scholarly journals Anti-CD19 CAR T Cells Administered after Low-Dose Chemotherapy Can Induce Remissions of Chemotherapy-Refractory Diffuse Large B-Cell Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 550-550 ◽  
Author(s):  
James N Kochenderfer ◽  
Robert Somerville ◽  
Lily Lu ◽  
Alex Iwamoto ◽  
James C Yang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Low Dose ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Car T Cells ◽  
Car T ◽  
Low Dose Chemotherapy

Abstract We have treated a total of 30 patients with autologous T cells genetically modified to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19; 22 of 27 evaluable patients obtained either complete remissions (CR) or partial remissions (PR). Ten patients remain in ongoing CRs of 1 to 37 months duration. The CAR was encoded by a gammaretroviral vector and included the variable regions of an anti-CD19 antibody along with CD28 and CD3-zeta moieties. The first 21 patients treated on this protocol have been reported (Kochenderfer et al. Blood 2010, Blood 2012, and Journal of Clinical Oncology 2014). To enhance the activity of the transferred CAR T cells, T-cell infusions in the previously reported patients were preceded by a chemotherapy regimen of high-dose cyclophosphamide (60-120 mg/kg) plus fludarabine. In an attempt to reduce the overall toxicity of our anti-CD19 CAR treatment protocol, we substantially reduced the doses of chemotherapy administered before CAR T-cell infusions. This abstract communicates results from 9 patients with B-cell lymphoma who received a single infusion of 1x106 anti-CD19-CAR-expressing T cells/kg bodyweight preceded by a low-dose chemotherapy regimen consisting of cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 (Table). Each chemotherapy agent was administered daily for 3 days. Eight of the 9 treated patients had DLBCL (diffuse large B-cell lymphoma) that was refractory to chemotherapy (chemo-refractory) or that had relapsed less than 1 year after autologous stem cell transplantation (ASCT). Both of these clinical situations carry a grim prognosis, with median overall survivals of only a few months. Despite the very poor prognoses of our patients, one patient with DLBCL obtained a CR and 4 DLBCL patients obtained PRs. In some patients, PRs included resolution of large lymphoma masses. Compared to our previous experience with anti-CD19 CAR T cells preceded by high-dose chemotherapy, toxicity was reduced when CAR T cells were infused after low-dose chemotherapy. None of the 9 patients treated with low-dose chemotherapy and CAR T cells required vasopressor drugs or mechanical ventilation, although some patients did have short-term neurological toxicity. Cytopenias were mild with a mean of only 1.4 days of blood neutrophils<500/microliter. Blood anti-CD19 CAR T-cell levels were assessed in 6 patients with a quantitative PCR assay; we detected CAR+ cells in the blood of all 6 patients. The mean peak absolute number of blood CAR+ T cells was 73 cells/microliter. Six months after infusion, persisting CAR+ T cells were detected in a lymphoma-involved lymph node by flow cytometry. These results demonstrate that anti-CD19 CAR T cells administered after low-dose chemotherapy have significant activity against chemo-refractory DLBCL and could potentially become a standard treatment for aggressive lymphoma. Table Patient Age/Gender Malignancy Number of Prior Therapies Clinical Situation Response (Duration in Months) 1 66/M DLBCL 3 Post ASCT relapse PR (7) 2* 63/F DLBCL 2 Chemo-refractory PR (7+) 3 63/M FL 7 Not chemo-refractory PR (6+) 4* 22/M DLBCL 6 Chemo-refractory Progression 5 65/M DLBCL 4 Post ASCT relapse PR (5+) 6 47/M DLBCL 2 Chemo-refractory PR (1) 7 28/M DLBCL 7 Chemo-refractory Progression 8 62/M DLBCL 7 Post ASCT relapse CR (1+) 9 54/M DLBCL 3 Chemo-refractory Progression * Compassionate exemption was obtained from regulatory agencies to enroll these patients because their poor performance status precluded standard enrollment; M = male; F = female; FL = follicular lymphoma; + indicates ongoing response Disclosures Rosenberg: Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Anti-CD19 chimeric antigen receptor T cells preceded by low-dose chemotherapy to induce remissions of advanced lymphoma.

2016 ◽  
Vol 34 (18_suppl) ◽  
pp. LBA3010-LBA3010 ◽  
Author(s):  
James Kochenderfer ◽  
Robert Somerville ◽  
Tangying Lu ◽  
Victoria Shi ◽  
James C. Yang ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Low Dose ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cell Transplant ◽  
Car T Cells ◽  
Car T ◽  
Low Dose Chemotherapy ◽  
Peak Blood

LBA3010 Background: T cells genetically-modified to express chimeric antigen receptors (CARs) targeting CD19 have potent activity against a variety of B-cell malignancies. Chemotherapy is administered prior to CAR T cells because depletion of recipient leukocytes enhances the anti-malignancy efficacy of adoptively-transferred T cells; an increase in serum interleukin (IL)-15 is one mechanism for this enhancement. Previously, we (Kochenderfer et al. Journal of Clinical Oncology, 2015) and others have reported patients treated with high-dose chemotherapy prior to anti-CD19 CAR T-cell infusions. This report describes treatment of 22 patients with low-dose conditioning chemotherapy followed by infusion of anti-CD19 CAR T-cells. Methods: Eighteen of 22 treated patients received 300 mg/m2 of cyclophosphamide (cy) daily for 3 days; 4 patients received 500 mg/m2 of cy on the same schedule. All patients received fludarabine 30 mg/m2daily for 3 days on the same days as cy. Patients received a single dose of CAR T cells 2 days after completion of chemotherapy. Blood CAR T cells and serum cytokines were analyzed in all patients. Results: Nineteen patients with various subtypes of diffuse large B-cell lymphoma (DLBCL) had the following responses: 8 CR, 5 PR, 2 SD, and 4 PD. One patient with mantle cell lymphoma obtained a CR. Two patients with follicular lymphoma both obtained CRs. Durations of response currently range from 1 to 20 months; 10 remissions are ongoing. All but 4 patients had either chemotherapy-refractory lymphoma or lymphoma that had relapsed after autologous stem cell transplant. The most prominent toxicities were various neurological toxicities. Other toxicities included fever and hypotension. The median peak blood CAR+ cell level was 47/μL (range 4-1217/μL). Patients obtaining CRs or PRs had higher peak blood CAR+ cell levels than patients experiencing SD or PD. The mean serum IL-15 level was 4 pg/mL before the conditioning chemotherapy and 32 pg/mL after chemotherapy (P < 0.0001). Conclusions: Anti-CD19 CAR T cells can induce remissions of advanced B-cell lymphoma when administered after low-dose chemotherapy. In the near future, CAR T cells will likely be a standard therapy for lymphoma. Clinical trial information: NCT00924326.

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.

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 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 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 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 &lt; 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.

Sign in / Sign up

Export Citation Format

Share Document