Cardiovascular Side Effects of Chimeric Antigen Receptor (CAR) T-Cell Products: A Single Center Experience in a Minority Rich, Ethnically Diverse Real-World Cohort

Abstract Introduction: Axicabtagene ciloleucel (Axi-Cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy demonstrated efficacy in patients with refractory large B cell lymphoma when conventional treatments failed. Cardiovascular side effects of CAR-T therapy that have been noticed so far include hypotension, left ventricular dysfunction, heart failure and cardiogenic shock in settings of CRS. We aimed to assess the cardiovascular side effects in a racially/ ethnically diverse patient population who underwent CAR-T cell therapy. Methods: This study included thirty-four consecutive adult patients who underwent treatment with CAR-T cell product Axi-Cel at an academic health system between 2018-2021. We performed detailed chart reviews and collected information related to the age, gender, hematological malignancy diagnosis, other medical comorbidities, therapeutic regimens, pretreatment cardiac risk factors, development of CRS with grading , pre and post treatment electrocardiograms ( EKG), transthoracic echocardiograms( TTE) , death, cause of death, and duration between administration of CAR-T products and death of the patients . We collected data pertaining to development of hypotension, EKG changes, arrhythmias, left ventricular systolic dysfunction, heart failure (HF), acute cardiac syndrome (ACS), troponin elevation, echocardiographic changes post CAR-T cell therapy, and follow up visits after 60 days to get information pertaining to development of hypotension, tachycardia or SOB, need for further cardiac work up, and cardiology referral. Results: Mean age of our study participants was 65 years ranging between ages of 30 and 84 years with 38 % (13/34) female and 62% (21/34) male study participants. Study population was predominantly Hispanic, white and African American with percentages of 35% (12/34), 32% (11/34), 26 %(9/34) respectively followed by categories Asian 2.9% (1/34) and other at 2.9 %( 1/34). Sixty seven percent (22/37) patients had primary diffuse large B cell lymphoma (DLBCL) and 32% (11/34) had different primary malignancy with transformation into DLBCL. Thirty eight percent individuals had received autologous stem cell transplant. Sixty one percent (21/34) of our study participants developed cytokine release syndrome, with CRS grades 1-3 in 57% (12/29), 25% (08/21) and 4.7% (1/21) respectively. Thirty four percent (09/34) study participants died after cellular therapy. Septic shock and disease progression each were primary cause of death in 55 % (5/9) of patients, followed by respiratory failure in 22% (2/9) and ventricular fibrillation leading to cardiac arrest in 11% (1/9) of the patients. Mean duration of time between administration of therapy and death was 70 days. The cardiovascular effects noted immediately post CAR-T treatment and observations from follow up oncology visits are listed in Table 1. Troponin elevation was noticed in two study participants in settings of CRS, but one participant exhibited troponin elevation in absence of CRS. Seventeen percent of patients (6/34) developed left ventricular dysfunction after Axi-Cel. Most of them had concurrent CRS but one case of fatal heart failure occurred in absence of CRS. Three patients developed fatal arrhythmias post CAR-T therapy (1- Non sustained ventricular tachycardia in settings of CRS, 2- supraventricular tachycardia in settings of CRS, and 3- ventricular tachycardia needing defibrillation without CRS). Only one patient developed ACS in settings of CRS which lead to patient's demise. Conclusions: In a real world, minority rich cohort, we observed that a significant number of our patients had preexisting cardiovascular findings including abnormal EKG (30% excluding sinus tachycardia) or abnormal echocardiographic findings (46%). Hypotension (68%) and sinus tachycardia (59%) were the most commonly observed cardiovascular toxicities. Although Axi-Cel was in general safe and well tolerated, we observed cardiovascular side effects associated with and independent of CRS. Notably, six patients (17%) developed left ventricular dysfunction including one fatality which was independent of CRS. There was only one fatal coronary syndrome and two cases of troponin elevation in our series. Our study stresses the importance of a thorough cardio-oncology evaluation before proceeding with cellular therapies as well as involved follow up during and after hospitalization. Figure 1 Figure 1. Disclosures Gritsman: iOnctura: Research Funding. Shastri: Kymera Therapeutics: Research Funding; Onclive: Honoraria; Guidepoint: Consultancy; GLC: Consultancy. Verma: BMS: Research Funding; GSK: Research Funding; Incyte: Research Funding; Medpacto: Research Funding; Curis: Research Funding; Eli Lilly: Research Funding; Stelexis: Consultancy, Current equity holder in publicly-traded company; Novartis: Consultancy; Acceleron: Consultancy; Celgene: Consultancy; Stelexis: Current equity holder in publicly-traded company; Throws Exception: Current equity holder in publicly-traded company.

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Costs of Postinfusion Monitoring By Site of Care for Patients with Relapsed/Refractory (R/R) Large B-Cell Lymphoma (LBCL) Who Received Third-Line or Later Treatment with Lisocabtagene Maraleucel (liso-cel) in the Transcend NHL 001 and Outreach Trials

Blood ◽

10.1182/blood-2020-141415 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 16-17

Author(s):

M. Lia Palomba ◽

Monika P. Jun ◽

Jacob Garcia ◽

James Lymp ◽

November McGarvey ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

Research Funding ◽

Cost Ratio ◽

Publicly Traded ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T ◽

Third Line

Background: Chimeric antigen receptor (CAR) T cell therapy is generally limited to inpatient settings; yet, exploration of outpatient infusion and monitoring is ongoing. Information on health care resource utilization (HCRU) and costs associated with CAR T cell therapy administration is limited and may differ by postinfusion monitoring site. Liso-cel is an investigational, CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells. An interim analysis from the OUTREACH study (NCT03744676) observed lower HCRU with outpatient vs inpatient administration (Bachier et al. J Clin Oncol 2020;38:8037). The patient journey after CAR T cell therapy administration may differ for patients with outpatient vs inpatient monitoring and may result in varying costs of care. This study estimated the cost of postinfusion monitoring by site of care for patients with R/R LBCL who received third-line or later treatment with liso-cel in the TRANSCEND NHL 001 (TRANSCEND; NCT02631044) and OUTREACH clinical trials. Methods: This retrospective study analyzed HCRU reported in clinical trial databases from TRANSCEND and OUTREACH. A 2-step microcosting method was used to identify key HCRU and to estimate postinfusion costs: (1) HCRU was analyzed from the index date (day of liso-cel infusion) through the 6-month follow-up; and (2) costs were applied to each HCRU. HCRU included standard inpatient and intensive care unit (ICU) length of stay (LOS), diagnostics (laboratory work and imaging), procedures (dialysis and intubation), and medications (supportive care, prophylactic treatment, and adverse event management). Unit costs were obtained from the health care system (provider) perspective and adjusted to 2020 US dollars. Cost per standard inpatient day ($2,542) was estimated from Healthcare Cost and Utilization Project databases, and cost per ICU day ($7,556) was sourced from Dasta et al (Crit Care Med. 2005;33:1266-77). All medication costs were obtained from REDBOOK (IBM Micromedex) using wholesale acquisition costs. Diagnostic and procedure costs were obtained from the Centers for Medicare & Medicaid Services laboratory fee schedule, physician fee schedule, or outpatient prospective payment system. A payment-to-cost ratio was applied to Medicare payment rates to estimate unit costs. Costs were adjusted to reflect the site of care where the HCRU occurred. A cost ratio was applied to adjust costs from the physician's office/community oncology clinic to the hospital outpatient department (Winfield, Muhlestein, Leavitt Partners; 2017) and from outpatient to inpatient (Meisenberg et al. Bone Marrow Transplant. 1998;21:927-32). Costs were aggregated by HCRU category, specifically medications, diagnostics, procedures, and facility costs. An average total cost by post-liso-cel infusion month was calculated for patients with ongoing status in that month (patients censored due to data cutoff were not included). Analyses were stratified by site of postinfusion monitoring (inpatients vs outpatients). Results: A total of 303 patients with R/R LBCL across the 2 trials received liso-cel and postinfusion monitoring (inpatients, n = 256; outpatients, n = 47). HCRU and LOS, including standard inpatient and ICU days, are shown in the Table. Inpatients had higher rates of inpatient stays (<100% vs 62%) and tocilizumab use (for CRS and/or NE; 20% vs 9%) than outpatients, respectively. Rates of ICU admission, corticosteroid use, vasopressor use, dialysis, and intubation were similar between groups. Median and average LOS in standard inpatient and ICU settings were higher among inpatients. Median (range) total LOS for inpatients and outpatients was 15 (0-88) and 4 (0-77) days, respectively. The estimated mean postinfusion cost of care was $89,535 for inpatients and $36,702 for outpatients. Over 6 months, most costs were incurred in the first month after infusion ($50,369 [56%] for inpatients and $19,837 [54%] for outpatients). Costs were largely driven by facility costs, namely standard inpatient and ICU stays (Figure). Conclusions: Lower overall HCRU was observed with outpatient liso-cel postinfusion monitoring, primarily due to hospitalizations, which resulted in a mean 6-month cost savings of $52,833 (59%) compared with inpatient monitoring. These results are based on national average costs and may not be generalizable to specific institutions. Disclosures Palomba: Regeneron: Research Funding; Juno Therapeutics, a Bristol-Meyers Squibb Company: Honoraria, Research Funding; Genentech: Research Funding; Merck: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Pharmacyclics: Honoraria. Jun:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Garcia:Bristol-Myers Squibb Company: Current equity holder in publicly-traded company; Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment. Lymp:Bristol-Myers Squibb Company: Current equity holder in publicly-traded company; Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment. McGarvey:Pfizer, Inc.: Ended employment in the past 24 months; BluePath Solutions: Current Employment. Gitlin:BMS: Research Funding. Pelletier:BMS: Current Employment, Current equity holder in publicly-traded company. Nguyen:BluePath Solutions: Current Employment.

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Qualitative Analysis of the Treatment Experience and Well-Being of Patients with Relapsed/Refractory (R/R) Large B-Cell Lymphoma (LBCL) Enrolled in 2 Trials of Lisocabtagene Maraleucel (liso-cel) during the Initial Stages of Therapy

Blood ◽

10.1182/blood-2020-137656 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 22-23

Author(s):

Tanya Siddiqi ◽

Ulrich Jaeger ◽

Olga Moshkovich ◽

Jennifer Devlen ◽

Matthew Miera ◽

...

Keyword(s):

Clinical Trials ◽

T Cell ◽

Cell Therapy ◽

Research Funding ◽

Well Being ◽

Publicly Traded ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

Background: Chimeric antigen receptor (CAR) T cell therapy is a novel treatment modality for patients with R/R LBCL. Limited information exists regarding patients' views of CAR T cell therapy. Our research aimed to better understand patients' needs by capturing their expectations/concerns, current well-being, and treatment experiences during the beginning stages of CAR T cell therapy in the clinical trial setting. Methods: Patients with R/R LBCL from 2 ongoing trials of the investigational, CD19-directed CAR T cell therapy liso-cel (TRANSCEND WORLD [NCT03484702] or PLATFORM [NCT03310619]) were invited to participate in an optional interview component. Semistructured interviews were conducted to gain insight about patients' experience with CAR T cell therapy in the clinical trials. Interviews of ≤1 hour (in-person or over the phone) were conducted in parallel with screening procedures (interview 1), after leukapheresis (interview 2), and up to 3 days after liso-cel infusion (interview 3). Interviews were audio recorded and transcribed. MAXQDA (VERBI GmbH, Berlin, Germany) qualitative analysis software was used to manage and thematically organize interview transcript data to identify key concepts related to each research objective. Previously reported results of interview 1 showed a high perception of unmet needs, lack of alternative options, and expectations for positive outcomes. The analysis presented here primarily focused on interviews 2 and 3. Denominators shown in the Results vary by question as some patients skipped questions. Results: A total of 75 interviews were analyzed, including 35, 24, and 16 patients at interviews 1, 2, and 3, respectively, across sites in the US (n = 14), Europe (n = 26), and Japan (n = 2). Among 42 patients who completed ≥1 interview, the mean age was 62 years and 69% were male. Treatment Experience: Of 24 patients who completed interview 2, 22 (92%) reported positive experiences during leukapheresis and 16 (67%) reported the procedure was as expected. Patients thought the most difficult part of leukapheresis was the length of the procedure (n = 8/21 [38%]). Of 15 patients who provided feedback on lymphodepleting chemotherapy, a majority reported that it was as expected (n = 8 [53%]) or easier than expected (n = 3 [20%]); when asked about the most difficult part, many patients (n = 7/17 [41%]) discussed side effects (eg, nausea, fatigue, and lack of appetite). Of patients who described liso-cel infusion as different than expected, differences included easier (n = 12/13 [92%]) or quicker (n = 3/12 [25%]) than expected, and 5/12 (42%) reported few/no side effects within 3 days post-infusion. Over half of patients (n = 8/14 [57%]) reported that the infusion, as a whole, was not difficult. Changes over Time: At interviews 1, 2, and 3, respectively, 47% (n = 14/30), 47% (n = 9/19), and 69% (n = 9/13) of patients reported hoping for successful treatment. Similarly, patients generally had fewer concerns later in the process, with 21 (64%) and 11 (33%) of 33 patients reporting side-effect and treatment efficacy concerns, respectively, during interview 1 vs 5 (33%) and 3 (20%) of 15 patients, respectively, during interview 3. At time of enrollment, most patients (n = 21/34 [62%]) were able to function normally or with minimal impact from their lymphoma, although most reported some symptoms like fatigue, pain, or stomach problems. At interview 1, 14 (40%) of 35 patients were employed; most patients reported no changes in their work life at interviews 2 (n = 19/20 [95%]) and 3 (n = 11/12 [92%]). From enrollment to immediately post-infusion, the physical health of most patients remained stable (n = 4/16 [25%]) or deteriorated (n = 9/16 [56%]). However, most patients (n = 14/15 [93%]) reported feeling positive at interview 3. Conclusions: This study provided the unique opportunity to gather feedback directly from patients participating in clinical trials of liso-cel therapy, specifically during the initial treatment stages. The overall impression of the treatment was positive, with most patients reporting that study procedures were easier than expected. The results of this qualitative research provide useful insight into the motivations, expectations, and experiences of patients with R/R LBCL receiving liso-cel therapy, which can inform the design of health care support systems and future clinical trials to better meet patients' needs. Disclosures Siddiqi: AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Juno: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Oncternal: Research Funding; TG Therapeutics: Research Funding; Janssen: Speakers Bureau; Seattle Genetics: Speakers Bureau. Jaeger:F. Hoffmann-La Roche: Honoraria, Research Funding; AbbVie: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Honoraria; CDR Life AG: Consultancy, Research Funding; Miltenyi: Consultancy, Honoraria. Moshkovich:Icon Plc: Current Employment. Devlen:Icon Plc: Current Employment, Current equity holder in publicly-traded company. Miera:Icon Plc: Current Employment. Williams:Icon Plc: Current Employment. Hasskarl:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Liu:Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Braverman:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Salles:MorphoSys: Consultancy, Honoraria, Other; Kite: Consultancy, Honoraria, Other; Debiopharm: Consultancy; Novartis: Consultancy, Honoraria, Other; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Gilead: Consultancy, Honoraria, Other: Participation in educational events; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Epizyme: Consultancy; Takeda: Consultancy, Honoraria, Other; Bristol Myers Squibb: Consultancy, Other; Karyopharm: Consultancy; Amgen: Honoraria, Other: Participation in educational events; Celgene: Consultancy, Honoraria, Other: Participation in educational events; Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Autolus: Consultancy; Genmab: Consultancy.

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Evaluation of Eligibility for CAR-T Cell Therapy in a Population-Based Cohort of 3550 Patients with Incident Diffuse Large B-Cell Lymphoma (DLBCL) in Sweden

Blood ◽

10.1182/blood-2020-138737 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 38-39

Author(s):

Karin Ekstroem Smedby ◽

Sara Harrysson ◽

Sara Ekberg ◽

Mats Jerkeman ◽

Per-Ola Andersson ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

Research Funding ◽

Eligibility Criteria ◽

T Cell Therapy ◽

Car T Cell ◽

Line Therapy ◽

Car T Cell Therapy ◽

Car T ◽

First Relapse

Background Today, even though most patients with diffuse large B-cell lymphoma (DLBCL) can be cured with standard immunochemotherapy, 20-30% are refractory to primary therapy or relapse during follow-up with a drastic worsening of the prognosis. In recent years, new promising treatment options including CAR-T cell therapy are becoming available for relapsed/refractory (R/R) DLBCL patients although so far with logistic challenges including disease control and toxicities, and a considerable cost. In view of these challenges, we aimed to estimate the proportion of patients with R/R DLBCL that are likely to be eligible for CAR-T cell therapy in clinical routine, and their expected outcome in the pre-CAR-T era. Methods All patients with DLBCL starting primary therapy with curative intent were identified in the Swedish Lymphoma Register for the period 2007-2014 (N=3550). Primary CNS and primary mediastinal B-cell lymphomas were excluded. Data regarding primary treatment response and relapse was validated through medical chart review in the entire cohort during follow-up until Dec 31st 2017, and information about additional treatment lines including disease characteristics, blood test results, and relapse treatment response was collected. Eligibility for CAR-T cell therapy was estimated retrospectively based on eligibility criteria specified in clinical trials, both at first relapse by applying similar criteria as in the ongoing TRANSFORM, ZUMA-7 or PILOT studies (hereafter termed "CAR-T-2ndline"), and at second relapse applying criteria similar to those specified in the JULIET trial (hereafter termed "CAR-T-3rdline"). Administration of second- and third-line therapies and corresponding response rates were considered as proxies for eligibility and response to bridging therapies. Criteria applied for "CAR-T-2ndline" included R/R DLBCL within 12 months of evaluation date of primary treatment, age 18-75 years, ECOG 0-1, and additional criteria as specified in the TRANSFORM trial (see figure footnote). Criteria applied for "CAR-T-3rdline" included relapse following second-line therapy, age 18-76 years, ECOG 0-1, and additional criteria as in the JULIET trial (see figure footnote). Individuals with missing data on performance status were assumed ineligible. We lacked information about other malignancies in the disease history. Overall survival probabilities were estimated with the Kaplan-Meier method among all R/R DLBCL patients in the trial-specified age intervals and separately among those fulfilling all trial criteria. Results In the cohort of 3550 curatively treated DLBCL patients, 847 (cumulative incidence 23%) experienced R/R disease during a median follow-up of 4.3 years. Median age at first relapse was 71 years (range 18-95 years). Overall, 308 patients ≤75 years experienced progression/relapse within 12 months and were able to start second-line therapy. Of these, 148 patients (17% of all R/R DLBCL patients) fulfilled trial eligibility criteria for "CAR-T-2ndline", of whom 60 responded with at least partial remission (overall response rate, ORR, 41%). At second relapse, 370 patients 76 years or younger received third-line therapy, of whom 55 (6.5% of all R/R DLBCL patients) were deemed eligible for "Car-T-3rdline", and 13 responded (ORR 24%, another 5 patients had SD). Two-year overall survival (OS) among all R/R DLBCL patients ≤75 years receiving second-line therapy was 20% (95% confidence interval, CI, 16-25%) (Fig 1). Among those eligible for "CAR-T-2ndline", 2-year OS was 24% (95% CI 17-31%). Among patients ≤76 years at second relapse, 2-year OS was 18% (95% CI 13-24%), and among those eligible for "CAR-T-3rdline", 21% (95% CI 11-32%). Conclusion In the population-based setting, one in six patients (17%) with R/R DLBCL fitted trial eligibility criteria for CAR-T-cell therapy at first relapse and only one in fifteen patients (6.5%) fitted trial criteria at second relapse at retrospective evaluation. Figures were reduced when adding requirement of response to relapse/bridging therapy. These estimates illustrate to what extent current CAR-T cell therapies may be applied in a routine setting when based on trial criteria, and the need for development of modified and additional therapies in this group. Outcome estimation confirmed a poor outcome in these groups and did not indicate that fulfillment of trial criteria led to selection bias in terms of survival. Disclosures Ekstroem Smedby: Janssen Cilag: Research Funding; Celgene: Other: Advisory Board; Takeda: Research Funding. Harrysson:Janssen Cilag: Research Funding. Jerkeman:Janssen: Research Funding; Roche: Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Gilead: Research Funding. Eloranta:Janssen Cilag: Research Funding.

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Single-Center Experience with Axicabtagene-Ciloleucel (Axi-cel) and Tisagenlecleucel (Tisa-cel) for Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Comparable Response Rates and Manageable Toxicity

Blood ◽

10.1182/blood-2020-142932 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 34-35

Author(s):

Veit Buecklein ◽

Viktoria Blumenberg ◽

Josephine Ackermann ◽

Christian Schmidt ◽

Kai Rejeski ◽

...

Keyword(s):

T Cell ◽

Research Funding ◽

B Cell Lymphoma ◽

Time Interval ◽

T Cell Therapy ◽

Car T Cell ◽

Single Center Experience ◽

Car T Cell Therapy ◽

Car T

The CD19 CAR T-cell products Axi-cel and Tisa-cel induce complete responses (CR) in 40-58% of patients (pts) with relapsed/refractory (r/r) Diffuse Large B-Cell Lymphoma (DLBCL). However, treatment can be associated with significant toxicity, with Cytokine release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) as the most prominent and specific adverse events of CAR T-cell therapy. Toxicity profiles differ between both commercially available products, mainly due to their divergent co-stimulatory domain (4-1BB in Tisa-cel vs. CD28 in Axi-cel). Here, we report our single-center experience of DLBCL patients treated with Axi-cel or Tisa-cel at the LMU Munich University Hospital between January 2019 and June 2020. Toxicities, response rates and survival of DLBCL patients were retrospectively assessed. As of June 2020, 48 patients were enrolled for CD19-CAR T-cell therapies at our centre, and 37 DLBCL patients (pts) were apheresed. Median time interval between apheresis and CAR T-cell treatment was 39 days. So far, 31 DLBCL pts were transfused (Axi-cel: 18, Tisa-cel: 13). Median age of transfused pts was 60 years (range 19-74, Axi-cel: 60 years, Tisa-cel: 60 years). ECOG was 0-1 in 19 and 2-3 in 12 pts at time of CAR T-cell transfusion (Axi-cel: 0-1 in 13 and 2-3 in 5 pts, Tisa-cel: 0-1 in 6 and 2-3 in 7 pts). 13 pts had undergone prior stem cell transplant (9 autologous, 3 allogeneic, Axi-cel: 4 auto, 2 allo; Tisa-cel: 5 auto, 1 allo). Median number of prior DLBCL therapy lines was four (range 2-9, Axi-cel: 4, Tisa-cel: 4). Only 9/31 pts (29%) met the inclusion criteria of the pivotal clinical trials (due to e.g. infection, CNS disease, thrombocytopenia) at time of enrolment into our CAR T-cell treatment program. 23 pts (74%) received bridging chemotherapy (Axi-cel: 13/18 pts [72%]; Tisa-cel: 10/13 [77%]). Further details on radiographic response and the incidence of toxicities for all treated pts are summarized in the accompanying table. Response assessment after three months using PET/CT was available for 28 pts. Objective response rate (ORR) was 46%, with CR in eight (28%) and partial remission (PR) in five pts (18%). CRS occurred in 29/31 pts (84% CRS °1-2, 10% °3). Tocilizumab was applied in all CRS pts, with a median of four total infusions (range 1-4). 16 pts (52%) developed ICANS (33% °1-2, 16% °3-4, and 3% °5), which was managed with steroids in 9/16 pts. With a median follow-up of seven months, median progression-free survival (PFS) was 2.4 months for all pts. PFS was significantly longer for pts with normal vs. elevated LDH at time of apheresis (not reached vs. 1.5 mo, p=0.031). PFS of patients with two prior lines of therapy (n=7) was comparable with pts with three (n=5) or more (n=15) lines (2 lines: 3.1 mo, ≥3 lines: 1.9 mo, p=0.520). The time interval of ≤ 12 months (n=8 pts) from initial diagnosis of DLBCL to CAR T-cell transfusion was not prognostic and did not identify patients with worse PFS (≤12 mo: 1.7 months, >12 mo: 2.8 mo, p=0.569). In summary, in our cohort of heavily pretreated patients with a median of four prior DLBCL therapy lines, we observed an ORR of 46% (28% CR) at 3 months after CAR T-cell therapy, with no significant differences between patients treated with Axi-cel and Tisa-cel. In line with results of the pivotal clinical trials, treatment with Axi-cel was associated with a moderately higher incidence of ICANS. Overall, CAR T-cell toxicities were well manageable. Normal LDH levels at time of apheresis identified patients with high probability of sustained remission. In contrast, the number of prior therapy lines or the time interval from initial diagnosis of DLBCL to CAR T-cell transfusion had no impact on PFS. These hypothesis-generating findings might be helpful for future clinical decision-making, but need to be confirmed in a larger cohort. Therefore, we have set up a comprehensive patient monitoring program to identify predictive clinical and immunological markers of response and survival in CAR T-cell treated DLBCL patients. We will present updated results with longer follow-up at the annual meeting. Figure Disclosures Buecklein: Celgene: Research Funding; Pfizer: Consultancy; Gilead: Consultancy, Research Funding; Novartis: Research Funding; Amgen: Consultancy. Blumenberg:Novartis: Research Funding; Celgene: Research Funding; Gilead: Consultancy, Research Funding. Subklewe:Seattle Genetics: Research Funding; Morphosys: Research Funding; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Pfizer: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria, Research Funding; Roche AG: Consultancy, Research Funding; AMGEN: Consultancy, Honoraria, Research Funding.

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Cytokine Release Syndrome: Inpatient Care for Side Effects of CAR T-Cell Therapy

Clinical Journal of Oncology Nursing ◽

10.1188/17.cjon.s2.29-34 ◽

2017 ◽

Vol 21 (2) ◽

pp. 29-34 ◽

Cited By ~ 10

Author(s):

Laura Smith ◽

Kimberly Venella

Keyword(s):

T Cell ◽

Side Effects ◽

Cell Therapy ◽

Inpatient Care ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

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Iomab with Adoptive Cellular Therapy (Iomab-ACT): A Pilot Study of 131-I Apamistamab Followed By CD19-Targeted CAR T-Cell Therapy for Patients with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia or Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2021-144994 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4810-4810

Author(s):

Mark B. Geyer ◽

Briana Cadzin ◽

Elizabeth Halton ◽

Peter Kane ◽

Brigitte Senechal ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Therapy ◽

B Cell ◽

Research Funding ◽

T Cell Therapy ◽

Car T Cells ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

Abstract Background: Autologous CD19-targeted chimeric antigen receptor-modified (CAR) T-cell therapy leads to complete responses (CR) in patients (pts) with (w/) relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL, >80% CR rate) and diffuse large B-cell lymphoma (DLBCL, ~40-55% CR rate). However, following fludarabine/cyclophosphamide (Flu/Cy) conditioning and CAR T-cell therapy w/ a CD28 costimulatory domain (e.g. 19-28z CAR T-cells), rates of grade ≥3 ICANS and grade ≥3 cytokine release syndrome (CRS) in pts w/ R/R DLBCL and morphologic R/R B-ALL exceed 30%. CRS and ICANS are associated w/ considerable morbidity, including increased length of hospitalization, and may be fatal. Host monocytes appear to be the major reservoir of cytokines driving CRS and ICANS post-CAR T-cell therapy (Giavradis et al. and Norelli et al., Nature Medicine, 2018). Circulating monocytic myeloid-derived suppressor cells (MDSCs) may also blunt efficacy of 19-28z CAR T-cells in R/R DLBCL (Jain et al., Blood, 2021). The CD45-targeted antibody radioconjugate (ARC) 131-I apamistamab is being investigated at myeloablative doses as conditioning prior to hematopoietic cell transplantation in pts w/ R/R acute myeloid leukemia. However, even at low doses (4-20 mCi), transient lymphocyte and blast reduction are observed. Preclinical studies in C57BL/6 mice demonstrate low-dose anti CD45 radioimmunotherapy (100 microCi) transiently depletes >90% lymphocytes, including CD4/CD8 T-cells, B-cells, NK cells, and T-regs, as well as splenocytes and MDSCs, w/ negligible effect on bone marrow (BM) hematopoietic stem cells (Dawicki et al., Oncotarget, 2020). We hypothesized a higher, yet nonmyeloablative dose of 131-I apamistamab may achieve more sustained, but reversible depletion of lymphocytes and other CD45 + immune cells, including monocytes thought to drive CRS/ICANS. We additionally hypothesized this approach (vs Flu/Cy) prior to CAR T-cell therapy would promote CAR T-cell expansion while reducing CSF levels of monocyte-derived cytokines (e.g. IL-1, IL-6, and IL-10), thus lowering the risk of severe ICANS (Fig 1A). Study design and methods: We are conducting a single-institution pilot study of 131-I apamistamab in lieu of Flu/Cy prior to 19-28z CAR T-cells in adults w/ R/R BALL or DLBCL (NCT04512716; Iomab-ACT); accrual is ongoing. Pts are eligible for leukapheresis if they are ≥18 years-old w/ R/R DLBCL (de novo or transformed) following ≥2 chemoimmunotherapy regimens w/ ≥1 FDG-avid measurable lesion or B-ALL following ≥1 line of multi-agent chemotherapy (R/R following induction/consolidation; prior 2 nd/3 rd gen TKI required for pts w/ Ph+ ALL) w/ ≥5% BM involvement and/or FDG-avid extramedullary disease, ECOG performance status 0-2, and w/ appropriate organ function. Active or prior CNS disease is not exclusionary. Pts previously treated w/ CD19-targeted CAR T-cell therapy are eligible as long as CD19 expression is retained. See Fig 1B/C: Post-leukapheresis, 19-28z CAR T-cells are manufactured as previously described (Park et al., NEJM, 2018). Bridging therapy is permitted at investigator discretion. Thyroid blocking is started ≥48h pre-ARC. 131-I apamistamab 75 mCi is administered 5-7 days pre-CAR T-cell infusion to achieve total absorbed marrow dose ~200 cGy w/ remaining absorbed dose <25 cGy at time of T-cell infusion. 19-28z CAR T-cells are administered as a single infusion (1x10 6/kg, B-ALL pts; 2x10 6/kg, DLBCL pts). The primary objective is to determine safety/tolerability of 131-I apamistamab 75 mCi given prior to 19-28z CAR T-cells in pts w/ R/R B-ALL/DLBCL. Secondary objectives include determining incidence/severity of ICANS and CRS, anti-tumor efficacy, and 19-28z CAR T-cell expansion/persistence. Key exploratory objectives include describing the cellular microenvironment following ARC and 19-28z CAR T-cell infusion using spectral cytometry, as well as cytokine levels in peripheral blood and CRS. The trial utilizes a 3+3 design in a single cohort. If dose-limiting toxicity (severe infusion-related reactions, treatment-resistant severe CRS/ICANS, persistent regimen-related cytopenias, among others defined in protocol) is seen in 0-1 of the first 3 pts treated, then up to 6 total (up to 3 additional) pts will be treated. We have designed this study to provide preliminary data to support further investigation of CD45-targeted ARCs prior to adoptive cellular therapy. Figure 1 Figure 1. Disclosures Geyer: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals, Inc: Research Funding; Amgen: Research Funding. Geoghegan: Actinium Pharmaceuticals, Inc: Current Employment. Reddy: Actinium Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Berger: Actinium Pharmaceuticals, Inc: Current Employment. Ludwig: Actinium Pharmaceuticals, Inc: Current Employment. Pandit-Taskar: Bristol Myers Squibb: Research Funding; Bayer: Research Funding; Clarity Pharma: Research Funding; Illumina: Consultancy, Honoraria; ImaginAb: Consultancy, Honoraria, Research Funding; Ymabs: Research Funding; Progenics: Consultancy, Honoraria; Medimmune/Astrazeneca: Consultancy, Honoraria; Actinium Pharmaceuticals, Inc: Consultancy, Honoraria; Janssen: Research Funding; Regeneron: Research Funding. Sauter: Genmab: Consultancy; Celgene: Consultancy, Research Funding; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Bristol-Myers Squibb: Research Funding; GSK: Consultancy; Gamida Cell: Consultancy; Novartis: Consultancy; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding. OffLabel Disclosure: 131-I apamistamab and 19-28z CAR T-cells are investigational agents in treatment of ALL and DLBCL

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Primary Progression on Frontline Therapy for Diffuse Large B-Cell Lymphoma Is Associated with a Poor Outcome Despite Subsequent CD19 Targeted CAR T-Cell Therapy

Blood ◽

10.1182/blood-2021-150735 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3855-3855

Author(s):

Ariel Perez Perez ◽

Grace Johnson ◽

Kedar Patel ◽

Brian Arciola ◽

Anthony Wood ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

B Cell ◽

Research Funding ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T ◽

Scientific Advisory ◽

Advisory Role

Abstract Introduction: Between 50-80% of patients with diffuse large B-cell lymphoma (DLBCL) are cured by frontline (1L) R-CHOP immunochemotherapy. Ultra-high risk (UHR) features for poor overall survival (OS) include: progression through the frontline therapy (primary progression, PP), presence of a MYC translocation (MYC-R+), and a high or high-intermediate National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) (Costa, Am. J. Hematol., 2017). We aim to explore the role of these UHR factors in the outcomes of DLBCL patients receiving standard of care (SOC) anti-CD19 CAR T-cell therapy. Methods: This is a retrospective single-center study of relapsed/refractory (R/R) DLBCL patients treated with either axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) as SOC at Moffitt Cancer Center according to the FDA label as of March 2021, or who were treated on the expanded access programs (EAP) for axi-cel (NCT03153462) and tisa-cel (NCT03601442) for the provision of CAR T when products fell outside of manufacturing specifications (OOS). We excluded patients who had received prior therapy for indolent B-cell lymphomas (iNHL). We defined patients with primary treatment failure (PTF) as: PP, residual disease after 1L therapy (RD), or early relapse within 6 months of 1L therapy (ER). For patients with PTF, we calculated the number of UHR features (0 to 3): MYC status, NCCN-IPI, and PP. Kaplan-Meier survival curves were used to compare progression free survival (PFS) and overall survival (OS) starting from the date of CAR T-cell infusion, with statistical significance determined using the log-rank test at the P<0.05 threshold. Results: A total of 187 R/R DLBCL patients received SOC or EAP CAR T-cell therapy, of which 116 had DLBCL with no prior therapy for iNHL and were included in this analysis. PTF occurred in 75 patients (65%), of which 30 (40%) patients had primary progression as the failure pattern, 23 (30.7%) patients had MYC-R detected by FISH, and 37 (49.3%) patients had intermediate-high/high NCCN-IPI scores at the time of PTF. The median follow up was 10.05 months. Of the 75 patients with PTF, 69 received axi-cel and 6 received tisa-cel. Main 1L therapies were R-CHOP in 59 (78.6%) cases and DA-EPOCH-R in 14 (18.7%). The median lines of therapy prior to CAR T-cell therapy was 3 (range 2-6 lines). The number of UHR features was associated with a shorter OS after CAR T-cell therapy. The OS for patients with 2-3 and 0-1 UHR were 5.3 months (95% CI, 3.7 to 15.13 months) and not reached, respectively (P=0.005; Figure 1A). In terms of PTF patterns, PP was associated with worse PFS and OS after CAR T-cell therapy compared to other patterns (RD/ER) (PP, mPFS 3.1 months vs RD/ER, mPFS not reached; p<0.001; PP, median OS 5.63 months vs RD/ER, mOS not reached, P<0.001; Figure 1B). Patients with PTF and MYC-R+ had no difference in PFS (P=0.51) but a shorter OS after CAR T-cell therapy compared to those without an identified MYC translocation (P=0.05). Patients with intermediate-high or high NCCN-IPI at time of PTF had similar PFS (P=0.75) and OS (P=0.34) to patients with intermediate-low or low NCCN-IPI. Conclusion: Patients with DLBCL who experience PP to frontline immunochemotherapy had shorter PFS and OS after subsequent CAR T-cell therapy compared to other PTF patterns. R/R DLBCL patients with PP represent a poor prognosis subgroup, even with CAR T-cell therapy. It will be important to determine if patients with primary progression have increased benefit from CAR T-cell therapy if it is provided at first relapse rather than after 2 or more prior lines of therapy. Our study suggests that mechanisms of tumor resistance to CAR T-cell therapy may be present in some patients from the time of upfront therapy. Figure 1 Figure 1. Disclosures Chavez: AstraZeneca: Research Funding; Merk: Research Funding; ADC Therapeutics: Consultancy, Research Funding; BMS: Speakers Bureau; MorphoSys, Bayer, Karyopharm, Kite, a Gilead Company, Novartis, Janssen, AbbVie, TeneoBio, and Pfizer: Consultancy; MorphoSys, AstraZeneca, BeiGene, Genentech, Kite, a Gilead Company, and Epizyme: Speakers Bureau. Shah: Pfizer: Consultancy, Other: Expenses; Incyte: Research Funding; Acrotech/Spectrum: Honoraria; BeiGene: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Precision Biosciences: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Other: Expenses; Servier Genetics: Other; Jazz Pharmaceuticals: Research Funding; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Adaptive Biotechnologies: Consultancy. Nishihori: Karyopharm: Research Funding; Novartis: Research Funding. Lazaryan: Kadmon: Consultancy; Avrobio: Membership on an entity's Board of Directors or advisory committees; Humanigen: Membership on an entity's Board of Directors or advisory committees. Davila: Precigen: Research Funding. Locke: Wugen: Consultancy, Other; Umoja: Consultancy, Other; Cowen: Consultancy; EcoR1: Consultancy; Takeda: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Legend Biotech: Consultancy, Other; Janssen: Consultancy, Other: Scientific Advisory Role; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; Calibr: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; Amgen: Consultancy, Other: Scientific Advisory Role; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding; Emerging Therapy Solutions: Consultancy; Gerson Lehrman Group: Consultancy; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy. Gaballa: Adaptive Biotechnologies: Research Funding; Epizyme: Consultancy, Research Funding; TG therapeutics: Consultancy, Speakers Bureau; Beigene: Consultancy; ADC Therapeutics: Consultancy. Jain: Kite/Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

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Evaluating Hematologist's Knowledge of CAR T-Cell Therapy in Hematologic Malignancies

Blood ◽

10.1182/blood-2018-99-115036 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2269-2269

Author(s):

Lauren Willis ◽

Sara R. Fagerlie ◽

Sattva S. Neelapu

Keyword(s):

T Cell ◽

Cell Therapy ◽

Board Of Directors ◽

Research Funding ◽

Hematologic Malignancies ◽

Advisory Committees ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

Abstract Background: The objective of this study was to assess current clinical practices of hematologist/oncologist (hem/onc) specialists related to chimeric antigen receptor (CAR) T-cell therapy in hematologic malignancies, in order to identify knowledge, competency, and practice gaps and barriers to optimal care. Methods: A continuing medical education (CME)-certified clinical practice assessment consisting of 25 multiple choice questions was developed to measure knowledge, skills, attitudes, and competence of hem/onc specialists regarding CAR T-cell therapy. The survey instrument was made available online to physicians without monetary compensation or charge. Respondent confidentiality was maintained, and responses were de-identified and aggregated prior to analyses. The activity launched on December 22, 2017 with global distribution, and participant responses are still being collected at the time of abstract submission. Results: At the time of this report there are 192 hem/onc activity participants, collection is on-going. Demographics are listed in Table 1 and levels of confidence and barriers to incorporating CAR T-cell therapy are listed in Table 2.Foundational KnowledgeSub-optimal knowledge was demonstrated in the area of CAR components, dosing, and FDA-approved indications.Over half (61%) could not correctly identify the components of a CAR construct (antigen-specific domain and the signaling domain).Almost half (45%) of the participants did not recognize that currently approved CAR T-cell therapies are dosed as a single infusion.25% demonstrated inaccurate knowledge by recommending patients wait 4 weeks after CAR T-cell infusion before driving.Over half (62%) of participants could not identify the FDA-approved indication for axicabtagene ciloleucel.Knowledge of Clinical Trial DataVery low awareness of efficacy data seen with various CAR T-cell products used to treat R/R B-cell ALL (ELIANA trial), R/R DLBCL (ZUMA-1, JULIET, TRANSCEND trials).Only 32% identified the correct CR/CRi rate seen with tisagenlecleucel in the ELIANA trial.Only 25% correctly identified the CR rate seen with axicabtagene ciloleucel in the ZUMA-1 trial.Only 32% demonstrated knowledge of the 6-month DFS rate for patients in the JULIET trial that had a CR at 3 months.Only 25% identified the association between the dose of JCAR017 and response rates from the TRANSCEND trial.Knowledge and Competence Managing Adverse EventsLack of competence recognizing and treating CAR T-cell associated adverse events such as cytokine release syndrome (CRS) and neurotoxicity.Almost half (44%) could not identify signs of CRS associated with CAR T-cell therapy and 43% lack knowledge that elevated serum C-reactive protein (CRP) is associated with the highest level of CRS (in patients with lymphoma receiving axicabtagene ciloleucel).41% could not identify that the mechanism of tocilizumab is to block IL-6 signaling.Over a third (35%) were unable to identify signs/symptoms/causes of neurotoxicity associated with CAR T-cell therapy.More than half of the learners (54%) could not identify the appropriate role of corticosteroid therapy after CAR T-cell administration in managing CRS and neurotoxicity. Conclusions: This activity found knowledge and competence deficits for hem/onc practitioners related to using CAR T-cell therapy for the treatment of patients with hematologic malignancies. Additionally, the activity demonstrated large gaps in confidence discussing CAR T-cell therapy with patients/families and managing adverse events. There is sub-optimal awareness of CAR T-cell foundational knowledge, clinical trial data, and recognition of common therapy related adverse events and management strategies. Additional education is needed to improve the knowledge, competence, and confidence of academic and community hem/onc specialists who care for patients with hematologic malignancies receiving CAR T-cell therapy as well as strategies for integrating novel agents into clinical practice. Disclosures Neelapu: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Karus: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Unum Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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CAR T cell therapy as a promising approach in cancer immunotherapy: challenges and opportunities

10.21203/rs.3.rs-203368/v1 ◽

2021 ◽

Author(s):

Maryam Akhoundi ◽

Mahsa Mohammadi ◽

Seyedeh Saeideh Sahraei ◽

Mohsen Sheykhhasan ◽

Nashmin Fayazi

Keyword(s):

T Cells ◽

T Cell ◽

Side Effects ◽

Cell Therapy ◽

Solid Tumors ◽

Hematologic Malignancies ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

Abstract Background Chimeric antigen receptor (CAR)-modified T cell therapy has shown great potential in the immunotherapy of patients with hematologic malignancies. In spite of this striking achievement, there are still major challenges to overcome in CAR T cell therapy of solid tumors, including treatment-related toxicity and specificity. Also, other obstacles may be encountered in tackling solid tumors, such as their immunosuppressive microenvironment, the heterogeneous expression of cell surface markers, and the cumbersome arrival of T cells at the tumor site. Although several strategies have been developed to overcome these challenges, aditional research aimed at enhancing its efficacy with minimum side effects, the design of precise yet simplified work flows and the possibility to scale-up production with reduced costs and related risks is still warranted.Conclusions Here, we review main strategies to establish a balance between the toxicity and activity of CAR T cells in order to enhance their specificity and surpass immunosuppression. In recent years, many clinical studies have been conducted that eventually led to approved products. To date, the FDA has approved two anti-CD19 CAR T cell products for non-Hodgkin lymphoma therapy, i.e., axicbtagene ciloleucel and tisagenlecleucel. With all the advances that have been made in the field of CAR T cell therapy for hematologic malignancies therapy, ongoing studies are focused on optimizing its efficacy and specificity, as well as reducing the side effects. Also, the efforts are poised to broaden CAR T cell therapeutics for other cancers, especially solid tumors.

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Targeted Integration of a CAR at a Novel Genomic Safe Harbor Directs Potent Therapeutic Outcomes

Blood ◽

10.1182/blood-2020-141967 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 28-28

Author(s):

Ashlesha Odak ◽

Han Yuan ◽

Judith Feucht ◽

Jorge Mansilla - Soto ◽

Justin Eyquem ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Mouse Model ◽

Research Funding ◽

Transgene Expression ◽

T Cell Therapy ◽

Car T Cell ◽

Therapeutic Outcomes ◽

Car T Cell Therapy ◽

Car T

Chimeric receptor antigen (CAR)-T cell therapy using CARs specific for CD19 have been remarkably successful for treating chemo-refractory/relapsed B cell malignancies. These successes not withstanding, therapeutic outcomes between patients are variable and occasional cases of clonal expansion of the transduced T cells have been observed, albeit without leukemic transformation. These issues are cause for concern and need to be addressed to achieve better and safer therapeutic outcomes. Clonal expansion due to insertional mutagenesis and variegated transgene expression due to position effects are well established to be the consequence of the semi-random integration pattern afforded by gamma-retroviral and lentiviral vectors. We previously established that integration of a CAR cDNA in the TCR alpha locus (TRAC) provides consistent, regulated expression of CD19 CARs and superior CAR T cell efficacy in a mouse model of B-cell acute lymphoblastic leukemia (B-ALL). Here, we identify a novel extragenic site devoid of any known function and remote from endogenous genes, i.e. a 'genomic safe harbor' (GSH), that can be efficiently targeted in human T cells and drives potent CAR T cell therapy in the B-ALL mouse model. To identify GSHs that could be efficiently targeted in T cells by CRISPR-Cas9 and that could also support durable transgene expression, we screened for genomic regions meeting both, GSH criteria and high chromatin accessibility in T cells as measured by ATAC-seq. In human primary T cells, we identified 379 such sites. Ten of the highest accessible sites were investigated. All showed high (>90%) cleavage efficiency and allowed for CAR cDNA targeted integration and expression which also translated into effective cytolytic activity of the CARs within a few days after transduction. However, thereafter CAR expression diminished over the course of a week at most but not all of these sites. In order to prevent possible heterochromatinization, we incorporated chromatin insulator elements with barrier activity flanking the CAR transcription unit. Incorporation of the chromatin insulator element dramatically improved CAR expression and functionality at one site, whereas 3 other GSHs tested were not affected. One of the 10 GSHs maintained long-term CAR expression without requiring an insulator and directed potent anti-leukemic CAR T cell efficacy in a B-ALL 'CAR stress test' mouse model, matching the T cell potency afforded by integrating the CAR cDNA at the TRAC locus. This finding highlights the major effect of the integration site on transgene expression and ensuing therapeutic efficacy. We identified an extragenic GSH site that can be used for effective T cell engineering and sustained expression of a CAR. Through this study, we provide a platform for identifying GSHs that could be reliably targeted for safe and predictable expression of CARs or other immunomodulatory transgenes to potentiate adoptive immunotherapy. Disclosures Sadelain: Fate Therapeutics: Patents & Royalties, Research Funding; Mnemo: Patents & Royalties; Atara: Patents & Royalties, Research Funding; Takeda: Patents & Royalties, Research Funding; Minerva: Other: Biotechnologies, Patents & Royalties.

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