Real-world outcomes of elderly patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) treated with chimeric antigen receptor T-cell (CAR-T) therapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8039-8039 ◽  
Author(s):  
Lindsey Fitzgerald ◽  
Adam Kittai ◽  
Loretta J. Nastoupil ◽  
Alexandra Waller ◽  
Caron A. Jacobson ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Hematopoietic Cell Transplantation ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
The Elderly ◽  
Tumor Characteristics ◽  
Car T ◽  
Baseline Characteristics

8039 Background: CAR-T has drastically improved outcomes for R/R DLBCL patients (pts). While CAR-T is now standard of care for the treatment of R/R DLBCL, little is known about its efficacy and toxicity in elderly pts. Methods: We conducted a multi-center retrospective analysis of pts age ≥ 70 years old with R/R DLBCL treated with either axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel). Pt demographics, tumor characteristics, CAR-T data, survival and toxicity outcomes were collected at the time of T cell infusion and follow up. Comorbidities were measured using the cumulative illness rating score (CIRS) and hematopoietic cell transplantation-specific comorbidity index (HCT-CI). Results: A total of 77 pts were analyzed with a median age of 73 (range, 70-88); 30 (39%) pts were age ≥75. Most pts received axi-cel (n = 61, 79%). Unfavorable tumor characteristics included 27 (35%) pts with activated B-cell subtype and 12 (16%) with double/triple hit lymphomas. Median CIRS was 8 (range 0-25) and median HCT-CI was 2 (range 0-9) with significantly higher median CIRS and HCT-CI in pts age ≥75. With a median time to follow up of 5.2 months (m), median progression free survival (PFS) was 12m and median overall survival (OS) was 15.5m. There was no difference in PFS when comparing younger pts (age 70-74) to older pts (age ≥ 75), but median OS was significantly shorter for older pts (7.8m vs. not reached; hazard ratio [HR] 0.46, CI 0.21-0.98; p = 0.04). In a multivariate analysis (MVA) of PFS adjusting for baseline characteristics, HCT-CI > 2 (HR 0.23, CI 0.07-0.77; p = 0.02) and use of axi-cel (HR 0.07, CI 0.02-0.32; p = < 0.001) were associated with worse PFS. Grade 3/4 (Lee criteria) cytokine release syndrome (CRS) and CAR-related encephalopathy syndrome (CRES) were assessed in MVA adjusting for baseline characteristics. CRS was associated with CIRS ≥6 (odds ratio [OR] 3.92, CI 1.07-14.3; p = 0.002) and use of axi-cel (OR 44.9, CI 8.20-245.6; p = 0.006). CRES was associated with older age (OR 6.10, CI 1.86-20.0; p = 0.003), CIRS ≥6 (OR 3.92, CI 1.07-14.3; p = 0.04) and use of axi-cel (OR 44.9, CI 8.2-245.6; p = < 0.0001). Conclusions: Pts age ≥75 treated with CAR-T had worse OS, but comparable PFS as compared to younger pts. Validated frailty measurements (CIRS) predicted for increased CRS and CRES. Use of axi-cel was associated with worse PFS and increased toxicities in the elderly, but propensity matched scoring analysis will need to confirm this. Additional pts and longer follow up are required to validate these results.

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.

scholarly journals Systematic Literature Review of the Clinical Evidence in Relapsed/Refractory (R/R) Large B-Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5821-5821
Author(s):  
David G. Maloney ◽  
Fei Fei Liu ◽  
Lisette Nientker ◽  
Cathelijne Alleman ◽  
Brian Hutton ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T ◽  
Large B Cell

Introduction: Large B-cell lymphoma (LBCL) is the most common subtype of non-Hodgkin lymphoma. Frontline treatment is curative in ~60% of patients (pts); however, ~30% of pts relapse and ~10% are refractory to frontline treatment. Treatment options for pts with relapsed/refractory (R/R) disease, especially in the third-line or greater (3L+) setting, have been primarily salvage chemotherapies (CTs). Recently, 2 CAR T cell products, axicabtagene ciloleucel (Yescarta®) and tisagenlecleucel (Kymriah®), and the antibody-drug conjugate, polatuzumab vedotin (Polivy®), were approved in the 3L setting. A systematic literature review (SLR) of R/R LBCL was conducted to identify relevant evidence on clinical outcomes in LBCL pts, including these new therapies, within the second-line and greater (2L+) or 3L+ setting, and to define the unmet medical need. Methods: This SLR was conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions and European Union Health Technology Assessment requirements. The review identified randomized and nonrandomized/observational studies within R/R LBCL, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma grade 3B (FL3B), primary mediastinal large B-cell lymphoma (PMBCL), DLBCL transformed from indolent lymphomas, and R/R DLBCL with secondary central nervous system (SCNS) involvement. Sources were EMBASE, MEDLINE, The Cochrane Library, and clinical conferences (ASCO, ESMO, EHA, ASH, ICML, AACR, and EORTC) from Jan 2000 to Apr 2019. Results : Following screening of 8683 database records and additional sources, 103 publications covering 78 unique studies were identified. Studies identified were characterized by line of treatment and R/R LBCL subtype (Figure). OS, PFS, DOR, OR, and safety observed from the identified studies were described. Disease subtypes, pt eligibility criteria, and length of follow-up varied notably across studies. In the 3L+ population, 11 salvage CT and 2 CAR T cell therapy studies reported survival outcomes. With salvage CT, the reported ORR across studies ranged from 0% to 54%, while CR ranged from 5.6%-31%. Median OS (mOS) ranged between 3-9 months, with one outlying study reporting mOS at 20 months. Median PFS (mPFS) reported within the salvage CT studies ranged from 2-6 months. Among CAR T cell therapies, pts treated with axicabtagene ciloleucel (n=101) reported a CR rate of 58% and median DOR (mDOR) was 11.1 months after a median follow-up of 27.1 months. mPFS was 5.9 months and mOS was not reached. At a median follow-up of 19.3 months, pts treated with tisagenlecleucel (n=115) had a CR of 40% but the mDOR was not reached. mOS was 11.1 months for all infused patients. In the 2L+ transplant-eligible population (36 studies), pts who received high-dose CT + HSCT achieved mOS between 9 months to 5 years. In the transplant noneligible population, 16 studies reported mOS between 3-20 months. Studies involving mixed transplant-eligible and noneligible populations (30 studies) reported mOS of 1-17 months. A few studies with limited sample sizes were found to report outcomes in LBCL subtypes (eg, PMBCL, SCNS lymphoma, DLBCL transformed from non-FL indolent lymphoma, FL3B). In the 3L+ setting, 1 study reported that mOS was not reached after a median of 6.6 months. In the 2L+ setting, 4 studies reported mPFS and mOS outcomes ranging between 2-9 months and 10-16 months, respectively. Among studies assessing safety of salvage CTs in R/R LBCL, neutropenia, leukocytopenia, thrombocytopenia, and infections were the most commonly reported adverse events (AEs), with neutropenia being the most reported. Among the 3 studies reporting safety outcomes of CAR T cell therapy, data suggest that hematologic AEs (possibly related to lymphodepleting CT), cytokine release syndrome, and neurotoxicity are the most reported. Conclusions : Despite the availability of new therapies for 2L+ and 3L + LBCL, examination of the current evidence has shown that there exists a high unmet need for additional therapeutic options that provide favorable benefit/risk and durable response for these patients. Furthermore, limited data are available for the rarer subtypes of LBCL. Both findings represent important treatment gaps for R/R LBCL that must be addressed in future research geared toward improvement of the current treatment landscape. Disclosures Maloney: Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; Celgene,Kite Pharma: Honoraria, Research Funding; BioLine RX, Gilead,Genentech,Novartis: Honoraria; A2 Biotherapeutics: Honoraria, Other: Stock options . Liu:Celgene Corporation: Employment. Nientker:Celgene Corporation: Consultancy; Pharmerit Cöoperatief U.A.: Employment. Alleman:Pharmerit Cöoperatief U.A.: Employment; Celgene Corporation: Consultancy. Garcia:Celgene: Employment, Equity Ownership.

scholarly journals Improved Safety and Efficacy of a Multi-Target Chimeric Antigen Receptor Modified T Cell Therapy (4SCAR2.0) Against Relapsed or Refractory Lymphomas

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 47-47 ◽  
Author(s):  
Rui Zhang ◽  
Yuhua Li ◽  
Sanfang Tu ◽  
Rui Huang ◽  
Xun Lai ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Average Dose ◽  
Therapy Regimen ◽  
Single Target ◽  
Car T ◽  
Dual Target

BACKGROUND: Chimeric antigen receptor-modified T cell (CART) therapy holds great promise as a novel cancer therapy approach. Although CART cell therapy has revolutionized the treatment of B-cell non-Hodgkin lymphomas (NHLs), relapsed/refractory NHLs including diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), and follicular lymphoma (FL) have not responded well to the currently approved CART cell products. The existing limitations include antigen escape, toxicities of currently approved CART cells, and the high cost of manufacture of a product which is only used for a single patient (pt). The development of an innovative multi-CART therapy using a safety improved CAR design may overcome the above limitations. METHODS: Lymphoma pts who have exhausted all available treatments with progressive or stable disease and life expectancy &gt;2 months were enrolled in the study. Lymphoma biopsies were immunostained for various target antigens including CD19, CD20, CD22, CD30, CD38, CD70 and PSMA. An advanced CART therapy regimen, CAR 2.0, has been developed, which involves a primary and a booster CAR-T cell infusions targeting multiple antigens identified on each pt's tumor. Autologous T cells were apheresis collected and transduced with an apoptosis-inducible, safety-engineered lentiviral CAR with the following intracellular signaling domains: CD28/CD27/CD3ζ-iCasp9 (4SCAR). Pts received cyclophosphamide/fludarabine chemotherapy conditioning 1-2 days before infusion of 1.21- 4.87x106 CART cells/kg per infusion. The quality of apheresis cells, efficiencies of gene transfer and T cell proliferation, CAR T infusion dose and blood CAR copies were quantitatively documented. RESULTS: Total 60 pts were evaluated at three months follow-up time, including 42 pts with DLBCL, 10 with PMBCL, 7 with FL and 1 with gastric mucosal associated lymphoid tissue lymphoma (MALT). The median age was 47 years (range, 2-77), including 31 males and 29 females. Pt characteristics include 16 pts with stage IV disease (27%), 2 after allo-transplantation (3.3%), 4 with bone marrow involvement (6.7%), 8 with CNS involvement (13%), and 7 received prior PD-1 antibody treatment (12%). The performance status of 52 of the 60 patients (87%) was Eastern Co-operative Oncology Group score 0 at time of infusion. The study included two treatment cohorts: 30 pts received single 4SCAR19 cells, and 30 pts received CAR2.0 targeting CD19 plus an additional target, depending on the individual pt's tumor antigen staining results. In the DLBCL cohort, 25 pts received single target 4SCAR19 cell infusion, at an average dose of 1.42x106 CART cells/kg, and resulted in 7 complete response (CR), 9 partial response (PR), 3 stable disease (SD) and 6 progressive disease (PD). The other 17 DLBCL pts received dual target CART infusions (CD19 plus CD20, CD22, CD38 or CD70) at an average dose of 2.32x106 CART cells/kg, and resulted in 7 CR, 8 PR ,1 SD and 1 PD. The 5 FL pts received dual target CD19+CD22 CART infusions, at an average dose of 4.64x106 CAR-T cells/kg, and resulted in 4 CR, and 1 PR. The 10 PMBCL pts, 3 received single target 4SCAR19 cell infusions, at an average dose of 2.85x106 CART cells/kg, and resulted in 1 PR and 2 PD; the other 7 PMBCL pts received dual target CART infusions (CD19+CD22, CD30, or CD20), at an average dose of 4.87x106 CART cells/kg, and resulted in 4 CR, 2 PR and 1 PD. The MALT pt received double CART cell infusions, 2.8x106 4SCAR19 cells/kg and 2x106 4SCAR-PSMA cells/kg, and achieved PR. None of these pts developed greater than grade 2 CRS response, except for 1 DLBCL pt, who achieved CR following a grade 3 CRS. The toxicity profile of the 4SCART is consistent with our previous experience with B cell acute lymphoblastic leukemia. In summary, the comparison between single versus double CART cell infusions clearly illustrates an increased response rate for the double CART cohorts, either in DLBCL pts or in all lymphoma pts, as illustrated in the summary pie graphs below. CONCLUSIONS: The results of the multi-target 4SCAR2.0 therapy for the treatment of highly resistant lymphomas have demonstrated increased safety and improved response rate with this novel approach. There is clear overall clinical benefit with the multi-target CART regimen as compared with the single CD19 CART treatment. Continued follow-up will verify whether the 4SCAR2.0 therapy regimen can achieve long term overall survival. Figure Disclosures No relevant conflicts of interest to declare.

REAL-WORLD RESULTS ON CD19 CAR T-CELL FOR 60 FRENCH PATIENTS WITH RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA INCLUDED IN A TEMPORARY AUTHORIZATION FOR USE PROGRAM

2019 ◽  
Vol 37 ◽  
pp. 301-301 ◽  
Author(s):  
C. Thieblemont ◽  
S. Le Gouill ◽  
R. Di Blasi ◽  
G. Cartron ◽  
F. Morschhauser ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Real World ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T ◽  
Large B Cell

scholarly journals Influence of TP53 Mutation on Survival of Diffuse Large B-Cell Lymphoma in the CAR T-Cell Era

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5592
Author(s):  
Edit Porpaczy ◽  
Philipp Wohlfarth ◽  
Oliver Königsbrügge ◽  
Werner Rabitsch ◽  
Cathrin Skrabs ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Tp53 Mutation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Refractory/relapsed diffuse large B-cell lymphoma (DLBCL) is associated with poor outcome. The clinical behavior and genetic landscape of DLBCL is heterogeneous and still not fully understood. TP53 mutations in DLBCL have been identified as markers of poor prognosis and are often associated with therapeutic resistance. Chimeric antigen receptor T-cell therapy is an innovative therapeutic concept and represents a game-changing therapeutic option by supporting the patient’s own immune system to kill the tumor cells. We investigated the impact of TP53 mutations on the overall survival of refractory/relapsed DLBCL patients treated with comparable numbers of therapy lines. The minimum number of therapy lines was 2 (median 4), including either anti-CD19 CAR T-cell therapy or conventional salvage therapy. A total of 170 patients with DLBCL and high-grade B-cell lymphoma with MYC, BCL2, and/or BCL6 rearrangements (DHL/THL), diagnosed and treated in our hospital between 2000 and 2021, were included. Twenty-nine of them received CAR T-cell therapy. TP53 mutations were found in 10/29 (35%) and 31/141 (22%) of patients in the CAR T-cell and conventional groups, respectively. Among the 141 patients not treated with CAR T cells, TP53 mutation was an independent prognostic factor for overall survival (OS) (median 12 months with TP53 vs. not reached without TP53 mutation, p < 0.005), but in the CAR T cell treated group, this significance could not be shown (median OS 30 vs. 120 months, p = 0.263). The findings from this monocentric retrospective study indicate that TP53 mutation status does not seem to affect outcomes in DLBCL patients treated with CAR T-cell therapy. Detailed evaluation in large cohorts is warranted.

scholarly journals Real-World Outcome of Dose-Adjusted EPOCH-R, a Single-Centre Experience

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 27-28
Author(s):  
Rachel Wong ◽  
Roopesh R. Kansara
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Time Interval ◽  
Cns Involvement ◽  
Free Survival ◽  
Aggressive B Cell Lymphoma

Introduction Dose adjusted (DA) EPOCH-R is an intensive outpatient infusional regimen, that incorporates intrathecal (IT) methotrexate to treat patients with aggressive B-cell lymphoma including HIV associated aggressive B-cell lymphoma, double-hit lymphoma (DHL), primary mediastinal B-cell lymphoma (PMBCL), Burkitt's lymphoma (BL) ineligible for intensive therapy, and gray zone lymphoma (GZL) with features in between BL and diffuse large B-cell lymphoma (DLBCL). We aimed to evaluate non-trial, progression-free survival (PFS) and overall survival (OS) of Manitoba patients treated with DA-EPOCH-R, assess the role of prophylactic IT chemotherapy and toxicities. Methods Patients in MB approved to receive DA-EPOCH-R were identified through the CCMB Provincial Oncology Drug Program (PODP) database. Patients were included if they were older than 17 years, received at least 1 cycle of DA-EPOCH-R and with a diagnosis of HIV associated aggressive B-cell lymphoma, DHL, PMBCL, BL ineligible for more aggressive therapy, or GZL. All other diagnoses were excluded. Baseline demographic data, treatment characteristics, treatment responses, and treatment toxicity were collected. The primary endpoints of the study were progression free survival (PFS) and overall survival (OS). PFS was the time interval between the date of diagnosis to date of progression, last follow-up, or death from any cause. OS was the time interval between date of diagnosis to date of death by any cause, or last follow-up. The study was approved by the University of Manitoba Research Ethics Board and the CancerCare Manitoba Research Resource Impact Committee. Results A total of 40 patients were approved for DA-EPOCH-R between 2013 and 2019. 10 of these patients were excluded. 4 patients never received the therapy, 4 patients were treated in the relapsed setting, and 2 patients had histologies outside the inclusion criteria. Of the 30 patients included, 19 (63%) were male, 11 (37%) were female. The median age at diagnosis was 55 years (range 20-88). Our cohort was composed of DHL (n=9), triple hit lymphoma (THL, n=5), BL (n=4), GZL (n=3), and HIV-associated DLBCL (n=2). 87% (n=26) had advanced stage disease. By revised-IPI, 19 (63.3%) had poor prognosis (R-IPI ≥ 3). Response rate was 90%; CR 53.3% (n=16) and PR 37% (n=11). At a median follow-up of 25.3 months, the median PFS was 33.3 months and median OS was not reached. By histological subtype, median PFS was not reached in DHL, however THL, BL and PMBCL had worse median PFS (6.1, 8.4, and 5.6 months, respectively). Only 1 patient had CNS involvement at time of diagnosis. Of the patients with no documented CNS disease at presentation (n=29), none developed CNS involvement, including those who did not receive IT methotrexate. Median chemotherapy cycles per patient was 6 (range 1-6) and median IT treatment was 3 (range 0-6). 3 patients did not receive IT prophylaxis, and 2 stopped after 1 cycle due to intolerance. 56.7% (n=17) were able to undergo dose escalation beyond dose level 1, and 40% (n=T12) tolerated maximum dose level 3 or higher.77% of patients (n=23) experienced at least one adverse event of grade 3 or higher. 17 (57%) patients required blood transfusion at least once. 10 (33%) experienced neuropathy, 4 requiring vincristine dose reduction. 9 (30%) patients had febrile neutropenia complicating a total of 22 treatment cycles. 8 patients had grade 2-3 infectious complications. Conclusions While the real-world survival data for patients with DHL and HIV-associated lymphoma treated with DA-EPOCH-R are encouraging, those with THL, BL, and PMBCL did not attain durable response. Considering no patients (including those who did not receive IT chemotherapy) experienced CNS relapse, the role of IT chemotherapy needs to be further clarified. Disclosures No relevant conflicts of interest to declare.

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.

scholarly journals Accelerated, but not conventional, radiotherapy of murine B-cell lymphoma induces potent T cell–mediated remissions

2018 ◽  
Vol 2 (19) ◽  
pp. 2568-2580 ◽  
Author(s):  
Suparna Dutt ◽  
Michelle B. Atallah ◽  
Yoshitaka Minamida ◽  
Alexander Filatenkov ◽  
Kent P. Jensen ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cell ◽  
Cd8 T Cells ◽  
Hematopoietic Cell Transplantation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Tumor Irradiation ◽  
Total Radiation Dose

Abstract Conventional local tumor irradiation (LTI), delivered in small daily doses over several weeks, is used clinically as a palliative, rather than curative, treatment for chemotherapy-resistant diffuse large B-cell lymphoma (DLBCL) for patients who are ineligible for hematopoietic cell transplantation. Our goal was to test the hypothesis that accelerated, but not conventional, LTI would be more curative by inducing T cell–mediated durable remissions. We irradiated subcutaneous A20 and BL3750 lymphoma tumors in mice with a clinically relevant total radiation dose of 30 Gy LTI, delivered in 10 doses of 3 Gy over 4 days (accelerated irradiation) or as 10 doses of 3 Gy over 12 days (conventional irradiation). Compared with conventional LTI, accelerated LTI resulted in more complete and durable tumor remissions. The majority of these mice were resistant to rechallenge with lymphoma cells, demonstrating the induction of memory antitumor immunity. The increased efficacy of accelerated LTI correlated with higher levels of tumor cell necrosis vs apoptosis and expression of “immunogenic cell death” markers, including calreticulin, heat shock protein 70 (Hsp70), and Hsp90. Accelerated LTI–induced remissions were not seen in immunodeficient Rag-2−/− mice, CD8+ T-cell–depleted mice, or Batf-3−/− mice lacking CD8α+ and CD103+ dendritic cells. Accelerated, but not conventional, LTI in immunocompetent hosts induced marked increases in tumor-infiltrating CD4+ and CD8+ T cells and MHCII+CD103+CD11c+ dendritic cells and corresponding reductions in exhausted PD-1+Eomes+CD8+ T cells and CD4+CD25+FOXP3+ regulatory T cells. These findings raise the possibility that accelerated LTI can provide effective immune control of human DLBCL.

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