scholarly journals The differential effects of tumor burdens on predicting the net benefits of ssCART-19 cell treatment on r/r B-ALL patients

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Minghao Li ◽  
Sheng-Li Xue ◽  
Xiaowen Tang ◽  
Jiayu Xu ◽  
Suning Chen ◽  
...  
Keyword(s):  
T Cell ◽  
Therapeutic Efficacy ◽  
Study Groups ◽  
Tumor Burden ◽  
Term Survival ◽  
Car T Cell ◽  
Grouping Strategy ◽  
Car T ◽  
Net Benefits

AbstractThe tumor burden (TB) is significantly related to the severity of cytokine release syndrome (CRS) caused by CAR-T cells, but its correlation with therapeutic efficacy has not been systematically studied. This study focused on the effects of the TB level on both the safety and efficacy of ssCART-19 as a treatment for r/r B-ALL. Taking the 5% tumor burden as the boundary, the study participants were divided into 2 groups, high and low tumor burden groups. Under this grouping strategy, the impacts of differential r/r B-ALL TBs on the clinical therapeutic efficacy (CR rate and long-term survival) and safety profiles after ssCART-19 cell treatment were analysed. 78 patients were reported in this study. The differential B-ALL TBs significantly affected the complete remission (CR) rates of patients treated with ssCART-19, with rates of 93.94% and 75.56% in the low and high TB groups, respectively (P = 0.0358). The effects of TBs on long-term therapeutic efficacy were further studied based on event-free survival (EFS) and overall survival (OS) profiles; both the OS and EFS of the low TB group were better than those of the high TB group, but the differences were not statistically significant. Importantly, the time points of TB measurement did not significantly affect the OS and EFS profiles regardless of whether the TBs were measured before or after fludarabine-cyclophosphamide (FC) preconditional chemotherapy. On the other hand, the severity of CRS was significantly correlated with the TB level (P = 0.0080), and the incidence of sCRS was significantly related to the TB level (the sCRS incidence increased as the TB level increased, P = 0.0224). Unexpectedly, the ssCART-19 cell expansion peaks were not significantly different (P = 0.2951) between the study groups. Patients with a low r/r B-ALL TB yield more net benefits from CAR-T treatment than those with a high TB in terms of safety and CR rate. These findings are critical and valuable for determining the optimal CAR-T cell treatment window for r/r B-ALL patients and will further the development of comprehensive and reasonable CAR-T cell treatment plans for r/r B-ALL patients with differential TBs.Trial registration: ClinicalTrials.gov identifier, NCT03919240.

scholarly journals Humanized Anti-CD19 CAR-T Cell Therapy and Sequential Allogeneic Hematopoietic Stem Cell Transplantation Achieved Long-Term Survival in Refractory and Relapsed B Lymphocytic Leukemia: A Retrospective Study of CAR-T Cell Therapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Wei Chen ◽  
Yuhan Ma ◽  
Ziyuan Shen ◽  
Huimin Chen ◽  
Ruixue Ma ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Cell Therapy ◽  
Term Survival ◽  
T Cell Therapy ◽  
Hematopoietic Stem ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Early response could be obtained in most patients with relapsed or refractory B cell lymphoblastic leukemia (R/R B-ALL) treated with chimeric antigen receptor T-cell (CAR-T) therapy, but relapse occurs in some patients. There is no consensus on treatment strategy post CAR-T cell therapy. In this retrospective study of humanized CD19-targeted CAR-T cell (hCART19s) therapy for R/R B-ALL, we analyzed the patients treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT) or received a second hCART19s infusion, and summarized their efficacy and safety. We retrospectively studied 28 R/R B-ALL patients treated with hCART19s in the Affiliated Hospital of Xuzhou Medical University from 2016 to 2020. After the first hCART19s infusion, 10 patients received allo-HSCT (CART+HSCT group), 7 patients received a second hCART19s infusion (CART2 group), and 11 patients did not receive HSCT or a second hCART19s infusion (CART1 group). The safety, efficacy, and long-term survival were analyzed. Of the 28 patients who received hCART19s treatment, 1 patient could not be evaluated for efficacy, and 25 (92.6%) achieved complete remission (CR) with 20 (74.7%) achieving minimal residual disease (MRD) negativity. Seven (25%) patients experienced grade 3-4 CRS, and one died from grade 5 CRS. No patient experienced ≥3 grade ICANS. The incidence of second CR is higher in the CART+HSCT group compared to the CART2 group (100% vs. 42.9%, p=0.015). The median follow-up time was 1,240 days (range: 709–1,770). Significantly longer overall survival (OS) and leukemia-free survival (LFS) were achieved in the CART+HSCT group (median OS and LFS: not reached, p=0.006 and 0.001, respectively) compared to the CART2 group (median OS: 482; median LFS: 189) and the CART1 group (median OS: 236; median LFS: 35). In the CART+HSCT group, the incidence of acute graft-versus-host disease (aGVHD) was 30% (3/10), and transplantation-related mortality was 30% (3/10). No chronic GVHD occurred. Multivariate analysis results showed that blasts ≥ 20% in the bone marrow and MRD ≥ 65.6% are independent factors for inferior OS and LFS, respectively, while receiving allo-HSCT is an independent factor associated with both longer OS and LFS. In conclusion, early allo-HSCT after CAR-T therapy can achieve long-term efficacy, and the adverse events are controllable.

Regnase-1 suppresses TCF-1+ precursor exhausted T cell formation to limit CAR T cell responses against ALL

Blood ◽  
2021 ◽  
Author(s):  
Wenting Zheng ◽  
Jun Wei ◽  
Caitlin Zebley ◽  
Lindsay L Jones ◽  
Yogesh Dhungana ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Therapeutic Efficacy ◽  
Lymphoblastic Leukemia ◽  
Cell Formation ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Tumor Clearance

Chimeric antigen receptor T cell (CAR-T cell) therapeutic efficacy is associated with long-term T cell persistence and acquisition of memory. Memory subset formation requires TCF-1, a master transcription factor for which few regulators have been identified. Here, we demonstrate using an immune-competent mouse model of B cell acute lymphoblastic leukemia (B-ALL) that Regnase-1 deficiency promotes TCF-1 expression to enhance CAR-T cell expansion and memory-like cell formation. This leads to improved CAR-T-mediated tumor clearance, sustained remissions, and protection against secondary tumor challenge. Phenotypic, transcriptional, and epigenetic profiling identified increased tumor-dependent programming of Regnase-1-deficient CAR-T cells into TCF-1+ precursor exhausted (TPEX) cells characterized by upregulation of both memory and exhaustion markers. Regnase-1 directly targets Tcf7 mRNA; its deficiency augments TCF-1 expression leading to the formation of TPEX that support long-term CAR-T cell persistence and function. Regnase-1 deficiency also reduces exhaustion and enhances the activity of TCF-1- CAR-T cells. We further validate these findings in human CAR-T cells, where Regnase-1 deficiency mediates enhanced tumor clearance in a xenograft B-ALL model. This is associated with increased persistence and expansion of a TCF-1+ CAR-T cell population. Our findings demonstrate pivotal roles of TPEX, Regnase-1, and TCF-1 in mediating CAR-T cell persistence and recall responses, and identify Regnase-1 as a modulator of human CAR-T cell longevity and potency that may be manipulated for improved therapeutic efficacy.

CD33-Directed Chimeric Antigen Receptor (CAR) T Cells for the Treatment of Acute Myeloid Leukemia (AML)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2825-2825 ◽  
Author(s):  
Sarwish Rafiq ◽  
Terence J. Purdon ◽  
Liora M. Schultz ◽  
Renier J. Brentjens
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Myeloid Leukemia ◽  
Term Survival ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Acute Myeloid

Abstract Therapies for acute myeloid leukemia (AML) have not improved patient long-term survival for decades. Novel treatment options, such as chimeric antigen receptor (CAR) T cells, are needed for patients with this disease. However, AML cells lack ideal targeting antigens that are safe to target with CAR T cells. CD33, a commonly targeted antigen, is expressed in about 85-90% of AML cases but is also present on normal myeloid progenitors and myelocytes. Our aim was to engineer and validate CD33-directed CAR T cells, with the intention to open a phase I clinical trial in patients with relapsed AML. Given the potential toxicity associated with targeting CD33 in patients, an elimination gene was included in the construct design to allow CAR T cell clearance after disease eradication. We constructed a CAR specific for CD33 by utilizing the variable heavy and light chains of the humanized M-195 antibody (HuM-195), CD28 and zeta signaling domains, and the IL-12 gene. To facilitate CAR T cell elimination if necessary, a truncated epidermal growth factor receptor (EGFRt) gene was also inserted into the retroviral vector to create the EGFRt/HuM195-28z/IL-12 CAR construct. Retroviral transduction with this tri-cistronic construct resulted in high transduction efficiency of human T cells, as determined by detection of EGFRt with fluorescently-labeled cetuximab or CAR with fluorescently-labeled CD33 molecule by flow cytometry. T cells transduced with the EGFRt/HuM195-28z/IL-12 CAR secreted functional IL-12, as assessed by culturing CAR cell supernatant with peripheral blood mononuclear cells and detecting IFN-g produced in response to IL-12. When stimulated through the CAR by co-culturing with the CD33+ AML cell line Molm-13, EGFRt/HuM195-28z/IL-12 CAR T cells proliferated and produced significant levels of the pro-inflammatory cytokines IFN-g and IL-2. In addition, EGFRt/HuM195-28z/IL-12 CAR T cells mediated significantly cytotoxicity against Molm-13 at a range of effector-to-target ratios in standard 51Cr-release assays, as compared to control CAR T cells. The in vivo anti-tumor efficacy of EGFRt/HuM195-28z/IL-12 CAR T cells was tested in two preclinical mouse models of AML. First, SCID/Beige mice were xenografted with Molm-13 cells. Mice subsequently treated with EGFRt/HuM195-28z/IL-12 CAR T cells exhibited significant long-term survival, as compared to untreated or control CAR T cell-treated mice (p = <0.0001). In addition, NSG mice were engrafted with patient-derived CD33+ AML (PDX) cells. PDX mice treated with EGFRt/HuM195-28z/IL-12 CAR T cells exhibited reduction of peripheral CD33+ disease, as compared to untreated or control CAR T cell-treated mice. These studies demonstrate the capacity of the EGFRt/HuM195-28z/IL-12 CAR to redirect the specific anti-tumor function of T cells to CD33+ AML tumor cells. Ongoing studies aim to validate elimination of CAR T cells via EGFRt in vitro in antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity assays, as well as in mice are currently underway. These data support the utilization of CD33-specific CAR T cells in the clinic for patients with relapsed AML as a means to decrease disease burden prior to consolidative therapies such as allogeneic transplantation. Disclosures Brentjens: Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Durable long-term survival of adult patients with relapsed B-ALL after CD19 CAR (19-28z) T-cell therapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7008-7008 ◽  
Author(s):  
Jae Hong Park ◽  
Isabelle Riviere ◽  
Xiuyan Wang ◽  
Brigitte Senechal ◽  
Yongzeng Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Disease Burden ◽  
Adult Patients ◽  
Term Survival ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

7008 Background: CD19-specific chimeric antigen receptor (CAR) T cells have demonstrated high initial responses in patients with relapsed B-ALL. However, clinical characteristics associated with the durability of response remain undefined. Herein, we report the results from analysis of our phase I clinical trial of 19-28z CAR T cells in adult patients with relapsed B-ALL (NCT01044069) with a focus to identify those patients who optimally benefit from 19-28z CAR T cell therapy with durable long-term survival and reduced toxicities. Methods: Adults with relapsed B-ALL were infused with autologous T cells expressing the 19-28z CAR following conditioning chemotherapy. Disease burden was assessed by bone marrow biopsy immediately prior to T cell infusion; patients with < 5% blasts were classified as minimal residual disease (MRD) cohort vs. patients ≥5% blasts as morphologic disease cohort. Response assessment occurred at 4 weeks. Median follow-up duration was 18 months (range, 0.2-57.3). Results: 51 adults received 19-28z CAR T cells; 20 in the MRD and 31 in the morphologic cohort. Complete remission (CR) rates were comparable (95% and 77%, respectively). However, median event-free and overall survivals widely diverged among the 42 patients who achieved MRD-negative CR: not reached (NR) (95% confidence interval [CI]: 4.2-NR) vs. 6.3 months (95% CI, 4.8-9.0) (p = 0.0005), and NR (95% CI, 15.3-NR) vs. 17 months (95% CI, 8.5 – 36.2) (p = 0.0189), in the MRD and morphologic cohorts, respectively. Subsequent allogeneic HSCT in either cohort did not improve survival (p = 0.8). MRD cohort patients developed substantially less severe cytokine release syndrome (CRS) and neurotoxicity, both correlating with peak CAR T cell expansion (p = 0.0326 and p = 0.0001, respectively). Conclusions: Despite comparable initial CR rates regardless of pre-treatment disease burden, durability of 19-28z CAR T cell mediated remissions and survival in adult patients with relapsed B-ALL positively correlated to a low disease burden and do not appear to be enhanced by allogeneic transplant. Our findings strongly support the early incorporation of CD19 CAR therapy before morphologic relapse in B-ALL. Clinical trial information: NCT01044069.

scholarly journals Long-Term Follow-Up of Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy

2020 ◽  
Vol 38 (32) ◽  
pp. 3805-3815
Author(s):  
Kathryn M. Cappell ◽  
Richard M. Sherry ◽  
James C. Yang ◽  
Stephanie L. Goff ◽  
Danielle A. Vanasse ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T

PURPOSE Anti-CD19 chimeric antigen receptors (CARs) are artificial fusion proteins that cause CD19-specific T-cell activation. Durability of remissions and incidence of long-term adverse events are critical factors determining the utility of anti-CD19 CAR T-cell therapy, but long-term follow-up of patients treated with anti-CD19 CAR T cells is limited. This work provides the longest follow-up of patients in remission after anti-CD19 CAR T-cell therapy. METHODS Between 2009 and 2015, we administered 46 CAR T-cell treatments to 43 patients (ClinicalTrials.gov identifier: NCT00924326 ). Patients had relapsed B-cell malignancies of the following types: diffuse large B-cell lymphoma or primary mediastinal B-cell lymphoma (DLBCL/PMBCL; n = 28), low-grade B-cell lymphoma (n = 8), or chronic lymphocytic leukemia (CLL; n = 7). This report focuses on long-term outcomes of these patients. The CAR used was FMC63-28Z; axicabtagene ciloleucel uses the same CAR. Cyclophosphamide plus fludarabine conditioning chemotherapy was administered before CAR T cells. RESULTS The percentages of CAR T-cell treatments resulting in a > 3-year duration of response (DOR) were 51% (95% CI, 35% to 67%) for all evaluable treatments, 48% (95% CI, 28% to 69%) for DLBCL/PMBCL, 63% (95% CI, 25% to 92%) for low-grade lymphoma, and 50% (95% CI, 16% to 84%) for CLL. The median event-free survival of all 45 evaluable treatments was 55 months. Long-term adverse effects were rare, except for B-cell depletion and hypogammaglobulinemia. Median peak blood CAR-positive cell levels were higher among patients with a DOR of > 3 years (98/µL; range, 9-1,217/µL) than among patients with a DOR of < 3 years (18/µL; range, 0-308/μL, P = .0051). CONCLUSION Complete remissions of a variety of B-cell malignancies lasting ≥ 3 years occurred after 51% of evaluable anti-CD19 CAR T-cell treatments. Remissions of up to 9 years are ongoing. Late adverse events were rare.

Updated outcomes with axicabtagene ciloleucel (axi-cel) retreatment (reTx) in patients (pts) with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL) in ZUMA-5.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7548-7548
Author(s):  
Julio C. Chavez ◽  
Caron A. Jacobson ◽  
Alison Sehgal ◽  
Sattva Swarup Neelapu ◽  
David G. Maloney ◽  
...  
Keyword(s):  
T Cell ◽  
Neutralizing Antibodies ◽  
Complete Response ◽  
Tumor Burden ◽  
Primary Analysis ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

7548 Background: ZUMA-5 is a Phase 2 study of axi-cel anti-CD19 CAR T-cell therapy in pts with R/R iNHL (follicular lymphoma [FL]; marginal zone lymphoma [MZL]). In the primary analysis, 11 pts (9 FL; 2 MZL) were retreated with axi-cel, achieving an overall response rate (ORR) of 100% (91% complete response [CR] rate) at a median follow-up of 2.3 mo post-reTx, with no Grade ≥3 cytokine release syndrome (CRS) or neurologic events (NEs; Chavez et al. ASH 2020. #2036). Here, we report updated clinical and translational outcomes with longer follow-up in pts retreated with axi-cel in ZUMA-5. Methods: Eligible pts with FL or MZL had R/R disease after ≥2 lines of therapy. Pts were considered for reTx if they progressed after a response at mo 3, had no evidence of CD19-negative relapse in biopsy, had no axi-cel neutralizing antibodies, and had no Grade 4 CRS or NEs with 1st Tx. Retreatment was per investigator discretion. At both Txs, pts received axi-cel (2×106 CAR T cells/kg) after conditioning chemotherapy. Results: As of 9/14/2020, 13 pts with iNHL (11 FL; 2 MZL) received axi-cel reTx, with 2 pts retreated after the primary analysis. Before their 1st Tx, pts had median 4 prior lines of therapy; 85% had stage 3–4 disease; 82% had FLIPI of ≥3; 46% were POD24; 77% had refractory disease. Among the 13 retreated pts, 85% had a CR to 1st Tx. Median 1st duration of response (DOR) was 8.2 mo. Detectable CD19 was confirmed in all evaluable biopsies from retreated pts at relapse, and median time from 1st Tx to reTx was 10.6 mo. Following reTx, the ORR was 100% (77% CR rate). After a median follow-up of 11.4 mo, the median DOR had not yet been reached; 46% of retreated pts had ongoing responses at data cutoff. At 1st Tx, CRS occurred in 9 pts (5 Grade 1, 4 Grade 2); NEs occurred in 5 (3 Grade 1, 1 Grade 2, 1 Grade 3). At reTx, CRS occurred in 8 pts (6 Grade 1, 2 Grade 2); NEs occurred in 4 (3 Grade 1, 1 Grade 2). Median peak levels of biomarkers typically associated with severe CRS and NEs were similar at reTx and 1st Tx (IL-6, 7.7 vs 5.7 pg/mL; IL-2, 1.8 vs 0.9 pg/mL; IFN-γ, 62.9 vs 64.2 pg/mL). In the 11 retreated pts with FL, tumor burden (median sum of product diameters [SPD]) was lower before reTx vs 1st Tx (1416 vs 4770 mm2). Engraftment index (CAR T-cell expansion relative to SPD) is an indirect proxy for effector:target ratio and a key covariate of response to axi-cel (Locke et al. Blood Adv. 2020). Though median peak CAR T-cell levels appeared lower at reTx vs 1st Tx (5.2 vs 14.3 CAR+ cells/µL blood), engraftment index was similar (0.003 vs 0.005 cells/µL×mm2). Conclusions: Axi-cel reTx achieved deep and durable responses, with an acceptable safety profile. Tumor CD19 positivity was maintained at relapse, and engraftment index was similar at both Txs, comparing favorably to previous reports in aggressive lymphomas (Locke et al. ASCO 2020. #8012). These data suggest axi-cel reTx is a promising option for pts with R/R iNHL. Clinical trial information: NCT03105336.

scholarly journals Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma

2020 ◽  
Vol 4 (19) ◽  
pp. 4898-4911 ◽  
Author(s):  
Frederick L. Locke ◽  
John M. Rossi ◽  
Sattva S. Neelapu ◽  
Caron A. Jacobson ◽  
David B. Miklos ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Tumor Burden ◽  
Durable Response ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T Cell Therapy ◽  
Car T

Abstract ZUMA-1 demonstrated a high rate of durable response and a manageable safety profile with axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with refractory large B-cell lymphoma. As previously reported, prespecified clinical covariates for secondary end point analysis were not clearly predictive of efficacy; these included Eastern Cooperative Oncology Group performance status (0 vs 1), age, disease subtype, disease stage, and International Prognostic Index score. We interrogated covariates included in the statistical analysis plan and an extensive panel of biomarkers according to an expanded translational biomarker plan. Univariable and multivariable analyses indicated that rapid CAR T-cell expansion commensurate with pretreatment tumor burden (influenced by product T-cell fitness), the number of CD8 and CCR7+CD45RA+ T cells infused, and host systemic inflammation, were the most significant determining factors for durable response. Key parameters differentially associated with clinical efficacy and toxicities, with both theoretical and practical implications for optimizing CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT02348216.

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