BASELINE CLINICAL AND PET-CT TUMOR BURDEN PARAMETERS DO NOT PREDICT OUTCOME OF RELAPSE/REFRACTORY AGGRESSIVE B CELL LYMPHOMA PATIENTS TREATED WITH ANTI-CD19 CAR T-CELLS

2019 ◽  
Vol 37 ◽  
pp. 504-505
Author(s):  
A. Avigdor ◽  
T. Davidson ◽  
A. Shimoni ◽  
R. Yerushalmi ◽  
N. Shem-Tov ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Tumor Burden ◽  
Car T Cells ◽  
Pet Ct ◽  
Car T ◽  
Aggressive B Cell Lymphoma

scholarly journals CD19/CD22 Dual-Targeted Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory Aggressive B-Cell Lymphoma: a Safety and Efficacy Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-34
Author(s):  
Yongxian Hu ◽  
Yanlei Zhang ◽  
Houli Zhao ◽  
Yiyun Wang ◽  
Arnon Nagler ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Target Cells ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T ◽  
Aggressive B Cell Lymphoma

Introduction Chimeric antigen receptor (CAR)-T-cell therapy has revolutionized the treatment of relapsed/refractory (R/R) B-cell hematological malignancies, primarily acute lymphoblastic leukemia (ALL), and B-cell non-Hodgkin lymphoma (NHL). CD19 CAR-T cells have been extensively studied and have been shown to yield complete remission (CR) rates of about 90% in R/R ALL, but substantially lower (50%) rates in R/R NHL. Moreover, persistence is usually limited, and antigen escape-mediated relapse is a major limitation. Dual CAR-T cells targeting both CD19 and CD22 may address these limitations. Patients and methods We developed a bispecific CAR-T cells that could concomitantly recognize CD19- and CD22-expressing targets by incorporating both CD19 and CD22 single-chain variables in a single CAR construct (Figure 1A). We designed a prospective study to assess the safety and efficacy profiles of the dual CAR-T therapy in patients with R/R aggressive B-cell lymphoma. Results The preclinical cytotoxicity evaluation of the CD19/CD22 dual-targeted CAR-T cells was performed in comparison with mono-specific CD19-BB-002 and CD22-BB-002 CAR-T cells in HeLa cells that were engineered to express CD19, CD22, or both antigens. The dual-antigen specific CAR-T cells performed equally well when compared with the mono-specific CAR-T cells when there was only a single antigen present on the target cells; better performance was observed when both antigens were present on target cells (Figure 1B). In addition, the dual-antigen specific CAR-T cells induced equal amounts of interleukin (IL)-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon (IFN)-γ, when compared with the two mono-specific CAR-T cells (Figure 1C). Furthermore, the CD19 CAR-T cells induced more IL-2 and tumor necrosis factor (TNF)-α than the CD22 CAR-T cells and dual-antigen CAR-T cells. However, in the presence of both CD19 and CD22 antigens, the dual-specific CAR-T cell tended to produce more granzyme B, which may explain the higher degree of cytotoxicity when compared with the two mono-specific CAR-T cells (Figure 1D). Twenty-four patients were screened. Of the 16 eligible patients 14 (87.5%) achieved objective response (RR), with 10 (62.5%) achieving complete response (CR). The 2-year overall survival (OS) and progression-free survival (PFS) rates were 77.3% and 40.2%, respectively (Figure 2A). Achieving CR (HR: 0.017, 95% CI: 0.000-0.935; P=0.046) and number of prior lines of chemotherapy (n=2) (HR:135.784, 95% CI: 1.069-17248.110, P=0.047) were found as independent prognostic factors associated with favorable PFS. The 2-year OS and PFS of the CR patients were higher than those of the non-CR patients (100% versus 41.7%, P=0.015; 66.7% versus 0%, P < 0.001), respectively (Figure 2B). The 2-year PFS in patients received 2 prior lines of chemotherapy was higher as compared to those that received more than 2 lines of chemotherapy (68.6% versus 16.7%, P=0.049) whereas the OS in the 2 groups did not differ significantly (83.3% and 71.1%, P=0.613) (Figure 2C). Severe grade 3 cytokine release syndrome (CRS) was observed in only one patient, while 4 had grade one and 11 had grade 2, respectively. No patient developed neurotoxicity. Conclusions Immunotherapy with a novel CD19/CD22 dual targeted CAR-T cells yields a potent and durable anti-lymphoma response with no neurotoxicity or severe CRS. Bispecific CD19/CD22 CAR-T cells represent a safe and potent anti-lymphoma cellular based targeted immunotherapy. Figure 1 Disclosures No relevant conflicts of interest to declare.

Prognostic Impact of 18F-FDG PET/CT in Patients With Aggressive B-Cell Lymphoma Treated With Anti-CD19 Chimeric Antigen Receptor T Cells

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Pierre Sesques ◽  
Jérémie Tordo ◽  
Emmanuelle Ferrant ◽  
Violaine Safar ◽  
Florent Wallet ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Chimeric Antigen Receptor ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Prognostic Impact ◽  
Pet Ct ◽  
18F Fdg ◽  
Fdg Pet Ct ◽  
Aggressive B Cell Lymphoma

scholarly journals Third-generation anti-CD19 chimeric antigen receptor T-cells incorporating a TLR2 domain for relapsed or refractory B-cell lymphoma: a phase I clinical trial protocol (ENABLE)

BMJ Open ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. e034629 ◽  
Author(s):  
Philip George ◽  
Nathaniel Dasyam ◽  
Giulia Giunti ◽  
Brigitta Mester ◽  
Evelyn Bauer ◽  
...  
Keyword(s):  
T Cells ◽  
Phase I ◽  
B Cell ◽  
Chimeric Antigen Receptor ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Third Generation ◽  
Car T Cells ◽  
Car T

IntroductionAutologous T-cells transduced to express a chimeric antigen receptor (CAR) directed against CD19 elicit high response rates in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). However, r/r B-NHL remissions are durable in fewer than half of recipients of second-generation CAR T-cells. Third-generation (3G) CARs employ two costimulatory domains, resulting in improved CAR T-cell efficacy in vitro and in animal models in vivo. This investigator-initiated, phase I dose escalation trial, termed ENABLE, will investigate the safety and preliminary efficacy of WZTL-002, comprising autologous T-cells expressing a 3G anti-CD19 CAR incorporating the intracellular signalling domains of CD28 and Toll-like receptor 2 (TLR2) for the treatment of r/r B-NHL.Methods and analysisEligible participants will be adults with r/r B-NHL including diffuse large B-cell lymphoma and its variants, follicular lymphoma, transformed follicular lymphoma and mantle cell lymphoma. Participants must have satisfactory organ function, and lack other curative options. Autologous T-cells will be obtained by leukapheresis. Following WZTL-002 manufacture and product release, participants will receive lymphodepleting chemotherapy comprising intravenous fludarabine and cyclophosphamide. A single dose of WZTL-002 will be administered intravenously 2 days later. Targeted assessments for cytokine release syndrome and immune cell effector-associated neurotoxicity syndrome, graded by the American Society Transplantation and Cellular Therapy criteria, will be made. A modified 3+3 dose escalation scheme is planned starting at 5×104 CAR T-cells/kg with a maximum dose of 1×106 CAR T-cells/kg. The primary outcome of this trial is safety of WZTL-002. Secondary outcomes include feasibility of WZTL-002 manufacture and preliminary measures of efficacy.Ethics and disseminationEthical approval for the study was granted by the New Zealand Health and Disability Ethics Committee (reference 19/STH/69) on 23 June 2019 for Protocol V.1.2. Trial results will be reported in a peer-reviewed journal, and results presented at scientific conferences or meetings.Trial registration numberNCT04049513

G-CSF does not worsen toxicities and efficacy of CAR-T cells in refractory/relapsed B-cell lymphoma

2020 ◽  
Vol 55 (12) ◽  
pp. 2347-2349
Author(s):  
Eugenio Galli ◽  
Vincent Allain ◽  
Roberta Di Blasi ◽  
Sophie Bernard ◽  
Laetitia Vercellino ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Car T Cells ◽  
Car T

Direct Comparison of In Vivo Fate of Second and Third-Generation CD19-Specific Chimeric Antigen Receptor (CAR)-T Cells in Patients with B-Cell Lymphoma: Reversal of Toxicity from Tonic Signaling

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1851-1851 ◽  
Author(s):  
Diogo Gomes da Silva ◽  
Malini Mukherjee ◽  
Madhuwanti Srinivasan ◽  
Olga Dakhova ◽  
Hao Liu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
2Nd Generation ◽  
Car T Cells ◽  
Car T ◽  
Equity Ownership

Abstract Although adoptive transfer of T cells with second-generation CD19-specific CARs containing CD28 or 4-1BB costimulatory endodomains shows remarkable clinical efficacy against B cell malignancies, the optimal choice of costimulatory domains in these and other CARs remains controversial. Depending on the precise CAR structure and specificity, individual endodomains may be associated with deleterious ligand-independent tonic signaling in the transduced T cell. Long et al. (Nat Med 2015) established the CD28 co-stimulatory endodomain can have a toxic tonic signaling effect, but it is unclear if tonic 4-1BB signaling may have deleterious consequences as well, and if such effects can be reversed. We therefore modeled tonic CAR signaling in T cells by transducing them with gammaretroviral vectors expressing 2nd-generation CD19.CAR constructs containing either the CD28 or 4-1BB costimulatory endodomain (in addition to the CD3-ζ chain endodomain). Compared to CAR-T cells with the CD28 endodomain alone, those with 4-1BB alone expanded 70% more slowly following transduction. Impaired expansion of 4-1BB CD19.CAR-T cells was coupled with a 4-fold increase in apoptosis and a gradual downregulation of CAR expression, and was a consequence of 4-1BB-associated tonic TRAF2-dependent signaling, leading to activation of NF-κB, upregulation of Fas and augmented Fas-dependent activation-induced T cell death (AICD). Moreover, expression of 4-1BB CAR from a gammaretroviral vector increased tonic signaling through a self-amplifying/positive feedback effect on the retroviral LTR promoter. Because of the toxicity of 4-1BB in our gammaretroviral CAR.CD19 construct (manifest by delayed expansion and increased apoptosis) we could not directly compare the in vivo fate of T cells expressing CAR.CD19 4-1BB with that of co-administered CAR.CD19 CD28 T cells in patients with lymphoma. We found, however, that the adverse effects of tonic 4-1BB costimulation could be overcome in a 3rd-generation CAR.CD19 vector, containing both CD28 and 4-1BB costimulatory molecules in tandem. We thus compared the fate of a 3rd-generation vector containing both CD28 and 4-1BB costimulatory domains with that of a 2nd-generation vector containing CD28 alone. Six patients with refractory/relapsed diffuse large B-cell lymphoma received 2 cell populations, one expressing 2nd and one expressing 3rd generation vectors. To determine whether CD28 alone was optimal (which would suggest 4-1BB is antagonistic) or whether 4-1BB had an additive or synergistic effect contributing to superior persistence and expansion of the CD28-41BB combination, patients were simultaneously infused with 1-20×106 of both 2nd and 3rd generation CAR+ T cells/m2 48-72 hours after lymphodepletion with cyclophosphamide (500 mg/m2/d) and fludarabine (30 mg/m2/d) × 3. Persistence of infused T cells was assessed in blood by CD19.CAR qPCR assays specific for each CAR. Molecular signals peaked approximately 2 weeks post infusion, remaining detectable for up to 6 months. The 3rd-generation CAR-T cells had a mean 23-fold (range 1.1 to 109-fold) higher expansion than 2nd-generation CAR-T cells and correspondingly longer persistence. Two patients had grade 2 cytokine release syndrome, with elevation of proinflammatory cytokines, including IL-6, at the time of peak expansion of T cells. Of the 5 patients evaluable for response, 2 entered complete remission (the longest ongoing for 9 months), 1 has had continued complete remission after autologous stem cell transplantation, 1 had a partial response, and 1 progressed. In conclusion, our data indicate that infusion of T cells carrying a CD19.CAR containing CD28 and 4-1BB endodomains is safe and can have efficacy at every dose level tested. Additionally, in a side-by-side comparison, the 3rdgeneration vector produced greater in vivo expansion and persistence than an otherwise identical CAR-T cell population with CD28 alone. Disclosures Rooney: Cell Medica: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Viracyte: Equity Ownership. Heslop:Celgene: Patents & Royalties, Research Funding; Chimerix: Other: Endpoint adjudication committee; Viracyte: Equity Ownership; Cell Medica: Patents & Royalties: Licensing agreement EBV-specific T cells.

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.

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