shown remarkable activity in relapsed DLBCL with complete response (CR) rate of 40% and 54% for the two of the FDA-approved CAR T-cell products, tisagenlecleucel and axicabtagene ciloleucel, respectively. However, at a median follow-up of 18 months, only 36% of patients treated with tisagenlecleucel remained in CR; with longer follow-up for axicabtagene ciloleucel the median progression free survival (PFS) was 5.9 months. Immune escape and immune evasion are primary mechanisms of CAR-T resistance; clearly improvements are needed to increase response rate and cure. While CRISPR-based loss-of-function screens have shown promise for high-throughput identification of genes that modulate T-cell response, these methods have been limited thus far to negative regulators of T-cell functions, and raise safety concerns due to the permanent nature of genome modification. Here we identify positive T-cell regulators via overexpression of ~12,000 barcoded human open reading frames (ORFs). Using this genome-scale ORF screen, we found modulator genes which increased primary human CD4+ and CD8+ T-cell proliferation, including activation markers like CD25 and CD40L, and secretion of key cytokines like interleukin-2 and interferon-gamma. In addition, we developed a single-cell genomics method (OverCITE-seq) for high-throughput quantification of the transcriptome and surface proteome in ORF-engineered T-cells. The top-ranked ORF, lymphotoxin beta receptor (LTBR), is typically expressed in a subset of myeloid cells but absent in lymphocytes. When expressed in T-cells, LTBR induces a profound transcriptional remodelling, resulting in increased resistance to exhaustion and activation-induced apoptosis, as well as upregulation of a plethora of proinflammatory cytokines, co-stimulatory molecules and antigen presentation machinery. In order to investigate the mechanism of action of LTBR, we developed an epistasis assay which allows for simultaneous gene knockout and LTBR overexpression in primary T cells. Thus, LTBR appears to induce both canonical and non-canonical NFkB pathways - but the phenotype observed in T cells is dependent only on the former. Finally, we co-expressed several top-ranked genes, including LTBR, with FDA approved CD19-targeting CARs utilizing either 4-1BB or CD28 co-stimulatory domains. In line with previous results, co-expression of top-ranked ORFs increased proinflammatory cytokine secretion and cytotoxicity against CD19+ positive cancer cell lines. This functional improvement was also observed when top-ranked ORFs and CARs were delivered to T cells isolated from DLBCL patients as shown in Figure 1. Our results provide several strategies for improving next generation CAR T-cell therapies via induction of new synthetic cell programs which may optimize immune activation and enhance the efficacy of these important therapies, a high priority for patients with relapsed and refractory DLBCL and other lymphomas. Figure 1 Figure 1. Disclosures Mimitou: Immunai: Current Employment. Smibert: Immunai: Current Employment. Diefenbach: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; IMab: Research Funding; Gilead: Current equity holder in publicly-traded company; Celgene: Research Funding; AbbVie: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; Morphosys: Consultancy, Honoraria, Research Funding; MEI: Consultancy, Research Funding; Perlmutter Cancer Center at NYU Langone Health: Current Employment; Incyte: Research Funding; Trillium: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Genentech, Inc./ F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding. Sanjana: Qiagen: Consultancy; Vertex: Consultancy.

scholarly journals Unbiased Metabolomic Screening Reveals Pre-Existing Plasma Signatures in Large B-Cell Lymphoma Patients Treated with Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cells: Association with Cytokine Release Syndrome (CRS) and Neurotoxicity (ICANS)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 42-43
Author(s):  
Akansha Jalota ◽  
Courtney E. Hershberger ◽  
Manishkumar S. Patel ◽  
Agrima Mian ◽  
Daniel M. Rotroff ◽  
...  
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T Cell Therapy ◽  
Car T

Background: CAR T-cells that target CD19 have been approved by the FDA for treatment of relapsed/refractory large B cell lymphoma (r/r LBCL). Despite clinical efficacy in chemo-refractory patients, the benefit of this approach is often complicated by potentially severe toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The physiological basis of these limitations remains poorly understood, and represents an unmet clinical need. Metabolomics is a global approach that can be used to identify diverse low molecular weight biochemical entities with a wide range of functions. In this study we have employed an untargeted metabolomics approach to identify novel metabolites present in the plasma of patients treated with CAR T-cell therapy that associate with clinical outcomes and toxicities of treatment. Methods: Peripheral blood specimens were collected at the time of apheresis from 41 r/r LBCL patients treated with Axicabtagene Ciloleucel (Axi-cel; n=31) and Tisagenlecleucel (Tisa-cel; n=10). Baseline clinical characteristics and details of prior treatment were captured for all patients. Response outcomes and toxicity grading as measured by ASTCT consensus criteria for CRS and ICANS were recorded. Plasma was isolated from blood and analyzed for metabolites using a commercial Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectrometry platform. Association analysis was performed using ordinal logistic regression to identify the metabolites whose plasma abundance at the time of apheresis correlated with ICANS and CRS grade (FDR ≤0.2). In addition, significant metabolites were utilized to identify perturbations of biologically relevant pathways associated with CRS/ICANS grade. Results: The median age of patients studied was 61 (range 25 - 77), with 25 (61%) males. All patients were previously treated with R-CHOP or R-EPOCH. Twenty (48.8%) patients had high or high-intermediate IPI at baseline. The patients had received a median of 3 (range, 2-6) lines of therapy prior to CAR T-cell therapy, with 21 (51.22%) having received prior autologous stem cell transplantation. At the 3-month time point, response evaluation was available for 28 Axi-cel and 10 Tisa-cel recipients. An objective response was seen in 16 (57%) and 2 (20%) patients, and death was documented in 3 (11%) and 2 (20%) patients, in the Axi-cel and Tisa-cel groups, respectively. Untargeted metabolomics revealed a total of 1,241 metabolites, detected in positive, negative and polar modes, of which 1,011 were named. These include lipids, amino acids, xenobiotics, nucleotides, partially characterized compounds, cofactors and vitamins. In examining toxicities of CAR-T cell treatment, we identified three metabolites whose abundance was negatively associated with ICANS grade (FDR ≤0.2), indicating that high abundance of these metabolites at the time of apheresis was associated with a decreased risk of (i.e. protection from) ICANS. Plasma metabolites were also found to be associated with CRS, with 23 associated with an increased risk (i.e. predisposing to) of CRS, and 204 associated with decreased risk (i.e. protection from) of CRS. Using a hypergeometric test for over-represented metabolites in the KEGG metabolic pathways (FDR ≤0.2), caffeine metabolism, glycine, serine, and threonine metabolism, arginine biosynthesis, and aminoacyl-tRNA biosynthesis were identified as the most significantly represented pathways. Conclusion: Pre-existing biochemical signatures present in the plasma at the time of apheresis are strongly associated with toxicities observed in response to commercial CD19 CAR T-cell therapies. These endogenous metabolites may serve as biomarkers for monitoring risk of toxicity associated with CD19 CAR T cell treatment and provide insight into rational clinical interventions to mitigate such risks. Disclosures Rotroff: Interpares Biomedicine LLC.: Current equity holder in publicly-traded company; CAR-T Response: Patents & Royalties. Hill:Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; AstraZenica: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding.

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