scholarly journals Comparing Survival for Different CAR Ts: Need for Addressing Bias Due to Differences in the Pre-Infusion Period

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4795-4795
Author(s):  
Aaron Jacob Katz ◽  
Vincent Lin ◽  
Barbara Blaylock ◽  
Jeroen Jansen
Keyword(s):  
Treatment Initiation ◽  
Risk Group ◽  
Time Dependent ◽  
Survival Outcomes ◽  
Time To Treatment ◽  
Car T Cells ◽  
Car T ◽  
Time To Treatment Initiation ◽  
Infusion Period

Abstract Introduction Patients with relapsed/refractory large B-cell lymphoma (RR-LBCL) treated with salvage chemotherapy have a poor prognosis, with a median survival of 6.3 months (Crump 2017). Given the recent approval of chimeric antigen receptor T-cell therapies (CAR T) for patients with RR-LBCL, efforts to demonstrate the comparative effectiveness of different CAR Ts are imminent. In the absence of head-to-head trials, such an assessment will likely be based on indirect or between-trial comparisons of reported survival estimates. Due to differences in the multi-step manufacturing process preceding the infusion of CAR T cells, the duration of the pre-infusion period, which accounts for time from leukapheresis to infusion, may vary across CAR Ts. This variability may be associated with differences in the prognostic characteristics of patients who endure the pre-infusion period. As such, comparisons of reported survival among these selected patients with the different CAR Ts evaluated in different trials may be biased. Estimating the comparative effects of CAR T therapies on survival requires careful attention to these potential differences and the use of thoughtful analytic approaches to address bias. We aimed to review current methodological approaches used to address bias related to time-to-treatment initiation and assess their potential utility in comparative analyses of CAR T based on between-trial comparisons. Methods A targeted literature review was performed to identify studies that used methods to adjust for bias related to time-to-treatment initiation when estimating relative treatment effects regarding survival outcomes between interventions in oncology. Relevant studies published in English from 2008 onwards were identified by searching the Medical Literature Analysis and Retrieval System Online (MEDLINE) and Excerpta Medica dataBASE (EMBASE). In addition, manual searches of the reference lists of the identified studies were performed. Studies that provided the most recent application of a proposed method were selected for inclusion. Results We identified several manuscripts that utilized methods to address survival or survival treatment selection bias (STSB) in observational studies where the classification of "treated" individuals required them to have survived until treatment initiation, and individuals who died early without the opportunity to get treatment were classified as "untreated". The identified methods to adjust for the over-estimation of the treatment effect include landmark survival and time-dependent exposure assignment. The landmark method restricts the analysis sample to patients who are event-free and alive at a given point (i.e, landmark) during follow-up; patients are assigned to risk groups based on their status at the landmark and survival outcomes are estimated from that point. Time-dependent exposure assignment addresses STSB by accounting for changes in patient exposure or treatment status during the course of follow-up. All patients begin in the same risk group; when exposure changes, patients and person-time are switched to the applicable risk group at that point. However, these methods do not address bias resulting from a comparison of reported survival estimates between different CAR Ts for a follow-up starting at the successful infusion of the CAR T cells. When comparing CAR Ts, the differences in prognostic patient characteristics due to differences in the pre-infusion phase are similar to channeling bias or confounding-by-indication. These concepts are well known, and established methods are available. However, those methods have limited applicability without access to individual patient data for the CAR Ts of interest. Conclusion Comparing survival upon successful infusion with different CAR Ts reported in separate studies is likely to be biased due to differences in the duration of the pre-infusion period. Methods previously used to address bias related to differences in time-to-treatment initiation may not be relevant or applicable, particularly in the absence of patient-level data. A between-trial comparison of reported survival estimates with the different CAR Ts might benefit from incorporating external evidence to inform the mortality during the pre-infusion periods. Disclosures Katz: Amgen: Other: Former employee and stockholder; Kite, a GILEAD Company: Consultancy. Lin:Kite/Gilead: Employment. Blaylock:Kite, A Gilead Company: Consultancy. Jansen:Kite, A Gilead Company: Consultancy.

scholarly journals Comparative outcomes in patients receiving pirfenidone or nintedanib for idiopathic pulmonary fibrosis

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Manon Belhassen ◽  
Faustine Dalon ◽  
Maëva Nolin ◽  
Eric Van Ganse
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Treatment Initiation ◽  
Proportional Hazards Model ◽  
Research Question ◽  
National Health System ◽  
Cox Proportional Hazards Model ◽  
Time To Treatment ◽  
All Cause Mortality ◽  
Time To Treatment Initiation

Abstract Background Real-world data regarding outcomes of idiopathic pulmonary fibrosis (IPF) are scarce, outside of registries. In France, pirfenidone and nintedanib are only reimbursed for documented IPF, with similar reimbursement criteria with respect to disease characteristics, prescription through a dedicated form, and IPF diagnosis established in multidisciplinary discussion. Research question The data of the comprehensive French National Health System were used to evaluate outcomes in patients newly treated with pirfenidone or nintedanib in 2015–2016. Study design and methods Patients aged < 50 years or who had pulmonary fibrosis secondary to an identified cause were excluded. All-cause mortality, acute respiratory-related hospitalisations and treatment discontinuations up to 31 December 2017 were compared using a Cox proportional hazards model adjusted for age, sex, year of treatment initiation, time to treatment initiation and proxies of disease severity identified during a pre-treatment period. Results During the study period, a treatment with pirfenidone or nintedanib was newly initiated in 804 and 509 patients, respectively. No difference was found between groups for age, sex, time to treatment initiation, Charlson comorbidity score, and number of hospitalisations or medical contacts prior to treatment initiation. As compared to pirfenidone, nintedanib was associated with a greater risk of all-cause mortality (hazard ratio [HR], 1.8; 95% confidence interval [CI] 1.3–2.6), a greater risk of acute respiratory-related hospitalisations (HR 1.3; 95% CI 1.0–1.7) and a lower risk of treatment discontinuation at 12 months (HR 0.7; 95% CI 0.6–0.9). Interpretation This observational study identified potential differences in outcome under newly prescribed antifibrotic drugs, deserving further explorations.

Impact of upfront Xpert testing on time to treatment initiation for multidrug-resistant TB

2021 ◽  
Vol 25 (7) ◽  
pp. 584-586
Author(s):  
S. S. Habib ◽  
A. A. Malik ◽  
U. Khan ◽  
S. Khowaja ◽  
H. Hussain ◽  
...  
Keyword(s):  
Treatment Initiation ◽  
Multidrug Resistant ◽  
Time To Treatment ◽  
Time To Treatment Initiation

PSMA targeted armored chimeric antigen receptor (CAR) T-cells in patients with advanced mCRPC: A phase I experience.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2534-2534
Author(s):  
Matthew H. Carabasi ◽  
Meredith McKean ◽  
Mark N. Stein ◽  
Michael Thomas Schweizer ◽  
Jason J. Luke ◽  
...  
Keyword(s):  
T Cells ◽  
Dose Level ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Dominant Negative ◽  
Car T Cells ◽  
Car T ◽  
Level 1 ◽  
Immune Toxicity

2534 Background: CART-PSMA-TGFβRDN cells are autologous T cells engineered via lentiviral transduction to express a dominant negative form of TGFβRII (TGFβRDN) and a chimeric antigen receptor (CAR) with specificity to prostate specific membrane antigen (PSMA). The TGFβRDN renders CAR T cells resistant to TGFβ-mediated immunosuppression. CART-PSMA-02 is a multi-center, open-label, Phase 1 study evaluating the safety and feasibility of dosing patients with metastatic castration resistant prostate cancer (mCRPC) with CART-PSMA-TGFβRDN (NCT04227275). Methods: This is a 3+3 dose escalation study to determine the recommended phase 2 dose and schedule of CART-PSMA-TGFβRDN cells following lymphodepleting chemotherapy with cyclophosphamide and fludarabine. Single and fractionated doses are being evaluated. A cohort expansion will enroll patients to further explore the safety of the selected dose and schedule. Results: As of January 2021, 6 patients (pts) have been treated. Two pts were treated in the first dose level (1-3 x107 transduced T cells (TDN)). Four pts were treated in the second dose level (1-3 x 108 TDN with fractionated dosing). AEs occurring in ≥50 % of pts included cytokine release syndrome (CRS), anemia, thrombocytopenia, increased creatinine, nausea, fatigue, pyrexia and dehydration. No DLTs occurred in the 1st dose level. Four pts in the 2nd dose level developed CRS (3 Gr 1 and 1 Gr 2). One pt developed rapid G2 CRS that progressed to Gr 5 encephalopathy and Gr 5 multi-organ failure. Ferritin levels peaked at 56,974 ng/ml (baseline 2,903 ng/mL) despite aggressive immunosuppressive therapy including tocilizumab, dexamtheasone and anakinra. The post infusion cytokine profile indicated elevations in IL-1RA, TNF-alpha, VEGF, IL-10, MIP-1b, IFN-gamma, GM-CSF and notably lower levels of IL6 compared to published reports of CD19 CART-mediated CRS. Autopsy findings were consistent with HLH/MAS, confirming overactivity of the monocyte/macrophage compartment. Based on these observations, a modified immune toxicity management strategy that includes prophylactic anakinra (an IL1R antagonist) was instituted. Preliminary evidence of clinical activity of CART-PSMA-TGFβRDN was noted in the 2nd dose level. Two of 3 pts with 1 month follow-up demonstrated PSA decreases from baseline (1 with >95% decrease, 1 with >50% decrease). Both pts had stable disease per RECIST v1.1. A third pt with only 1 week follow-up had a 40% PSA decrease. Additional data analyses from all infused patients are ongoing and data from pts managed with modified immune toxicity management will be presented. Conclusions: Initial data indicates a unique immune toxicity profile and the potential for anti-tumor activity in mCRPC pts treated with CART-PSMA-TGFβRDN. Modified immune toxicity management could lead to identification of a manageable safety profile and therapeutically active dose. Clinical trial information: NCT04227275.

scholarly journals Feasibility, and Efficacy of Donor-Derived cd19-Targeted Car t-Cell Therapy in Refractory/Relapsed(r/r)b-Cell Acute Lymphoblastic Leukemia (b-all) Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-6
Author(s):  
Xian Zhang ◽  
Junfang Yang ◽  
Wenqian Li ◽  
Gailing Zhang ◽  
Yunchao Su ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Backgrounds As CAR T-cell therapy is a highly personalized therapy, process of generating autologous CAR-T cells for each patient is complex and can still be problematic, particularly for heavily pre-treated patients and patients with significant leukemia burden. Here, we analyzed the feasibility and efficacy in 37 patients with refractory/relapsed (R/R) B-ALL who received CAR T-cells derived from related donors. Patients and Methods From April 2017 to May 2020, 37 R/R B-ALL patients with a median age of 19 years (3-61 years), were treated with second-generation CD19 CAR-T cells derived from donors. The data was aggregated from three clinical trials (www.clinicaltrials.gov NCT03173417; NCT02546739; and www.chictr.org.cn ChiCTR-ONC-17012829). Of the 37 patients, 28 were relapsed following allogenic hematopoietic stem cell transplant (allo-HSCT) and whose lymphocytes were collected from their transplant donors (3 HLA matched sibling and 25 haploidentical). For the remaining 9 patients without prior transplant, the lymphocytes were collected from HLA identical sibling donors (n=5) or haploidentical donors (n=4) because CAR-T cells manufacture from patient samples either failed (n=5) or blasts in peripheral blood were too high (&gt;40%) to collect quality T-cells. The median CAR-T cell dose infused was 3×105/kg (1-30×105/kg). Results For the 28 patients who relapsed after prior allo-HSCT, 27 (96.4%) achieved CR within 30 days post CAR T-cell infusion, of which 25 (89.3%) were minimal residual disease (MRD) negative. Within one month following CAR T-cell therapy, graft-versus-host disease (GVHD) occurred in 3 patients including 1 with rash and 2 with diarrhea. A total of 19 of the 28 (67.9%) patients had cytokine release syndrome (CRS), including two patients (7.1%) with Grade 3-4 CRS. Four patients had CAR T-cell related neurotoxicity including 3 with Grade 3-4 events. With a medium follow up of 103 days (1-669days), the median overall survival (OS) was 169 days (1-668 days), and the median leukemia-free survival (LFS) was 158 days (1-438 days). After CAR T-cell therapy, 15 patients bridged into a second allo-HSCT and one of 15 patients (6.7%) relapsed following transplant, and two died from infection. There were 11 patients that did not receive a second transplantation, of which three patients (27.3%) relapsed, and four parents died (one due to relapse, one from arrhythmia and two from GVHD/infection). Two patients were lost to follow-up. The remaining nine patients had no prior transplantation. At the time of T-cell collection, the median bone marrow blasts were 90% (range: 18.5%-98.5%), and the median peripheral blood blasts were 10% (range: 0-70%). CR rate within 30 days post CAR-T was 44.4% (4/9 cases). Six patients developed CRS, including four with Grade 3 CRS. Only one patient had Grade 3 neurotoxicity. No GVHD occurred following CAR T-cell therapy. Among the nine patients, five were treated with CAR T-cells derived from HLA-identical sibling donors and three of those five patients achieved CR. One patient who achieved a CR died from disseminated intravascular coagulation (DIC) on day 16. Two patients who achieved a CR bridged into allo-HSCT, including one patient who relapsed and died. One of two patients who did not response to CAR T-cell therapy died from leukemia. Four of the nine patients were treated with CAR T-cells derived from haploidentical related donors. One of the four cases achieved a CR but died from infection on day 90. The other three patients who had no response to CAR T-cell therapy died from disease progression within 3 months (7-90 days). Altogether, seven of the nine patients died with a median time of 19 days (7-505 days). Conclusions We find that manufacturing CD19+ CAR-T cells derived from donors is feasible. For patients who relapse following allo-HSCT, the transplant donor derived CAR-T cells are safe and effective with a CR rate as high as 96.4%. If a patient did not have GVHD prior to CAR T-cell therapy, the incidence of GVHD following CAR T-cell was low. Among patients without a history of transplantation, an inability to collect autologous lymphocytes signaled that the patient's condition had already reached a very advanced stage. However, CAR T-cells derived from HLA identical siblings can still be considered in our experience, no GVHD occurred in these patients. But the efficacy of CAR T-cells from haploidentical donors was very poor. Disclosures No relevant conflicts of interest to declare.

scholarly journals Allogeneic Hematopoietic Cell Transplantation Is Critical to Maintain Remissions after CD19-CAR T-Cell Therapy for Pediatric ALL: A Single Center Experience

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Aimee C Talleur ◽  
Renee M. Madden ◽  
Amr Qudeimat ◽  
Ewelina Mamcarz ◽  
Akshay Sharma ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Allogeneic Hct ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

CD19-CAR T-cell therapy has shown remarkable efficacy in pediatric patients with relapsed and/or refractory B-cell acute lymphoblastic leukemia (r/r ALL). Despite high short-term remission rates, many responses are not durable and the best management of patients who achieve a complete response (CR) post-CAR T-cell therapy remains controversial. In particular, it is unclear if these patients should be observed or proceed to consolidative allogeneic hematopoietic cell transplantation (HCT). To address this question, we reviewed the clinical course of all patients (n=22) who received either an investigational CAR T-cell product (Phase I study: SJCAR19 [NCT03573700]; n=12) or tisagenlecleucel (n=10) at our institution. The investigational CD19-CAR T cells were generated by a standard cGMP-compliant procedure using a lentiviral vector encoding a 2nd generation CD19-CAR with a FMC63-based CD19 binding domain, CD8a stalk and transmembrane domain, and 41BB.ζ signaling domain. Patients received therapy between 8/2018 and 3/2020. All products met manufacturing release specifications. Within the entire cohort, median age at time of infusion was 12.3 years old (range: 1.8-23.5) and median pre-infusion marrow burden using flow-cytometry minimal residual disease (MRD) testing was 6.8% (range: 0.003-100%; 1 patient detectable by next-generation sequencing [NGS] only). All patients received lymphodepleting chemotherapy (fludarabine, 25mg/m2 daily x3, and cyclophosphamide, 900mg/m2 daily x1), followed by a single infusion of CAR T-cells. Phase I product dosing included 1x106 CAR+ T-cells/kg (n=6) or 3x106 CAR+ T-cells/kg (n=6). Therapy was well tolerated, with a low incidence of cytokine release syndrome (any grade: n=10; Grade 3-4: n=4) and neurotoxicity (any grade: n=8; Grade 3-4: n=3). At 4-weeks post-infusion, 15/22 (68.2%) patients achieved a CR in the marrow, of which 13 were MRDneg (MRDneg defined as no detectable leukemia by flow-cytometry, RT-PCR and/or NGS, when available). Among the 2 MRDpos patients, 1 (detectable by NGS only) relapsed 50 days after CAR T-cell infusion and 1 died secondary to invasive fungal infection 35 days after infusion. Within the MRDneg cohort, 6/13 patients proceeded to allogeneic HCT while in MRDneg/CR (time to HCT, range: 1.8-2.9 months post-CAR T-cell infusion). All 6 HCT recipients remain in remission with a median length of follow-up post-HCT of 238.5 days (range 19-441). In contrast, only 1 (14.3%) patient out of 7 MRDneg/CR patients who did not receive allogeneic HCT, remains in remission with a follow up of greater 1 year post-CAR T-cell infusion (HCT vs. no HCT: p&lt;0.01). The remaining 6 patients developed recurrent detectable leukemia within 2 to 9 months post-CAR T-cell infusion (1 patient detectable by NGS only). Notably, recurring leukemia remained CD19+ in 4 of 5 evaluable patients. All 4 patients with CD19+ relapse received a 2nd CAR T-cell infusion (one in combination with pembrolizumab) and 2 achieved MRDneg/CR. There were no significant differences in outcome between SJCAR19 study participants and patients who received tisagenlecleucel. With a median follow up of one year, the 12 month event free survival (EFS) of all 22 patients is 25% (median EFS: 3.5 months) and the 12 month overall survival (OS) 70% (median OS not yet reached). In conclusion, infusion of investigational and FDA-approved autologous CD19-CAR T cells induced high CR rates in pediatric patients with r/r ALL. However, our current experience shows that sustained remission without consolidative allogeneic HCT is not seen in most patients. Our single center experience highlights not only the need to explore maintenance therapies other than HCT for MRDneg/CR patients, but also the need to improve the in vivo persistence of currently available CD19-CAR T-cell products. Disclosures Sharma: Spotlight Therapeutics: Consultancy; Magenta Therapeutics: Other: Research Collaboration; CRISPR Therapeutics, Vertex Pharmaceuticals, Novartis: Other: Clinical Trial PI. Velasquez:St. Jude: Patents & Royalties; Rally! Foundation: Membership on an entity's Board of Directors or advisory committees. Gottschalk:Patents and patent applications in the fields of T-cell & Gene therapy for cancer: Patents & Royalties; TESSA Therapeutics: Other: research collaboration; Inmatics and Tidal: Membership on an entity's Board of Directors or advisory committees; Merck and ViraCyte: Consultancy.

scholarly journals B Cell Maturation Antigen-Specific CAR T Cells for Relapsed or Refractory Multiple Myeloma: A Meta-Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3113-3113 ◽  
Author(s):  
Nico Gagelmann ◽  
Francis Ayuketang Ayuk ◽  
Djordje Atanackovic ◽  
Nicolaus Kroeger
Keyword(s):  
T Cells ◽  
T Cell ◽  
High Risk ◽  
Research Funding ◽  
Response Rates ◽  
Overall Response ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Background Cellular immunotherapies represent an enormously promising strategy for relapsed/refractory multiple myeloma (RRMM). Chimeric antigen receptor (CAR) T cells targeting B cell maturation antigen (BCMA) have shown impressive results in early-phase clinical studies. Here, we summarize the current body of evidence on the role of anti-BCMA CAR T cell therapy for RRMM. Methods We performed a systematic literature review to identify all publicly available prospective studies. We searched Medline, Cochrane trials registry, and www.clinicaltrials.gov. To include the most recent evidence, meeting abstracts from international hematology congresses were added. A conventional meta-analysis was conducted using meta and metafor packages in R statistical software. Pooled event rates and 95% confidence intervals (CIs) were calculated using the inverse variance method within a random-effects framework. Main efficacy outcomes were overall response, complete response (CR), and minimal residual disease (MRD). Furthermore, relapse rates, progression-free survival, and overall survival were evaluated. In terms of safety, outcomes were cytokine release syndrome (CRS), neurotoxicity, and hematologic toxic effects. Results Fifteen studies comprising a total of 285 patients with heavily pretreated RRMM were included in quantitative analyses. Patients received a median of seven prior treatment lines (such as proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, stem cell transplantation) which included autologous stem cell transplantation in 90% of patients. The median age of patients was 59 years and median follow-up duration ranged from 1.1 to 11.3 months. Most studies used 4-1BB (or CD137), a member of the TNF receptor superfamily, as an activation-induced T-cell costimulatory molecule. Most studies used fludarabine and cyclophosphamide for lymphodepletion while one study used busulfan and cyclophosphamide and one study used cyclophosphamide only. Most studies used the former Lee criteria for CRS grading. Anti-BCMA CAR T cells resulted in a pooled overall response of 82% (95% CI, 74-88%). The pooled proportion of CR in all evaluable patients was 36% (95% CI, 24-50%). Within responders, the pooled proportion of MRD negativity was 77% (95% CI, 67-85%). Higher dose levels of infused CAR+ cells were associated with higher overall response rates resulting in a pooled proportion of 88% (95% CI, 78-94%). In addition, peak CAR T cell expansion appeared to be associated with responses.The presence of high-risk cytogenetics appeared to be associated with lower overall response rates resulting in a pooled proportion of 68% (95% CI, 47-83%). The presence of extramedullary disease at time of infusion did not influence outcome and was associated with similar response rates compared with RRMM patients who did not have extramedullary disease, resulting in a pooled proportion of 78% (95% CI, 47-93%). The pooled relapse rate of all responders was 45% (95% CI, 27-64%) and the median progression-free survival was 10 months. In terms of overall survival, pooled survival rates were 84% (95% CI, 60-95%) at last follow-up (median, 11 months). In terms of safety, the pooled proportion of CRS of any grade was 69% (95% CI, 51-83%). Notably, the pooled proportions of CRS grades 3-4 and neurotoxicity were 15% (95% CI, 10-23%) and 18% (95% CI, 10-31%). Peak CAR T cell expansion appeared to be more likely in the setting of more severe CRS in three studies. Most hematologic toxic effects of grade 3 or higher were neutropenia (85%), thrombocytopenia (70%), and leukopenia (60%). Conclusion Anti-BCMA CAR T cells showed high response rates, even in high-risk features such as high-risk cytogenetics and extramedullary disease at time of CAR T cell infusion. Toxicity was manageable across all early-phase studies. However, almost half of the patients who achieved a response eventually relapsed. Larger studies with longer follow-up evaluating the association of response and survival are needed. Disclosures Ayuk: Novartis: Honoraria, Other: Advisory Board, Research Funding. Kroeger:Medac: Honoraria; Sanofi-Aventis: Honoraria; Neovii: Honoraria, Research Funding; Riemser: Research Funding; JAZZ: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; DKMS: Research Funding.

scholarly journals Efficacy and Safety of JWCAR029 in Adult Patients with Relapsed and Refractory B-Cell Non-Hodgkin Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4187-4187 ◽  
Author(s):  
Zixun Yan ◽  
Wen Wang ◽  
Zhong Zheng ◽  
Ming Hao ◽  
Su Yang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Dose Level ◽  
Car T Cells ◽  
Car T Cell ◽  
Non Hodgkin Lymphoma ◽  
Car T

Abstract Introduction JWCAR029 is a novel CD19-directed 4-1BB stimulated chimeric antigen receptor T (CAR-T) cell type, which is different from JWCAR017 with independent production of CD4 and CD8 T cells and transfusion in non-fixed ratio. We conducted a single arm, open-label, dose escalation Phase I trial of JWCAR029 in relapsed and refractory B-cell non-Hodgkin lymphoma (NCT03355859). Methods From January to July 2018, 10 patients have been enrolled in this trial, including eight diffused large B cell lymphoma (DLBCL) and two MALT lymphoma, with median age of 47 years (range 32 to 59 years). All the patients received immunochemotherapy as induction and more than two lines of salvage treatment. Two patients received bridging chemotherapy after T-cell collection due to rapid tumor progression, followed by re-evaluation before CAR-T cell infusion. Lymphodepletion preconditioning was accomplished by fludarabine 25mg/m2/d and cyclophosphamide 250mg/m2/d on Day-4 to D-2, followed by CAR-T cell infusion on Day0. JWCAR029 was administrated as a single infusion in escalation dose levels, from 2.5×107 CAR-T cells (dose level 1, DL1) to 5.0×107 CAR-T cells (dose level 2, DL2) and to 1.0×108 CAR-T cells (dose level 3, DL3) according to mTPI-2 algorithm. Circulating blood count, serum biochemistry, and coagulation status were follow-up after infusion. Cytokines were assessed on a Luminex platform. Tumor evaluation was performed on Day 29 by PET-CT. PK data were detected by flow cytometry and real-time quantitative polymerase chain reaction system. All the adverse events were recorded. The study was approved by the Shanghai Rui Jin Hospital Review Board with informed consent obtained in accordance with the Declaration of Helsinki. Results The demographic characteristics of the patients were demonstrated in Table 1. Among six evaluable patients (3 of DL1 and 3 of DL2), the ORR was 100% on Day 29, including four complete remission and 2 partial remission. Cytokine release syndrome (CRS) was 100% in Gr 1, with main symptoms as fever (<39.0 degrees), fatigue, and muscle soreness. No neurotoxicity was observed. Four of the six patients with fever >38.0 degrees used prophylactic IL-6 Inhibitor (8mg/kg, ACTEMRA, two patients administered twice). No patients received steroids. The CRS showed no difference between dose level groups (p>0.99). Adverse effects included leukopenia (Gr 3-4: 83.3%, Gr 1-2: 16.7%), hypofibrinogenemia (Gr 1: 16.7%, Gr 2-4: 0%), liver dysfunction (Gr 1: 33.3%, Gr 2-4: 0%), elevated CRP (Gr 1: 83.3%, Gr 2-4: 0%), ferritin (Gr 1-2: 83.3%, Gr 2-4: 0%), or IL-6 (Gr 1-2:100%, Gr 3-4: 0%, Table 2). Conclusion Although long-term follow-up was needed, the preliminary data of six patients in this trial have demonstrated high response rates and safety of JWCAR029 in treating relapsed and refractory B-cell non-Hodgkin lymphoma. Disclosures Hao: JW Therapeutics: Employment, Equity Ownership.

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