Regional delivery of mesothelin-targeted CAR T cells for pleural cancers: Safety and preliminary efficacy in combination with anti-PD-1 agent.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2511-2511 ◽  
Author(s):  
Prasad S. Adusumilli ◽  
Marjorie Glass Zauderer ◽  
Valerie W. Rusch ◽  
Roisin O'Cearbhaill ◽  
Amy Zhu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Metabolic Response ◽  
Dose Range ◽  
Breast Cancers ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

2511 Background: We conducted a phase I dose escalation trial of first-in-human autologous chimeric antigen receptor (CAR) T-cell immunotherapy targeting mesothelin (MSLN), a cell-surface antigen that is highly expressed in pleural cancers- malignant pleural mesothelioma (MPM) and metastatic lung and breast cancers. Methods: A single dose of CD28-costimulated MSLN CAR T cells with the I-caspase-9 safety gene was administered intrapleurally in patients with MSLN-expressing pleural tumors. Following a 3+3 design, patients were treated in dose escalating cohorts (dose range 3E5 to 1E7 CAR T cells/kg) following IV cyclophosphamide lymphodepletion (first 3 patients did not receive cyclophosphamide). A subset of MPM patients received subsequent anti-PD-1 therapy, off-protocol, which we have shown to prolong CAR T-cell functional persistence in preclinical models. Results: Twenty patients (18 MPM, 1 lung cancer, 1 breast cancer) were treated (prior lines of therapy 1–8, 35% received ≥3 lines of therapy). No CAR T-cell–related toxicities higher than grade 1 were observed. Intense monitoring for on-target, off-tumor toxicity by clinical (chest or abdominal pain), radiological (CT/PET or echocardiogram for pericardial effusion, ascites), laboratory (troponin elevation), and EKG evaluation found no evidence of toxicity. Fourteen MPM patients received subsequent anti-PD1 therapy (1–21 cycles, pretreatment tumor PD-L1 < 10% in all patients except one), with 1 patient developing grade 3 pneumonitis that responded to steroid treatment. CAR T cells were detected in the peripheral blood of 13 of 14 patients (1-39 weeks). At data cut-off date (Jan 31, 2019), among 14 MPM patients that received combination therapy (follow-up 13-77 weeks, median 31 weeks), best responses included 2 patients with complete metabolic response on PET (62 and 39 weeks ongoing); 5 partial responses and 4 stable disease by investigator assessment. Conclusions: Intrapleurally administered MSLN-targeted CAR T cells were safe. Encouraging antitumor activity of MSLN-targeted CAR T-cell therapy was observed when combined with anti-PD1 therapy and shows promise for future development of this approach. Clinical trial information: NCT02414269.

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 DLBCL patients treated with CD19 CAR T cells experience a high burden of organ toxicities but low nonrelapse mortality

2020 ◽  
Vol 4 (13) ◽  
pp. 3024-3033 ◽  
Author(s):  
Kitsada Wudhikarn ◽  
Martina Pennisi ◽  
Marta Garcia-Recio ◽  
Jessica R. Flynn ◽  
Aishat Afuye ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Abstract Cytokine release syndrome (CRS) immune effector cell–associated neurotoxicity syndrome are the most notable toxicities of CD19 chimeric antigen receptor (CAR) T-cell therapy. In addition, CAR T-cell–mediated toxicities can involve any organ system, with varied impacts on outcomes, depending on patient factors and involved organs. We performed detailed analysis of organ-specific toxicities and their association with outcomes in 60 patients with diffuse large B-cell lymphoma (DLBCL) treated with CD19 CAR T cells by assessing all toxicities in organ-based groups during the first year posttreatment. We observed 539 grade ≥2 and 289 grade ≥3 toxicities. Common grade ≥3 toxicities included hematological, metabolic, infectious, and neurological complications, with corresponding 1-year cumulative incidence of 57.7%, 54.8%, 35.4%, and 18.3%, respectively. Patients with impaired performance status had a higher risk of grade ≥3 metabolic complications, whereas elevated lactate dehydrogenase was associated with higher risks of grade ≥3 neurological and pulmonary toxicities. CRS was associated with higher incidence of grade ≥3 metabolic, pulmonary, and neurologic complications. The 1-year nonrelapse mortality and overall survival were 1.7% and 69%, respectively. Only grade ≥3 pulmonary toxicities were associated with an increased mortality risk. In summary, toxicity burdens after CD19 CAR T-cell therapy were high and varied by organ systems. Most toxicities were manageable and were rarely associated with mortality. Our study emphasizes the importance of toxicity assessment, which could serve as a benchmark for further research to reduce symptom burdens and improve tolerability in patients treated with CAR T cells.

scholarly journals Factors associated with outcomes after a second CD19-targeted CAR T-cell infusion for refractory B cell malignancies

Blood ◽  
2020 ◽  
Author(s):  
Jordan Gauthier ◽  
Evandro D. Bezerra ◽  
Alexandre V. Hirayama ◽  
Salvatore Fiorenza ◽  
Alyssa Sheih ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Severe Toxicity ◽  
B Cell Malignancies ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T cell therapy has shown significant efficacy for relapsed or refractory (R/R) B-cell malignancies. Yet CD19 CAR T cells fail to induce durable responses in most patients. Second infusions of CD19 CAR T cells (CART2) have been considered as a possible approach to improve outcomes. We analyzed data from 44 patients with R/R B-cell malignancies (ALL, n=14; CLL, n=9; NHL, n=21) who received CART2 on a phase 1/2 trial at our institution. Despite a CART2 dose increase in 82% of patients, we observed a low incidence of severe toxicity after CART2 (grade ≥3 CRS, 9%; grade ≥3 neurotoxicity, 11%). After CART2, CR was achieved in 22% of CLL, 19% of NHL, and 21% of ALL patients. The median durations of response after CART2 in CLL, NHL, and ALL patients were 33, 6, and 4 months, respectively. Addition of fludarabine to cyclophosphamide-based lymphodepletion before CART1 and an increase in the CART2 dose compared to CART1 were independently associated with higher overall response rates and longer progression-free survival after CART2. We observed durable CAR T-cell persistence after CART2 in patients who received Cy-Flu lymphodepletion before CART1 and a higher CART2 compared to CART1 cell dose. The identification of two modifiable pre-treatment factors independently associated with better outcomes after CART2 suggests strategies to improve in vivo CAR T-cell kinetics and responses after repeat CAR T-cell infusions, and has implications for the design of trials of novel CAR T-cell products after failure of prior CAR T-cell immunotherapies.

scholarly journals Easix Predicts Severe Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neuro-Toxicity Syndrome (ICANS) in Patients Receiving CD19-Directed Chimeric Antigen Receptor T (CAR-T) Cell Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3861-3861
Author(s):  
Felix Korell ◽  
Olaf Penack ◽  
Michael Schmitt ◽  
Carsten Müller-Tidow ◽  
Lars Bullinger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Validation Cohort ◽  
T Cell Therapy ◽  
Training Cohort ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

Abstract Background: Endothelial dysfunction underlies the two main complications of chimeric antigen receptor T (CAR-T) cell therapy, i.e. cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The purpose of this retrospective analysis was to evaluate and validate the Endothelial Activation and Stress Index (EASIX)) as predictor for CRS and ICANS in patients receiving CD19-directed CAR-T cells. Methods: In this retrospective study, the training cohort recruited 107 patients treated with CAR-T cells at the University Hospital Heidelberg (n=83) and Charité University Medicine Berlin (n=24) from Oct 1, 2018, to March 31, 2021. Patients from the validation cohort (n=93) received CAR-T cells within the ZUMA-1 trial (ClinicalTrials.gov number: NCT02348216). The training cohort included 37 and 34 patients with relapsed / refractory (r/r) large B-cell lymphoma (LBCL) treated with Axi-cel and Tisa-cel, respectively, 1 patient with acute lymphoblastic leukemia (ALL) treated with Tisa-cel, 2 patients with mantle cell lymphoma (MCL) treated with KTE-X19 on an early access program; and 5 patients with LBCL, 5 patients with MCL, 5 patients with chronic lymphocytic leukemia, 4 patients with follicular lymphoma, and 14 patients with ALL treated with the 3 rd generation CAR-T HD-CAR-1. Median age was 57 (20-81) years, 72% were male. The 93 patients of the validation cohort all had r/r LBCL and received Axi-Cel. EASIX and serum levels of endothelial stress markers (angiopoietin-2, suppressor of tumorigenicity-2, soluble thrombomodulin and interleukin-8) were measured before start of lymphodepletion (EASIX-pre), and on days 0, 3, and 7 after CAR-T infusion. Primary endpoints were severe CRS and/or ICANS (grades 3-4). Results: Of the 107 patients of the training cohort, 61 patients (58%) developed CRS grades 1-4 and 24 patients (22%) developed ICANS grades 1-4. Higher grade CRS (grade ≥ 3) was seen in 6 patients (6%) with a median onset of 4 (0-14) days, while grade ≥ 3 ICANS occurred in 11 patients (11%; median onset 8 (4-17) days). EASIX values increased continuously from lymphodepletion to day 7 after CAR-T cell application (EASIX-pre 2.0 (0.5-76.6, interquartile range (IQR) 1.2/4.1); EASIX-d0 2.0 (0.3-91.5, IQR 1.2/4.2); EASIX-d3 2.4 (0.3-69.1, IQR 1.3/4.9) and EASIX-d7 2.7 (0.4-94.0, IQR 1.4/7.5)). In the validation cohort, Grade ≥ 3 CRS was observed in 10 patients (11%) and grade ≥ 3 ICANS in 28 patients (30%). Similar to the training cohort, EASIX values rose from lymphodepletion to day 3 after CAR-T cell application (EASIX-pre 1.8 (0.3-106.1, IQR 1.0/4.7); EASIX-d0 2.0 (0.3-120.4, IQR 1.1/4.1) and EASIX-d3 2.7 (0.3-57.9, IQR 1.7/6.2). In both cohorts, all EASIX values (pre, d0, d3, d7) were significantly higher in patients who developed either grade 3-4 CRS, ICANS or both (see Figure 1 for the training cohort). EASIX predicted grade 3-4 CRS and ICANS before lymphodepleting therapy (-pre), on day 0 and on day 3 in both cohorts: AUC EASIX-pre, training cohort 0.73 (0.62-0.85, p=0.002), validation cohort 0.76 (0.66-0.87, p&lt;0.001). An optimized cut-off for EASIX-pre (1.86) identified in the training cohort associated with an odds ratio (OR) of 5.07 (1.82-14.10), p=0.002 in the validation cohort in multivariable binary logistic regression analysis including age, gender, diagnosis and disease stage. Serum endothelial stress markers did not predict the two complications when assessed before CAR-T infusion, but diagnostic markers were strongly associated with CRS and ICANS grade 3-4 on day+7. Conclusions: EASIX-pre is a validated predictor of severe complications after CAR-T therapy and may help to tailor safety monitoring measures according to the individual patient's needs. Data on patients from the ZUMA-1 trial were provided by Kite/Gilead. Figure 1 Figure 1. Disclosures Penack: Astellas: Honoraria; Gilead: Honoraria; Jazz: Honoraria; MSD: Honoraria; Novartis: Honoraria; Neovii: Honoraria; Pfizer: Honoraria; Therakos: Honoraria; Takeda: Research Funding; Incyte: Research Funding; Priothera: Consultancy; Shionogi: Consultancy; Omeros: Consultancy. Schmitt: MSD: Membership on an entity's Board of Directors or advisory committees; Apogenix: Research Funding; Hexal: Other: Travel grants, Research Funding; TolerogenixX: Current holder of individual stocks in a privately-held company; Kite Gilead: Other: Travel grants; Bluebird Bio: Other: Travel grants; Novartis: Other: Travel grants, Research Funding. Müller-Tidow: Janssen: Consultancy, Research Funding; Pfizer: Research Funding; Bioline: Research Funding. Bullinger: Pfizer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Astellas: Honoraria; Menarini: Consultancy; Sanofi: Honoraria; Novartis: Consultancy, Honoraria; Seattle Genetics: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Bayer: Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Gilead: Consultancy; Hexal: Consultancy; Janssen: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding. Dreger: Gilead Sciences: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Janssen: Consultancy; Novartis: Consultancy, Speakers Bureau; BMS: Consultancy; Bluebird Bio: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau.

scholarly journals Combination of Anti-CD19 and Anti-CD20 Chimeric Antigen Receptor T Cells for Relapsed and Refractory Diffuse Larger B Cell Lymphoma: An Open-Label, Single-Arm, Phase Ⅰ/Ⅱ Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1590-1590 ◽  
Author(s):  
Wei Sang ◽  
Ming Shi ◽  
Jingjing Yang ◽  
Jiang Cao ◽  
Linyan Xu ◽  
...  
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 ◽  
Anti Cd20

Objective Chimeric antigen receptor T (CAR-T) cells therapy demonstrated remarkable efficiency in refractory and relapsed diffuse large B cell lymphoma (R/R DLBCL). Antigen-loss potentially leads to failure after single-target CAR-T cellss therapy. Aim to evaluate the efficiency and safety of double-target CAR-T cellss therapy, we performed a phase Ⅰ/Ⅱ clinical trial of combination anti-CD19 and anti-CD20 CAR-T cellss therapy for R/R DLBCL. Methods A total of 21 patients were enrolled, and patients were monitored for treatment response, toxicity and persistence. Patients received a conditioning regimen of fludarabine and cyclophosphamide followed by infusion of anti-CD19 and anti-CD20 CAR-T cellss. Results Of the 21 patients, 17 had objective response, and the ORR was 81.0% (95% CI, 58 to 95). 11 had CR, the CR rate was 52.4% (95% CI, 26 to 70). 4 of 9 patients in completed remission at 3 months remain in remission by 6 months, the CR rate was 44.4% (95% CI, 14 to 79). The median OS was 8.1 months (95% CI, 7 to 10) and the median PFS was 5.0 months (95% CI, 2 to 8). The median duration response was 6.8 months (95% CI, 4 to 10). Cytokine release syndrome (CRS) occurred in all patients. Of the 21 patients, 15 (71.4%) had grade 1-2 CRS, 6 (28.5%) had severe (≥grade 3) CRS, and no grade 5 CRS occurred. There were 5 patients with different degrees of neurotoxicity, namely CAR-T associated encephalopathy syndrome (CRES). There were 2 cases with grade 3 or above CRES, 5 of them were self-limited, and none of them died of severe CRS or CRES. There were significant differences in peak levels of IL-6 (P=0.004)、ferritin (P=0.008) and CRP (P=0.000) secretion between CRS 1-2 and CRS 3-4 patients within one month after CAR-T cell infusion. In terms of hematological toxicity, there were 11 cases of neutropenia above grade 3 (52.4%), 6 cases of anemia (28.6%) and 6 cases of thrombocytopenia (28.6%). After 12 patients with response and 1 patient without response received CAR-T cell therapy, CD19 cell subsets all disappeared after 2 weeks. The level of serum immunoglobulin in 14 patients with response decreased progressively after 1 week of treatment with CAR-T cells, and maintained at a relatively low level. Eight patients received intravenous immunoglobulin during CAR-T cell therapy. Conclusion Anti-CD19 combined with anti-CD20 CAR-T cell is effective in the treatment of R/R DLBCL patients.2. Anti-CD19 combined with anti-CD20 CAR-T cell therapy has the occurrence of CRS, CRES and hematological toxicity, and adverse reactions could be controlled. This is the first report to our knowledge of successful treatment of combination of anti-CD19 and anti-CD20 CAR-T cellss in R/R DLBCL. Our results provide strong support for further multiple-target CAR-T cells therapy, which could potentially resolve antigen-loss related failure. Disclosures No relevant conflicts of interest to declare.

scholarly journals Efficacy and Safety of CAR-Modified T Cell Therapy in Patients with Relapsed or Refractory Multiple Myeloma: A Meta-Analysis of Prospective Clinical Trials

2020 ◽  
Vol 11 ◽  
Author(s):  
Xinrong Xiang ◽  
Qiao He ◽  
Yang Ou ◽  
Wen Wang ◽  
Yu Wu
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Target Selection ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Background: In recent years, chimeric antigen receptor-modified T (CAR-T) cell therapy for B-cell leukemia and lymphoma has shown high clinical efficacy. Similar CAR-T clinical trials have also been carried out in patients with refractory/relapsed multiple myeloma (RRMM). However, no systematic review has evaluated the efficacy and safety of CAR-T cell therapy in RRMM. The purpose of this study was to fill this literature gap.Methods: Eligible studies were searched in PUBMED, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), CNKI, and WanFang from data inception to December 2019. For efficacy assessment, the overall response rate (ORR), minimal residual disease (MRD) negativity rate, strict complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) were calculated. The incidence of any grade cytokine release syndrome (CRS) and grade ≥3 adverse events (AEs) were calculated for safety analysis. The effect estimates were then pooled using an inverse variance method.Results: Overall, 27 studies involving 497 patients were included in this meta-analysis. The pooled ORR and MRD negativity rate were 89% (95% Cl: 83–94%) and 81% (95% Cl: 67–91%), respectively. The pooled sCR, CR, VGPR, and PR were 14% (95% Cl: 5–27%), 13% (95% Cl: 4–26%), 23% (95% Cl: 14–33%), and 15% (95% Cl: 10–21%), respectively. Subgroup analyses of ORR by age, proportion of previous autologous stem cell transplantation (ASCT), and target selection of CAR-T cells revealed that age ≤ 55 years (≤55 years vs. &gt; 55 years, p = 0.0081), prior ASCT ≤70% (≤70% vs. &gt; 70%, p = 0.035), and bispecific CAR-T cells (dual B-cell maturation antigen (BCMA)/BCMA + CD19 vs specific BCMA, p = 0.0329) associated with higher ORR in patients. Subgroup analyses of remission depth by target selection suggested that more patients achieved a better response than VGPR with dual BCMA/BCMA + CD19 CAR-T cells compared to specific BCMA targeting (p = 0.0061). In terms of safety, the pooled incidence of any grade and grade ≥ 3 CRS was 76% (95% CL: 63–87%) and 11% (95% CL: 6–17%). The most common grade ≥ 3 AEs were hematologic toxic effects.Conclusion: In heavily treated patients, CAR-T therapy associates with promising responses and tolerable AEs, as well as CRS in RRMM. However, additional information regarding the durability of CAR-T cell therapy, as well as further randomized controlled trials, is needed.

Idecabtagene vicleucel (ide-cel; bb2121), a BCMA-targeted CAR T-cell therapy, in patients with relapsed and refractory multiple myeloma (RRMM): Initial KarMMa results.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8503-8503 ◽  
Author(s):  
Nikhil C. Munshi ◽  
Larry D. Anderson, Jr ◽  
Nina Shah ◽  
Sundar Jagannath ◽  
Jesus G. Berdeja ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dose Range ◽  
Efficacy And Safety ◽  
Target Dose ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

8503 Background: Outcomes are poor in triple-class exposed RRMM patients (pts) who progress on immunomodulatory agents (IMiDs), proteasome inhibitors (PIs), and CD38 antibodies (mAbs). Ide-cel, a BCMA targeted CAR T cell therapy, showed promising tolerability and efficacy in RRMM pts in the phase I CRB-401 study ( NEJM2019;380:1726). We present primary efficacy and safety data from the pivotal phase II KarMMa trial of ide-cel in RRMM (NCT03361748). Methods: Enrolled pts had ≥3 prior regimens (including IMiD, PI, and CD38 mAb) and were refractory to their last regimen per IMWG criteria. After lymphodepletion (cyclophosphamide 300 mg/m2+ fludarabine 30 mg/m2 x 3), pts received 150─450 × 106 CAR+ T cells (target dose range). Endpoints included overall response rate (ORR; primary), complete response (CR) rate, duration of response (DoR), and PFS. Results: Of 140 pts enrolled, 128 received ide-cel. Median age was 61 y; median no. of prior regimens was 6; 84% were triple- and 26% were penta-refractory. Most pts (88%) had bridging therapy. At data cutoff (16 Oct 2019), median follow up was 11.3 mo. ORR was 73% and median PFS was 8.6 mo; both increased with higher dose (Table). All subgroups had an ORR ≥50%, including older and high-risk pts. Most common any-grade (Gr) toxicities were cytopenias (97%) and cytokine release syndrome (CRS; 84%). CRS was mainly Gr 1/2; 5 pts (5%) had Gr 3, 1 had Gr 4, and 1 had Gr 5 (at 300 × 106). Neurotoxicity developed in 23 pts (18%); 4 (3%) Gr 3 and 0 Gr ≥4. Median peak CAR+ T cell expansion occurred at 11 d. Expansion was higher in responders and parameters (AUC0−28d, Cmax) increased with higher dose, with exposure overlap across doses. Persistence was durable, with CAR+ T cells detected in 29/49 (59%) and 4/11 pts (36%) at 6 and 12 mo. Conclusions: Ide-cel demonstrated deep, durable responses in heavily pretreated RRMM pts. Efficacy and safety reflected prior reports and support a favorable ide-cel clinical benefit-risk profile across the target dose range. Clinical trial information: NCT03361748 . [Table: see text]

scholarly journals Clinical presentation, management, and biomarkers of neurotoxicity after adoptive immunotherapy with CAR T cells

Blood ◽  
2019 ◽  
Vol 133 (20) ◽  
pp. 2212-2221 ◽  
Author(s):  
Philipp Karschnia ◽  
Justin T. Jordan ◽  
Deborah A. Forst ◽  
Isabel C. Arrillaga-Romany ◽  
Tracy T. Batchelor ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clinical Presentation ◽  
Massachusetts General Hospital ◽  
Lymphoblastic Leukemia ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

Abstract Chimeric antigen receptor (CAR) T cells have emerged as a promising class of cell-based immunotherapy in refractory malignancies. Neurotoxicity represents a common and potentially life-threatening adverse effect of CAR T cells, and clinical experience is limited. Here, we describe the clinical presentation and management of 25 adult patients who presented with neurotoxic syndromes after CAR T-cell therapy at the Massachusetts General Hospital. This cohort includes 24 patients treated with CD19-directed CAR T cells for non-Hodgkin lymphoma (n = 23) and acute lymphoblastic leukemia (n = 1), and 1 patient treated with α-fetoprotein–directed CAR T cells for hepatocellular carcinoma (n = 1). Twelve of the 25 patients (48%) developed grade 1-2 neurotoxicity and 13 patients (52%) presented with grade 3-4 neurotoxicity. We found that lower platelet counts at time of CAR T-cell infusion were associated with more severe neurotoxicity (P = .030). Cytokine release syndrome occurred in 24 of 25 patients (96%). Serum levels of ferritin peaked with onset of neurologic symptoms, and higher ferritin levels were associated with higher neurotoxicity grade. Grade 3-4 neurotoxicity correlated negatively with overall survival (OS) (P = .013). Median OS of the entire cohort was 54.7 weeks. Eight patients (32%) with grade 3-4 neurotoxicity were deceased at database closure, whereas none died with neurotoxicity grade 1-2. High pretreatment lactate dehydrogenase was frequently encountered in lymphoma patients with grade 3-4 neurotoxicity and correlated negatively with progression-free survival (P = .048). We did not find evidence that steroid use ≥7 days altered the patient’s outcome when compared with &lt;7 days of steroids. Management of CAR T cell–mediated neurotoxicity warrants evaluation in prospective clinical trials.

scholarly journals Feasibility of Outpatient CAR T Cell Therapy: Experience of a Single Institution

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4828-4828
Author(s):  
Yusra F Shao ◽  
Dipenkumar Modi ◽  
Andrew Kin ◽  
Asif Alavi ◽  
Lois Ayash ◽  
...  
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

Abstract Background Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a promising therapeutic option for relapsed/refractory non-Hodgkin lymphoma. However, access to CAR T cell therapy remains limited as CAR T cells are routinely administered in the hospital setting. Hence, there's a growing interest in standardizing outpatient administration of CAR T cells to increase patient access and minimize costs. Here, we describe our institution's experience with outpatient administration of CAR T cells. Methods In this retrospective study, we reviewed who received CAR T cell therapy in the outpatient setting at Karmanos Cancer Center between June 2019 and June 2021.Charts were reviewed for age, disease pathology, prior lines of therapy, need for hospitalization within 30 days, development of CRS and/or neurotoxicity, need for ICU admission, need for steroids and/or tocilizumab, length of admission, and disease state at last follow up. All patients received fludarabine and cyclophosphamide as lymphodepletion (LD) therapy day -5 to -3. CAR T cells were infused on day 0. Patients subsequently followed up in clinic daily for 2 weeks and were started on allopurinol, ciprofloxacin, fluconazole, acyclovir and levetiracetam. First response was assessed by FDG PET scan 4 weeks after CAR T cell . Results A total of 12 patients received CAR T cells during the study period. All patients had a diagnosis of DLBCL and received Tisagenlecleucel. Median age at CAR T cell therapy was 69.5 years (40-78 years). Median number of prior lines of therapy was (2-3) while 2 patients had received prior stem cell transplantation. Table 1 describes patient characteristics and lines of therapy. Two patients received bridging therapy prior to LD. Overall response rate was 58.3% (complete response-3, partial response-4). Median duration of follow up was 6.7 (0.6-13.8 months). Four patients required subsequent therapy after CAR T cell for disease progression while 9 patients were alive at the time of data cut off. Figure 1 summarizes disease response and follow . Table 2 summarizes complications during follow up. Nine (75%) patients developed anemia (grade 3-4 n=4, 33.3%), 8 (66.7%) developed thrombocytopenia (grade 3-4 n= 3, 37.5%), and 8 (66.7%) developed neutropenia (grade 3-4 n=8, 66.7%). Median time to platelet recovery to &gt;,000 and neutrophil recovery to &gt;500 was 66 days (44-81 days) and 11.5 days (6-65 days), respectively. Three (25%) patients required platelet and red blood cell transfusion support. Six (50%) patients developed cytokine release syndrome (CRS) with median grade 2 (range 1-3, grade 3-4 n=1). Five (5/6) patients required hospitalization, five (5/6) required tocilizumab, and one (1/6) required steroids. One (8.3%) patient developed neurotoxicity of grade 1 severity improved without systemic therapy. Six patients required hospitalization within 30 days of CAR T cell infusion. Median day of admission from CAR T cell infusion was 4 days (range 2-12 days (range 2-12 days, admission within 3 days n=2, admission under observation n=1). Patient characteristics at admission are summarized in table 3. Of these, 5 patients were diagnosed with CRS,1 patient with colitis and none with blood stream infection. Two patients required ICU admission. Median length of hospital admission was 5.5 days (2-9 days). All patients were alive at discharge while 1 patient required subsequent admission within 30 . Conclusion Outpatient administration of Tisagenlecleucel is feasible with low risk of hospital admission within 3 days of infusion. Adoption of outpatient CAR T cell therapy may increase patient access for treatment of DLBCL and diseases such as multiple myeloma while reducing administration costs for this novel therapy. Figure 1 Figure 1. Disclosures Modi: Genentech: Research Funding; Seagen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees. Deol: Kite, a Gilead Company: Consultancy.

scholarly journals Updated Analysis of a Phase 1, Open-Label Study of LCAR-B38M, a Chimeric Antigen Receptor T Cell Therapy Directed Against B-Cell Maturation Antigen, in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 955-955 ◽  
Author(s):  
Wan-Hong Zhao ◽  
Jie Liu ◽  
Bai-Yan Wang ◽  
Yin-Xia Chen ◽  
Xing-Mei Cao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Median Duration ◽  
Phase 1 ◽  
Open Label ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

Abstract LCAR-B38M is a bispecific chimeric antigen receptor T cell (CAR T) therapy directed against B-cell maturation antigen (BCMA). The bi-epitope BCMA binding moieties confer high avidity binding and distinguish LCAR-B38M from other BCMA CAR constructs. Preliminary results of LCAR-B38M in patients (pts) with relapsed/refractory (R/R) multiple myeloma (MM) showed encouraging efficacy and manageable safety (Fan et al.JCO 2017;35:18_suppl LBA3001). Here we present updated safety and efficacy results of the trial. LEGEND-2 (NCT03090659) is an ongoing phase 1, single-arm, open-label multicenter study evaluating LCAR-B38M in pts (18-80 years) with R/R MM. Lymphodepletion was performed using 3 doses of cyclophosphamide 300 mg/m2 on days -5, -4, and -3. Five days after lymphodepletion, LCAR-B38M CAR T cells (median CAR+ cell dose = 0.5x106 cells/kg, [range, 0.07-2x106]) were given in 3 infusions (20, 30, and 50% of total dose). The primary objective is to evaluate the safety of LCAR-B38M CAR T cells; the secondary objective is to evaluate the anti-myeloma response of the treatment. Adverse events (AEs) were graded using the Common Terminology Criteria for AE, v.4.03, and cytokine release syndrome (CRS) was assessed according to Lee et al. (Blood 2014;124:188-95). Response was evaluated using International Myeloma Working Group criteria. This analysis presents data from a single institution. As of June 25, 2018, 57 pts have been infused with LCAR-B38M CAR T cells. The median age was 54 years (range, 27-72), median number of prior therapies was 3 (range, 1-9), and 74% of pts had stage III disease by Durie-Salmon staging. The median duration of follow-up for all pts was 12 months (range, 0.7-25). AEs were reported by all pts; most common were pyrexia (91%), CRS (90%), thrombocytopenia (49%), and leukopenia (47%). Grade ≥3 AEs were reported by 65% of pts; most common were leukopenia (30%), thrombocytopenia (23%), and increased aspartate aminotransferase (21%). CRS was mostly grade 1 (47%) and 2 (35%); 4 pts (7%) had grade 3 cases. Liver function abnormalities were the most common signs of end organ injury among pts with CRS. The median time to onset of CRS was 9 days (range, 1-19). All but 1 CRS events resolved, with a median duration of 9 days (range, 3-57). No clear relationship was demonstrated between dose and CRS; there may be some effect at higher doses, but conclusions are limited by the small number of pts in the grade 3 CRS group (n=4; Figure 1A). Neurotoxicity was observed in 1 pt who had grade 1 aphasia, agitation, and seizure-like activity. The overall response rate (partial response [PR] or better) was 88% (95% confidence interval [CI], 76-95). Complete response (CR) was achieved by 42 pts (74%; 95% CI, 60-85), very good partial response was achieved by 2 pts (4%; 95% CI, 0.4-12), and PR was achieved by 6 pts (11%; 95% CI, 4-22; Figure 1B). Among pts with CR, 39/42 were minimal residual disease (MRD) negative by 8-color flow cytometry. The median time to initial response was 1 month (range, 0.4-4). No clear relationship between LCAR-B38M CAR T cell dose and response was observed (Figure 1C). BCMA expression did not correlate with clinical response. The median duration of response (DOR) was 16 months (95% CI, 12-not reached [NR]). The median DOR for pts who achieved a CR was 22 months (95% CI, 14-NR). At data cutoff, 18 pts (36%) who achieved PR or better progressed. The median progression-free survival (PFS) for all treated pts was 15 months (95% CI, 11-NR); median PFS for pts who achieved CR was 24 months (95% CI, 15-NR). The median overall survival was not reached. Overall, 17 pts died during the study and follow-up period; causes of death were progressive disease (PD; n=14), suicide after PD (n=1), esophagitis (n=1), and pulmonary embolism and acute coronary syndrome (n=1). Peak levels of LCAR-B38M (≥1x104 copies/µg genomic DNA) were observed in a majority of pts with blood samples for analysis (n=32). LCAR-B38M CAR T cells were not detectable in peripheral blood in 71% of pts at 4 months; 5 pts showed CAR T cell persistence up to 10 months. This ongoing first-in-human study has provided initial proof-of-concept that bispecific LCAR-B38M CAR T cells may be a highly effective therapy for R/R MM. LCAR-B38M CAR T cell therapy displayed a manageable safety profile consistent with its known mechanism of action and demonstrated deep and durable responses in pts with R/R MM. A phase 1/2 study of LCAR-B38M in R/R MM has been initiated in the US (NCT03548207). Disclosures Zhuang: Nanjing Legend Biotech: Employment. Fan:Nanjing Legend Biotech: Employment.

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