scholarly journals Efficacy and safety of humanized CD19 CAR‑T as a salvage therapy for recurrent CNSL of B‑ALL following murine CD19 CAR‑T cell therapy

2021 ◽  
Vol 22 (5) ◽  
Author(s):  
Xin Li ◽  
Mei-Jing Liu ◽  
Nan Mou ◽  
Zhen-Xing Yang ◽  
Jia  Wang ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Salvage Therapy ◽  
Efficacy And Safety ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

scholarly journals Decitabine in Combination with Fludarabine and Cyclophosphamide As Lymphodepletion Regimen Followed By CD19/CD22 Bispecific Targeted CAR-T Therapy Significantly Improves Survival in Relapsed/Refractory B-ALL Patients: A Pilot Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1754-1754
Author(s):  
Yunju Ma ◽  
Changju Qu ◽  
Haiping Dai ◽  
Sining Liu ◽  
Qingya Cui ◽  
...  
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Efficacy And Safety ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Background: CD19/CD22 bispecific targeted chimeric antigen receptor T cell (CAR-T) therapy has achieved impressive progress in patients with relapsed/refractory B cell acute lymphoblastic leukemia (R/R B-ALL), with high rates of complete remission (CR). However, T cell exhaustion caused by de novo DNA methylation restricts the capacity of CAR-T. Decitabine (DAC), a DNA methyltransferase inhibitor, has been demonstrated to reverse exhaustion-associated DNA-methylation programs, promote the rejuvenation of CAR-T cells and enhance anti-leukemic effect of CAR-T cells in vitro. To date, there are limited reports about the use of DAC as a part of lymphodepletion therapy before CAR-T cell therapy. Here, we report efficacy and safety of DAC in combination with fludarabine and cyclophosphamide (FC) regimen followed by CD19/CD22 CAR-T cell therapy for patients with R/R B-ALL. Method:We conducted a phase 1/2 clinical trial to investigate the efficacy and safety of CD19/CD22 CAR-T in the treatment of R/R B-ALL (NCT03614858). Fourteen patients were treated with DAC (total dose 100mg/m 2 in 3 days) followed by FC regimen (fludarabine 30mg/m 2 × 3d and cyclophosphamide 300mg/m 2 × 3d) (DAC group), while twelve patients received FC regimen prior to CAR-T cell infusion (CON group). A total of 1 or 2 × 10 7 CAR-T cells/kg were infused at dose escalation. Results: Baseline characteristics of patients in both groups had no significant differences except previous hematopoietic stem cell transplantation (HSCT). There were more patients with relapse after HSCT in DAC group (42.9% versus 0%, P=0.017). All patients did not achieve remission before lymphodepletion. The day 28 CR rates were 100% in DAC group and 91.7% in CON group. Furthermore, minimal residual disease (MRD) negative CR rates were 71.4% and 58.3%, respectively (P = 0.683). There was no significant difference in the proportion of nontransplant patients after CAR-T treatment between two groups. Among the nontransplant patients after CAR-T infusion in DAC group, 16.7% (1/6) of patients relapsed at 4 months. However, among 4 nontransplant patients in CON group, 1 patient achieved NR after CAR-T therapy and 3 patients relapsed at 1.5, 5, and 10 months. There were significant differences in overall survival (OS) and leukemia-free survival (LFS) between two groups: 3-year OS, 88.9% (DAC) versus 33.3% (CON), P = 0.01 and 3-year LFS, 92.3% (DAC) versus 21.8% (CON), P = 0.002. Multivariable analysis showed that addition of DAC to the lymphodepletion regimen was associated with better OS (hazard ratio [HR] 0.107, [95% CI, 0.013-0.875], P = 0.037) and LFS (HR 0.081, [95% CI, 0.01-0.65], P = 0.018). Cytokine release syndrome was observed in all patients. Conclusion: In summary, DAC in combination with FC regimen followed by CD19CD22 CAR-T cells was feasible and well tolerated. Our study demonstrated DAC combined with FC was an independent prognostic factor correlated with better survival in relapsed/refractory B-ALL patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals CD19 CAR-T expressing PD-1/CD28 chimeric switch receptor as a salvage therapy for DLBCL patients treated with different CD19-directed CAR T-cell therapies

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yun Liang ◽  
Hui Liu ◽  
Zheming Lu ◽  
Wen Lei ◽  
Chaoting Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Salvage Therapy ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

AbstractCD19-targeted chimeric antigen receptor T (CAR T) cell therapy is a promising option to treat relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). However, the majority of CAR T-treated patients will eventually progress and require salvage treatment, for which there is no current standard. In this study, we analyzed data from 6 patients with R/R DLBCL who experienced progression following CD19-CAR T therapy, and then received CD19-specific CAR T cells that express a PD-1/CD28 chimeric switch-receptor (CD19-PD-1/CD28-CAR T) as salvage therapy at our institution. After the second infusion of CAR T cells, 3 of 6 patients achieved complete remissions and the duration of the response of responsive patients ranged from 8 to 25 months. One patient showed a stable disease. In contrast, 2/6 patients died on 60 days because of progression disease. Importantly, no severe neurologic toxicity or cytokine release syndrome was observed. These data suggest that CD19-PD-1/CD28-CAR-T cells, a novel anti-CD19 CAR-T cell therapy, elicit a potent and durable anticancer response, and can be used in the post-CD19-CAR T failure setting.

scholarly journals Efficacy and Safety of Axicabtagene Ciloleucel and Tisagenlecleucel Administration in Lymphoma Patients With Secondary CNS Involvement: A Systematic Review

2021 ◽  
Vol 12 ◽  
Author(s):  
XiaoQin Wu ◽  
XinYue Zhang ◽  
RenDe Xun ◽  
MengSi Liu ◽  
Zhen Sun ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Risk Of Bias ◽  
Cns Lymphoma ◽  
Efficacy And Safety ◽  
Cns Involvement ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

BackgroundThe efficacy and safety of chimeric antigen receptor T (CAR-T) cell therapy in the treatment of non-Hodgkin’s lymphoma has already been demonstrated. However, patients with a history of/active secondary central nervous system (CNS) lymphoma were excluded from the licensing trials conducted on two widely used CAR-T cell products, Axicabtagene ciloleucel (Axi-cel) and Tisagenlecleucel (Tisa-cel). Hence, the objective of the present review was to assess whether secondary CNS lymphoma patients would derive a benefit from Axi-cel or Tisa-cel therapy, while maintaining controllable safety.MethodTwo reviewers searched PubMed, Embase, Web of Science, and Cochrane library independently in order to identify all records associated with Axi-cel and Tisa-cel published prior to February 15, 2021. Studies that included secondary CNS lymphoma patients treated with Axi-cel and Tisa-cel and reported or could be inferred efficacy and safety endpoints of secondary CNS lymphoma patients were included. A tool designed specifically to evaluate the risk of bias in case series and reports and the ROBINS-I tool applied for cohort studies were used.ResultsTen studies involving forty-four patients were included. Of these, seven were case reports or series. The other three reports were cohort studies involving twenty-five patients. Current evidence indicates that secondary CNS lymphoma patients could achieve long-term remission following Axi-cel and Tisa-cel treatment. Compared with the non-CNS cohort, however, progression-free survival and overall survival tended to be shorter. This was possibly due to the relatively small size of the CNS cohort. The incidence and grades of adverse effects in secondary CNS lymphoma patients resembled those in the non-CNS cohort. No incidences of CAR-T cell-related deaths were reported. Nevertheless, the small sample size introduced a high risk of bias and prevented the identification of specific patients who could benefit more from CAR-T cell therapy.ConclusionSecondary CNS lymphoma patients could seem to benefit from both Axi-cel and Tisa-cel treatment, with controllable risks. Thus, CAR-T cell therapy has potential as a candidate treatment for lymphoma patients with CNS involvement. Further prospective studies with larger samples and longer follow-up periods are warranted and recommended.

The efficacy and safety of CAR-T cell therapy in patients with refractory ALL and concomitant HBV infection

Leukemia ◽  
2020 ◽  
Vol 34 (10) ◽  
pp. 2790-2793
Author(s):  
Peilong Lai ◽  
Xiaomei Chen ◽  
Le Qin ◽  
Zhiwu Jiang ◽  
Chenwei Luo ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Hbv Infection ◽  
Efficacy And Safety ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

CAR T-cell therapy: Balance of efficacy and safety

2017 ◽  
Vol 51 (2) ◽  
pp. 237-250 ◽  
Author(s):  
S. V. Kulemzin ◽  
V. V. Kuznetsova ◽  
M. Mamonkin ◽  
A. V. Taranin ◽  
A. A. Gorchakov
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Efficacy And Safety ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

scholarly journals Diffuse Large B-Cell Lymphoma (DLBCL) Patients with Late Relapses Who Are Transplant-Eligible Have Excellent Outcomes and May Represent Unique Biology

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2499-2499
Author(s):  
Henry S. Ngu ◽  
Laura K Hilton ◽  
Judith Anula Rodrigo ◽  
Diego Villa ◽  
Alina S. Gerrie ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cell ◽  
Cell Therapy ◽  
Salvage Therapy ◽  
Research Funding ◽  
Late Relapse ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Introduction Approximately 30-40% of patients (pts) with DLBCL have refractory disease or relapse following R-CHOP. The majority of pts will experience disease progression or relapse early (within 1-2 years), although ~20% experience late relapse >24 months (m) from time of initial diagnosis. Salvage therapy followed by autologous stem cell transplantation (ASCT) has been standard therapy for transplant-eligible pts, regardless of timing of documented relapsed/refractory (rel/refr) disease. Recent studies exploring the use of CAR T-cell therapy in primary refractory and early relapsed pts is challenging this paradigm. However, pts with late relapses were omitted from these studies. Interestingly, emerging molecular data suggest tumors of pts with late relapses exhibit significant genetic diversity from the initial diagnostic tumor, and may in fact represent unique biology (Hilton et al, ICML 2021). We aimed to evaluate outcomes in transplant-eligible pts with rel/refr DLBCL according to timing of documented rel/refr disease in a population-based setting to further explore biological and treatment implications. Method We identified all pts within the BC Cancer Centre for Lymphoid Cancer Database, age 18 to 75y, diagnosed with biopsy-confirmed DLBCL treated with curative-intent R-CHOP-like immunochemotherapy between 2001-2020 with documented rel/refr disease. Only transplant-eligible pts treated with standard salvage immunochemotherapy with intention for hematopoeitic stem cell transolantation (HSCT) were included. Patients with incidental discordant bone marrow involvement with low grade B-cell lymphoma were included, but transformed pts and those with isolated central nervous system relapse were excluded. Pts were divided into three cohorts based on timing of documented rel/refr disease from time of initial diagnosis: (1) rel/refr < 12m; (2) relapse between 12 to 24 m; (3) late relapse >24 m. Overall survival (OS) was calculated from time of documented rel/refr disease and from the time of HSCT in pts undergoing SCT. Results 225 pts meeting the stated eligibily criteria were identified. Clinical characteristics at initial diagnosis were as follows: median age 58y (range 19-72y); 70% male; 46 % IPI score 3-5. Timing of rel/refr disease from initial diagnosis was: rel/refr <12m, n= 145, 64%; rel 12-24m, n=32, 14%; late relapse >24m, n= 48, 21%. 92% of pts with late relapse had biopsy-proven relapsed DLBCL. Approximately 95% of pts received a platinum-based salvage regimen, most commonly GDP (gemcitabine, dexamethasone, cisplatin) +/- rituximab (n= 200 (89%). The overall response rate (ORR) to initial salvage therapy was 54% (14% CR, 40% PR). Response rate to salvage therapy according to timing of rel/refr disease was as follows: rel/refr <12m 41%; rel 12-24m 71%; relapse >24m 82%, with patients with later relapses having higher liklihood of response (p < 0.01). In total, 122 pts (54%) underwent HSCT; 118 ASCT; 4 allo-SCT. The likelihood of proceeding to HSCT based on timing of rel/refr disease was significantly lower in pts with refr/rel <12m (p < 0.01): rel/refr <12m, 43%; rel 12-24m 72%; rel >24m 75%. Pts who did not proceed to HSCT were treated according to the discretion of their treating physicians, with 9 pts proceeding to CAR T-cell therapy. 8 additional patients received CAR T-cell therapy post-SCT failure. The medium follow-up time from documented rel/refr disease was 5.8y (range 0.1-14.5y). The 5-y OS was strongly correlated with timing of rel/refr disease (p<0.001): rel/refr <12m 15.8%, rel 12-24m 33%, rel >24m 58.5%. (Fig. A) The 5-y OS from HSCT in pts undergoing SCT was similarly correlated with timing of rel/refr disease (P<0.001): rel/refr < 12m 31.4%, rel 12-24m 46.5%; rel <24m 65.4%. (Fig. B) Conclusion In pts with transplant-eligible rel/refr DLBCL, response to salvage therapy, likelihood of proceeding to HSCT and OS are strongly correlated with timing of documented rel/refr disease. Pts with late relapses >24m after diagnosis have notably favorable outcomes, compared with pts who experience earlier relapse (rel/refr <12m and rel 12-24m), supporting emerging evidence that these patients represent a subgroup with distinct biology with greater chemo-sensitivity. These data support the early use of alternative therapies (such as CAR T-cell therapy) in pts with earlier relapse. Correlative studies to delineate the biological diversity of rel/refr DLBCL are underway. Figure 1 Figure 1. Disclosures Villa: Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Seattle Genetics: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria; Roche: Honoraria; NanoString Technologies: Honoraria. Gerrie: Sandoz: Honoraria; Roche: Research Funding; Astrazeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Song: Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; GlaxoSmithKline: Honoraria; Takeda: Consultancy, Honoraria; Kite, a Gilead Company: Honoraria; Bristol Myers Squibb: Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Honoraria. Slack: Seagen: Consultancy, Honoraria. Savage: Servier: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Roche: Research Funding; Takeda: Other: Institutional clinical trial funding; Seattle Genetics: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: Institutional clinical trial funding; Merck: Consultancy, Honoraria, Other: Institutional clinical trial funding; Astra-Zeneca: Consultancy, Honoraria; Beigene: Other: Institutional clinical trial funding; Genentech: Research Funding. Scott: Abbvie: Consultancy; AstraZeneca: Consultancy; Incyte: Consultancy; Janssen: Consultancy, Research Funding; Rich/Genentech: Research Funding; BC Cancer: Patents & Royalties: Patent describing assigning DLBCL COO by gene expression profiling--licensed to NanoString Technologies. Patent describing measuring the proliferation signature in MCL using gene expression profiling. ; NanoString Technologies: Patents & Royalties: Patent describing measuring the proliferation signature in MCL using gene expression profiling.; Celgene: Consultancy. Sehn: Novartis: Consultancy; Genmab: Consultancy; Debiopharm: Consultancy.

scholarly journals Characteristics of Patients with Relapsed/Refractory Burkitt Non-Hodgkin Lymphoma (NHL): Impact on the Feasibility of CAR-T Cell Therapy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5352-5352
Author(s):  
Sonia Fortin Gamero ◽  
Yi Lin ◽  
Saad S. Kenderian ◽  
N. Nora Bennani ◽  
Gita Thanarajasingam ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Mayo Clinic ◽  
Salvage Therapy ◽  
Research Funding ◽  
Advisory Board ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Background Burkitt NHL (BL) is a rare hematologic malignancy that occurs in younger adults and is highly curable with aggressive chemoimmunotherapy induction regimens. Unfortunately, patients that are refractory or relapse after these regimens fare poorly and treatment guidelines are not well established. The typical approach is with standard platinum-based salvage regimens; those who obtain a complete remission (CR) become eligible for autologous or allogeneic stem cell transplantation (SCT). Chimeric antigen receptor T (CAR-T) cell therapy and bispecific antibodies offer potential novel approaches for these patients, especially those who are unable to achieve remission in order to proceed with SCT; however, CAR-T therapy is not approved nor even tested in BL other than promising single case reports (Avigdor A, Bone Marrow Transplant. 2018 May 24). The goal of this study was to learn the clinical features and outcome of R/R BL in order to design a prospective strategy for novel therapy use in relapsed/refractory (R/R) BL patients. Methods We reviewed the Mayo Clinic Lymphoma database to find cases of BL diagnosed and treated between 1/1/2000 - 9/30/2018. Forty-two cases were identified and 32 (76%) entered CR and never relapsed; 10 (24%) did not respond or relapsed and are the focus of this report. Demographic, clinical response to treatment regimens, and long-term outcomes were extracted from the Mayo Clinic electronic medical record. Results The 10 patients with R/R BL had a median age of 41 years (range, 28-59); all had received aggressive chemoimmunotherapy induction regimens; 7 were primary refractory and 3 relapsed within 3 months (2-4) of achieving first CR. All 3 patients that relapsed did so in the central nervous system (CNS) despite receiving CNS prophylaxis with their induction therapy regimen. The response to salvage therapy was 30% (3/10) with 10% CR and 30% (3/10) proceeded to autologous SCT (no patients made it to allogenic SCT). The median progression free survival (PFS) and overall survival (OS) from diagnosis of all 10 patients was 4 months (1-9) and 70% (7/10) died within 6±4 months from date of relapse. The 3 patients with relapsed BL survived 7, 10, and17 months from date of relapse. The 3 patients who did survive to receive a SCT lived 2, 4, and 13 months from date of SCT. None of the 10 patients survived past 26 months from date of diagnosis. Conclusions Patients with R/R BL represent an uncommon and unique subset of aggressive NHL that require a new therapeutic approach such as CAR-T. Our study demonstrates the very poor outcome with traditional salvage therapies and the very short OS of these young, otherwise healthy patients. We recommend that these patients be considered as emergencies and referred promptly for novel therapies such as CAR-T trials at the very first sign of treatment failure. Waiting with the intent of attaining response to traditional therapies is futile. Insurance approval initiation and harvesting of T-cells should be rapidly performed, preferably prior to initiating salvage therapy, given the rapid clinical deterioration and demise of these patients. Disclosures Kenderian: Lentigen: Research Funding; Novartis: Patents & Royalties, Research Funding; Tolero: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Morphosys: Research Funding; Kite/Gilead: Research Funding. Bennani:Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Bristol-Myers Squibb: Research Funding. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

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