Prediction of CAR T-Related Toxicities in R/R DLBCL Patients Treated with Axicabtagene Ciloleucel Using Point of Care Cytokine Measurements

Abstract Introduction: One of the main complications of adoptive T cell therapy (ACT) is the en-masse activation of tumor-reactive T cells inducing a large release of cytokines followed by activation of other immune cells leading to adverse events. These are classified as a cytokine release syndrome (CRS) or neurotoxicity described as a CAR T Related Encephalopathy Syndrome (CRES). Several biomarkers have been associated with CRS and/or neurotoxicity such as LDH, ferritin and CRP. Cytokines have also been associated with CRS and and/or CRES, but present approaches rely on retrospective study of collected biomarkers. Here, we report the results of cytokine analysis using a point of care (POC) device to predict immune-related toxicities in patients with relapsed/refractory (R/R)DLBCL treated with axicabtagene ciloleucel (axi-cel). Methods: Patients with R/R DLBCL treated with commercial axi-cel were included in this study. Baseline serum samples were collected prior to lymphodepleting chemotherapy and then daily during hospitalization. To select which cytokines to monitor, we retrospectively analyzed 38 serum cytokines in a cohort of 53 patients with R/R B cell acute lymphoblastic leukemia (B-ALL) who were treated with 19-28z CAR T cells. The patients were divided into those requiring treatment with tocilizumab and/or steroids versus those who did not require treatment. We observed several cytokines, including IL-2, IL-6, IL-15 and IFNg, which were significantly elevated in patients with CRS and/or CRES requiring treatment (Figure 1a). Based on this analysis and results of published studies, eight serum proteins were selected in our study including IL-1b, IL-2, IL-6, IL-15, IFNg, TNFa, and angiopoietin-1 &2. We monitored these proteins using a POC device that allows for rapid daily monitoring with a turnaround time of two hours. We established that the results from the POC device strongly correlate with a current gold standard device(Luminex), which has a typical two day turn around time. CRS and CRES were prospectively graded using revised Lee criteria (Lee et al Blood 2014) and the CARTOX group (Neelapu et al. NRCO 2017) respectively by an experienced clinical team and confirmed by chart review retrospectively. Results: A total of 20 patients with R/R DLBCL treated with commercial axi-cel were identified. Median age 64 years ( range 43-73) with 80% male.In our cohort, grades 1-3 CRS were observed in 45%, 40% and 5% respectively. There were no observed grade 0 or grade 4 CRS. There were two patients (10%) who died in the setting of severe toxicity. Patients with grade 5 CRS had higher levels of IL-6 and angiopoietin 2/angiopoietin 1 ratio at day one, which correlated with severity of toxicity r=0.52 (p= 0.039) , and r=0.53 (p=0.033) respectively (Fig. 1b). Furthermore, patients with high grades CRS had elevated levels of IL-15 at day seven (r=0.83, p=0.006). The majority of patients (55%) had grade 1-2 CRES.There were no significant correlations between serum cytokine levels and CRES or between those who required tocilizumab/steroids vs. those who did not, likely due to the small sample size. In select cases, daily monitoring of cytokines using the POC device provided clinical insight that wasn't evident from standard biomarkers. For example, one patient who developed delayed CRS had high serum levels of IL-6 but did not have elevated levels of CRP(Fig.1c). Discussion: In this analysis of 20 patients, we observed a correlation between severe CRS and elevated serum cytokine levels of IL-6 and angiopoietin 2/angiopoietin 1 ratio at day one suggesting that these biomarkers may be utilized to predict severe toxicity in patients treated with ACT. While this study is limited by small sample size, our observations correlate with previously published biomarkers data in patients enrolled in clinical trials. To our knowledge this is the first reported cytokine data using commercial axi-cel. Monitoring of cytokines using a POC device is feasible and will be useful clinically. High risk patients may be identified early and help guide intervention in real time, for example day one elevated IL-6 levels might inform earlier use of tocilizumab. We continue to enroll patients to validate cytokines as predictive biomarkers with the goal of informing the development of preventative strategies to mitigate CAR T cell therapy immune related adverse events. Disclosures Locke: Cellular BioMedicine Group Inc.: Consultancy; Kite Pharma: Other: Scientific Advisor; Novartis Pharmaceuticals: Other: Scientific Advisor. Brentjens:Juno Therapeutics, a Celgene Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Park:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Kite Pharma: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Shire: Consultancy. Davila:Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Profiling T-Cell Receptor Diversity and Dynamics during Lymphoma Immunotherapy Using Cell-Free DNA (cfDNA)

Blood ◽

10.1182/blood-2020-141655 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 49-50

Author(s):

Navika D Shukla ◽

Alexander F. M. Craig ◽

Brian Sworder ◽

David M. Kurtz ◽

Charles Macaulay ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

Board Of Directors ◽

Research Funding ◽

Advisory Committees ◽

T Cell Therapy ◽

Car T Cell ◽

Car T ◽

Tcr Repertoire ◽

Support Research

Background: Characterization of T-cell receptor (TCR) diversity and dynamics is increasingly critical to understanding therapeutic immune responses targeting tumors. Current TCR profiling methods generally require invasive tissue biopsies that capture a single snapshot of immune activity or are limited by the sheer diversity of the circulating TCR repertoire. In theory, T-cells with the greatest turnover could best reflect pivotal immune dynamics from both circulating and tissue-derived compartments, including non-circulating tissue-resident memory T-cells (Trm). To noninvasively capture such responses in the blood, we developed and benchmarked a high-throughput TCR profiling approach using plasma, optimized for the fragmented nature of cfDNA and the non-templated nature of rearranged TCRs. We then applied this method for residual disease monitoring in mature T-cell lymphomas (TCL) without circulating disease and for characterizing immune dynamics after anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy of B-cell lymphomas with axicabtagene ciloleucel. Methods: We developed SABER (Sequence Affinity capture & analysis By Enumeration of cell-free Receptors) as a technique for TCR enrichment and analysis of fragmented rearrangements shed in cfDNA and applied this method using Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq). We used SABER to profile a total of 381 samples (300 cfDNA and 81 PBMC samples) from 75 lymphoma patients and 18 healthy controls. After mapping sequencing reads (hg38) to identify candidate rearrangements within TCR loci, unique cfDNA fragments were resolved by a novel strategy to define consensus of unique molecular identifiers clustered by Levenshtein distances, followed by CDR3-anchoring for enumeration of final receptor clonotypes. SABER thus leverages information from fragmented TCRs, a critical requirement for cfDNA, to make V gene, CDR3, and J gene assignments after deduplication-mediated error-correction. We benchmarked SABER against established amplicon-based TCR-β targeted sequencing (LymphoTrack, Invivoscribe) and repertoire analysis methods (MiXCR; Bolotin et al, 2015 Nature Methods) when considering both cfDNA and PBMC samples from healthy adults and TCL patients. We assessed SABER performance for tracking clonal molecular disease in patients with mature TCLs from both cellular and cell-free circulating compartments (n=9). Malignant TCL clonotypes were identified in tumor specimens using clonoSEQ (Adaptive Biotechnologies). Finally, we evaluated TCR repertoire dynamics over time in 66 DLBCL patients after CAR19 T-cell therapy. Results: SABER demonstrated superior recovery of TCR clonotypes from cfDNA compared to both amplicon sequencing (LymphoTrack, Invivoscribe) and hybrid-capture methods when enumerating receptors using MiXCR (Fig. 1A). When applied to blood samples from TCL patients, SABER identified the malignant clonal TCR-β rearrangement in 8/9 (88.9%) cases, with significantly improved detection in cfDNA (p=0.015, Fig. 1B). Specifically, tumoral TCR clonotype was detectable only in cfDNA in 6 cases (75%), cfDNA-enriched in 1 case (12.5%), and detectable only in PBMCs in 1 case (12.5%). We applied SABER to monitor TCR repertoire dynamics in cfDNA after CAR T-cell therapy of patients with relapsed/refractory DLBCL and observed increased T-cell turnover and repertoire expansion (greater total TCR-β clonotypes) (Fig. 1C). As early as 1-week after CAR19 infusion, TCR repertoire size was significantly correlated both with cellular CAR19 T-cell levels by flow cytometry (p=0.008) as well as with retroviral CAR19 levels in cfDNA (p=2.20e-07) suggesting faithful monitoring of CAR T-cell activity (Fig. 1D). TCR repertoire size one month after infusion was significantly associated with longer progression-free survival (HR 0.246, 95% CI 0.080-0.754, p=0.014). Conclusions: SABER has a favorable profile for cfDNA TCR repertoire capture when compared to existing methods and could thus have potential broad applicability to diverse disease contexts. Given the higher abundance of lymphoma-derived TCRs in cfDNA than intact circulating leukocytes, SABER holds promise for monitoring minimal residual disease in T-cell lymphomas. This approach also holds promise for monitoring T-cell repertoire changes including after CAR T-cell therapy and for predicting therapeutic responses. Disclosures Kurtz: Genentech: Consultancy; Foresight Diagnostics: Other: Ownership; Roche: Consultancy. Kim:Corvus: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Elorac: Research Funding; Forty Seven Inc: Research Funding; Galderma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa-Kirin Pharma: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; miRagen: Research Funding; Neumedicine: Consultancy, Research Funding; Portola: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Solingenix: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding. Mackall:Lyell Immunopharma: Consultancy, Current equity holder in private company; BMS: Consultancy; Allogene: Current equity holder in publicly-traded company; Apricity Health: Consultancy, Current equity holder in private company; Nektar Therapeutics: Consultancy; NeoImmune Tech: Consultancy. Miklos:Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Adaptive Biotech: Consultancy, Other: Travel support, Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Novartis: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Janssen: Consultancy, Other: Travel support; Miltenyi Biotec: Research Funding. Diehn:Varian Medical Systems: Research Funding; Illumina: Research Funding; Roche: Consultancy; AstraZeneca: Consultancy; RefleXion: Consultancy; BioNTech: Consultancy. Khodadoust:Seattle Genetics: Consultancy; Kyowa Kirin: Consultancy. Alizadeh:Janssen: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Chugai: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Roche: Consultancy; Pfizer: Research Funding.

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T-Cell Telomere Length As a Biomarker to Predict Outcome in Patients Receiving CAR-T Immunotherapy

Blood ◽

10.1182/blood-2021-153183 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4798-4798

Author(s):

Enzo Tedone ◽

Mohammed Sayed ◽

Tsung-Po Lai ◽

Aishwarya Sannareddy ◽

Dheepthi P. Ramasamy ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Therapy ◽

Telomere Length ◽

Board Of Directors ◽

Advisory Committees ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

Abstract Introduction: CAR T-cells remain in a quiescent or dormant state when unstimulated, showing no proliferative activity. In contrast, upon specific antigen stimulation (i.e., CD19) CAR T-cells divide both in-vitro and in-vivo, initiate immune responses and can kill their target cells in the body. However, one of the major physiological immune changes with increased age is the progressive impairment of T-cell responses. This process termed immunosenescence (which may be similar T-cell exhaustion) is associated with the shortening of telomeres, specific DNA repeated sequences that protect the end of linear chromosomes from degradation and fusion with neighbor chromosomes. We aim to investigate change in T-cell telomere length with CAR-T cell therapy and its potential impact on outcome in patients receiving CART immunotherapy. Methods: We enrolled adult patients (age range: 30-80 years old) receiving CART immunotherapy for diffuse large B cell lymphoma (DLBCL), multiple myeloma (MM), mantle cell lymphoma (MCL), or follicular lymphoma (FL). We collected peripheral blood at two time points: i) pre-lymphodepletion therapy and ii) two weeks post CAR-T cell infusion. Peripheral blood mononuclear cells were isolated from blood via density gradient and T-cells isolated from PBMC with magnetic beads (negative selection). Telomere lengths are quantified from T-cells by using a highly sensitive technique called TeSLA (Telomere Shortest Length Assay) that allows absolute quantification of both the average telomere length and the lengths of critically short telomeres, which are believed to play a major role in promoting cell cycle arrest and T-cell exhaustion. Results: We identified 7 patients receiving CAR T cell therapy for hematological malignancies at University of Texas Southwestern Medical Center. The cohort included 7 patients, 2 patients with DLBCL and 1 patient with MCL receiving CD19 CAR-T Cell therapy and 4 patients with MM receiving BCMA CAR-T cell therapy. Median age of patient was 65 yrs. Median follow up was 273 days post CAR T-cell therapy with all patients being alive at last follow-up. Two patients experienced Grade I Cytokine release syndrome (CRS), two patients with Grade 2 CRS and one patient with Grade 2 ICANS. Our initial analysis shows that patients telomere lengths changes pre and post CAR T-cell infusion. Regarding change in critically short telomere (<1.6kb); 6 out of 7 patients had reduction the shorter telomere from BL to post CAR-T. We are currently evaluating the effect of change in telomere length on outcomes. Conclusions: CAR T-cell therapy is a game-changer for hematological malignancies; however, disease still relapse. Understanding the mechanics of poor response or relapse after CAR T-cell therapy is critical in advancing the field. Initial results suggest T-cell telomere length are significantly affected during CAR T-cell manufacturing process and post infusion. These results are potentially important as telomere length can be utilized as a biomarker to predict CAR T-cell therapy outcomes. Figure 1 Figure 1. Disclosures Anderson: Celgene, BMS, Janssen, GSK, Karyopharm, Oncopeptides, Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Awan: Verastem: Consultancy; Incyte: Consultancy; Cardinal Health: Consultancy; Dava Oncology: Consultancy; BMS: Consultancy; ADCT therapeutics: Consultancy; Beigene: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy; Pharmacyclics: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Kite pharma: Consultancy; Gilead sciences: Consultancy; Johnson and Johnson: Consultancy; Abbvie: Consultancy; Janssen: Consultancy; Astrazeneca: Consultancy; Genentech: Consultancy. Madanat: Onc Live: Honoraria; Blue Print Pharmaceutical: Honoraria; Geron Pharmaceutical: Consultancy; Stem line pharmaceutical: Honoraria. Patel: Celgene-BMS: Membership on an entity's Board of Directors or advisory committees; PVI: Honoraria; Agios: Membership on an entity's Board of Directors or advisory committees. Sweetenham: EMA Wellness: Membership on an entity's Board of Directors or advisory committees. Kansagra: Alynylam, Celgene/BMS, Cota Health, GSK, Janssen, Karyopharm, Oncopeptide, Pfizer, Takeda, Sanofi: Membership on an entity's Board of Directors or advisory committees.

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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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Hospitalization Patterns with Commercial CAR T-Cell Therapy: A Single Institution Experience

Blood ◽

10.1182/blood-2019-130650 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3240-3240 ◽

Cited By ~ 2

Author(s):

Sunita Dwivedy Nasta ◽

Esin C. Namoglu ◽

Mitchell E. Hughes ◽

Elise A. Chong ◽

Jakub Svoboda ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Mental Status ◽

Research Funding ◽

Altered Mental Status ◽

Outpatient Setting ◽

Advisory Committees ◽

T Cell Therapy ◽

Car T

Introduction: Chimeric antigen receptor T-cell therapy (CAR-T) is a revolutionary adoptive immunotherapy approach in lymphoma; however, there are substantial costs associated with CAR-T therapy. The current practice of admission for tisa-cel infusion and subsequent monitoring may contribute to these costs. Generally, our institution administers tisa-cel in the outpatient setting (Schuster NEJM 2017), and we now report our clinical approach and analyze the frequency of hospitalization post outpatient tisa-cel infusion with in the first 30 days of infusion. Patients and Methods: We conducted a single institution, retrospective study investigating hospitalization after CAR-T of adult lymphoma patients treated with commercial tisa-cel at the University of Pennsylvania between 6/2018 and 7/2019. Data collected included number and timing of hospitalizations, symptoms leading to hospitalization, diagnosis during hospitalization, and length of stay. Patients were eligible for inclusion if they had at least 30 days of follow-up after tisa-cel or hospitalization within the first 30 days after tisa-cel. Patients were followed for hospitalization events until progression of lymphoma. Admissions for elective surgical procedures were not included in hospitalization count. Patients received lymphodepleting therapy as an outpatient, followed by evaluation in clinic and outpatient infusion of tisa-cel. Indications for hospitalization at our institution included bulky disease, suboptimal organ function at time of tisa-cel infusion, or progressive lymphoma symptoms requiring inpatient management. After infusion, patients returned for follow-up on day 2 and day 4, then weekly starting day 8 through day 30 for physical examination, labs, and assessment for cytokine release syndrome (CRS) and neurotoxicity. Patients were instructed to contact our clinic with fever > 100.4F, any change in mental status, or for malaise. Patients were also required to stay within 1 hour driving distance of our clinic and have identified a caregiver who will remain with them for the first 28 days. Results: 30 patients with relapsed/refractory non-Hodgkin lymphoma who received commercial tisa-cel were identified; 28 (93%) patients received outpatient tisa-cel; two pts were admitted at the time of T-cell infusion due to progressive lymphoma symptoms requiring urgent management. The length of stay for the two patients who received inpatient tisa-cel was 17.5 days (17-18). Nine of 28 patients were admitted after tisa-cel infusion a median of 5 days after tisa-cel infusion (range: day +1 to +7). No patient required a second admission within 30 days. In most instances, 8/9 (89%) patients were referred for fever (fever range: 99.6F-102.0F) and one patient was referred for altered mental status. Of those hospitalized with fever, 5/8 (63%) patients had CRS and 3/8 (37%) patients had an infection. The patient with altered mental status was diagnosed with grade 3 neurotoxicity. One of the admitted patients died during hospitalization; however, this was due to progression of lymphoma after initial admission for an infection. There were no deaths due to tisa-cel related toxicity. Conclusion: Our experience suggests that treatment with tisa-cel in the outpatient setting is safe and feasible with close supervision and adequate institutional experience. After infusion, most admissions within the first 30 days were triggered by fever and the etiology of fever was either CRS or infection. Admission diagnoses matched prior experience with tisa-cel as previously reported. Disclosures Dwivedy Nasta: Millenium/Takeda: Research Funding; Aileron: Research Funding; Pharmacyclics: Research Funding; Rafael: Research Funding; Celgene: Honoraria; Merck: Membership on an entity's Board of Directors or advisory committees; ATARA: Research Funding; Debiopharm: Research Funding; Roche: Research Funding; 47 (Forty Seven): Research Funding. Hughes:Acerta Pharna/HOPA: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees. Chong:Novartis: Consultancy; Tessa: Consultancy; Merck: Research Funding. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Landsburg:Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Takeda: Research Funding; Takeda: Research Funding; Triphase: Research Funding; Triphase: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Barta:Celgene: Research Funding; Mundipharma: Honoraria; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Takeda: Research Funding; Bayer: Consultancy, Research Funding; Seattle Genetics: Honoraria, Research Funding. Gerson:Seattle Genetics: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy. Ruella:Nanostring: Consultancy, Speakers Bureau; Novartis: Patents & Royalties: CART for cancer; AbClon: Membership on an entity's Board of Directors or advisory committees. Frey:Novartis: Research Funding. Schuster:Novartis: Other: a patent (with royalties paid to Novartis) on combination therapies of CAR and PD-1 inhibitors.; Novartis, Nordic Nanovector, and Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis, Celgene, Genentech, Merck, Pharmacyclics, Acerta, and Gilead: Other: Grants, Research Funding; Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, Acerta, and Celgene: Honoraria. Porter:Wiley and Sons: Honoraria; Immunovative: Membership on an entity's Board of Directors or advisory committees; American Board of Internal Medicine: Membership on an entity's Board of Directors or advisory committees; Genentech: Employment; Kite: Membership on an entity's Board of Directors or advisory committees; Glenmark Pharm: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees.

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Fever Characteristics Associated with Toxicity and Outcome after Anti-CD19 CAR T-Cell Therapy for Aggressive Lymphoma

Blood ◽

10.1182/blood-2019-126148 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1612-1612 ◽

Cited By ~ 1

Author(s):

Hamza Hashmi ◽

Alicia Darwin ◽

Christina A Bachmeier ◽

Julio Chavez ◽

Bijal Shah ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

Board Of Directors ◽

Research Funding ◽

Advisory Committees ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T ◽

Grade 3

Background: Fever is a cardinal symptom of cytokine release syndrome (CRS) after CAR T-cell therapy with 84% of patients experiencing fever on the ZUMA-1 trial of axicabtagene ciloleucel (axi-cel). Knowledge of the patterns of fever and associated symptoms may inform the clinical management of these patients. Methods: We performed a single center retrospective study in 78 patients receiving axi-cel for large B cell lymphoma (LBCL) as of 12/31/2018. We evaluated all the patients who developed fever during lymphodepleting chemotherapy with fludarabine (Flu) and cyclophosphamide (Cy), after CAR T-cell infusion, and after administration of tocilizumab (toci); and analyzed the association of fever with toxicity rates (grade 3+ CRS and neurotoxicity) and efficacy [overall response rates (ORR) and complete response (CR) rate 6 months post CAR T-cell infusion]. Fever was defined per the Lee criteria [equal to or greater than 38 °C], CRS used the modified Lee criteria and neurotoxicity used the CARTOX grading system. Results: Fever occurred in 71/78 (91%) of patients. Rates of grade 3+ CRS and neurotoxicity were 9% (7/78) and 26% (20/78) respectively. The CR rate at 6 months was 41% (32/78). Toxicities and outcomes in patients with the described fever characteristics are shown in the Table. During lymphodepletion with Flu/Cy, fever was observed in 11% (9/78) of patients. Fever occurred within 24 hours of axi-cel infusion in 47% (37/78) and within 72 hours of axi-cel infusion in 71% (55/78) of the patients. In total, 41% (32/78) of patients were treated with anti-IL6R therapy (tocilizumab; toci) for CAR T toxicity. After the first dose of toci, fever recurred in 69% of patients (22/32), of which 34% (11/32) experienced fever recurrence within 24 hours of toci infusion. Conclusions: This is the first study to our knowledge that describes in detail the characteristics of fever after CAR T-cell therapy with axi-cel. Fever was common and occurred in 71% of the patients within 72 hours of axi-cel infusion. When toci was used, fever recurred in a majority of patients (69%) and in 1/3 of patients the fever recurred within 24 hours of toci infusion. These descriptive data may be used by clinicians to inform their expectations of fever occurring after treatment with axi-cel and/or toci. Table Disclosures Bachmeier: Kite/Gilead: Speakers Bureau. Chavez:Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals, Inc.: Speakers Bureau. Shah:AstraZeneca: Honoraria; Novartis: Honoraria; Spectrum/Astrotech: Honoraria; Adaptive Biotechnologies: Honoraria; Pharmacyclics: Honoraria; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria; Celgene/Juno: Honoraria. Pinilla Ibarz:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Sanofi: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Nishihori:Novartis: Research Funding; Karyopharm: Research Funding. Lazaryan:Kadmon: Consultancy. Davila:Bellicum: Consultancy; Anixa: Consultancy; GlaxoSmithKline: Consultancy; Precision Biosciences: Consultancy; Novartis: Research Funding; Adaptive: Consultancy; Celgene: Research Funding; Atara: Research Funding. Locke:Cellular BioMedicine Group Inc.: Consultancy; Kite: Other: Scientific Advisor; Novartis: Other: Scientific Advisor. Jain:Kite/Gilead: Consultancy.

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Infectious Complications in Patients Treated with Idecabtagene Vicleucel for Relapsed and Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2021-153942 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3839-3839

Author(s):

Jessica S. Little ◽

Parth Shah ◽

Adam S. Sperling ◽

Andrew R. Branagan ◽

Omar Nadeem ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Bacterial Infections ◽

Infectious Complications ◽

Advisory Committees ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

Abstract Introduction: Chimeric antigen receptor (CAR) T-cell therapy is a novel adoptive immunotherapy utilizing autologous T cells expressing synthetic fusion proteins that target specific antitumor antigens. Over recent years, novel CAR T-cell constructs have shown efficacy for the treatment of hematologic malignancies. The B-cell maturation antigen (BCMA)-directed CAR T-cell product idecabtagene vicleucel (ide-cel) is the first approved CAR T-cell therapy for the treatment of multiple myeloma (MM). While ide-cel represents an important advance in MM treatment, it is critical to better characterize the risk of infectious diseases following this novel therapy. Methods: We investigated infectious complications in 27 (CRB-401, n/62; KarMMa, n/128) adult patients who received ide-cel for relapsed and refractory MM at two institutions. Patients were enrolled in an open label, multi-site Phase 1 or 2 clinical trial (NCT02658929; NCT03361748) evaluating the safety and efficacy of ide-cel. All participants received a 3-day cycle of lymphodepleting chemotherapy with fludarabine and cyclophosphamide 5 days prior to infusion and ide-cel was administered at target doses of 150×10 6 to 450×10 6 CAR-positive T cells. All patients but one received antiviral prophylaxis with val/acyclovir or famciclovir. Seventeen patients received pneumocystis prophylaxis with atovaquone or trimethoprim-sulfamethoxazole. Only 2 patients received antibacterial prophylaxis with levofloxacin and no patients received antifungal prophylaxis. Infections were retrospectively identified from day of cell infusion (day 0) up to day 100 after infusion. Infections were reported if patients experienced symptoms with a microbiologic or histopathologic diagnosis, or for symptomatic site-specific infections in conjunction with radiographic or exam findings and treatment with systemic antimicrobials. Infection severity was determined using the Blood and Marrow Transplant Clinical Trials Network criteria. Cytokine release syndrome (CRS) events were graded according to the Lee criteria. Patients were censored on date of disease relapse, the last day of the study period, or death. Results: Median age was 59 (range 41 - 79), 56% were males. Patients had received a median of 6 previous antimyeloma regimens (range 3 - 10); and 74% had undergone prior autologous hematopoietic cell transplantation. Following infusion of cells, 24 patients (89%) developed CRS with 54% of those receiving ≥ 1 dose of tocilizumab and 17% receiving ≥ 1 dose of corticosteroid. Only two patients (7%) developed CAR T cell associated neurotoxicity (ICANS) and one of those patients received treatment with corticosteroids. Eight patients experienced 19 infection-related events over the first 100 days after ide-cel infusion. To determine infection density, we evaluated 27 patients contributing 667 days at risk between d0 and d30 and 1777 days at risk between d0 and d100. Median time to first infection was 22 days (range 0 - 85). The estimated infection density was 1.8 infections per 100 patient days over the first 30 days, and decreased to 1.1 infections per 100 patient days from day 30 to d100. Among the infection events, bacterial infections were the most common (74%) with 6 bloodstream infections (32%) observed. Viral infections were less frequent (21% of events) and only one fungal infection (5% of events) was observed during the at-risk period. Four infections were of moderate severity; 10 were severe; and 5 were life-threatening. Eleven of the 27 patients (41%) had persistent neutropenia (absolute neutrophil count <1000) after day 30. Conclusions: Our study in this cohort of patients provides clarity on specific infectious complications in a unique population, and is of particular relevance given the recent FDA approval of ide-cel. Of note, these results represent a cross study single institution subgroup analysis that may not reflect the complete trial data. The overall incidence of infection was similar to what has previously been reported in patients receiving CD-19 directed CAR T-cell therapy, even with persistent neutropenia after one month documented in 41% of patients. Bacterial infections were the most common, and there were 5 life-threatening bacterial infections within the first 30 days after infusion. Notably, patients in this group experienced only 1 fungal infection, despite no patients receiving antifungal prophylaxis. Figure 1 Figure 1. Disclosures Sperling: Adaptive: Consultancy. Branagan: Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; CSL Behring: Consultancy; Karyopharm: Consultancy; Pharmacyclics: Consultancy; Sanofi Genzyme: Consultancy. Nadeem: Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees. Yee: GSK: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy; Oncopeptides: Consultancy; Adaptive: Consultancy; Bristol Myers Squibb: Consultancy; Sanofi: Consultancy; Amgen: Consultancy. Raje: Celgene, Amgen, Bluebird Bio, Janssen, Caribou, and BMS: Other. Munshi: Abbvie: Consultancy; Amgen: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; Adaptive Biotechnology: Consultancy; Legend: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Janssen: Consultancy; Bristol-Myers Squibb: Consultancy. Hammond: Merck: Research Funding; F2G: Research Funding; Synexis: Research Funding; Biointelect: Consultancy.

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Eight-Day Point of Care CAR T-Cell Manufacturing on Clinimacs Prodigy from Healthy Donors As a Proof-of-Concept Study

Blood ◽

10.1182/blood-2021-154013 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2851-2851

Author(s):

Kim G. Hankey ◽

Tim Luetkens ◽

Stephanie Avila ◽

John McLenithan ◽

John Braxton ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Board Of Directors ◽

Point Of Care ◽

Transduction Efficiency ◽

Advisory Committees ◽

Car T Cells ◽

Car T Cell ◽

Car T ◽

Experimental Runs

Abstract Introduction Chimeric Antigen Receptor (CAR) T-cell therapy has emerged as a powerful immunotherapy for various forms of cancer, especially hematologic malignancies. However, several factors limit use of CAR T-cells to a wider number of patients. Long manufacturing time (usually 3-4 weeks with standard of care products) poses a big challenge in treating these chemorefractory patients in a timely fashion. Thus, we evaluated the feasibility of a fresh in and fresh out, short, eight-day manufacturing process performed locally to expedite CAR T-cell drug product delivery. Herein we report the results of two experimental runs using this modified short eight-day culture process. Methods We used the CliniMACS Prodigy® closed manufacturing system and modified the 12-day T Cell Transduction (TCT) activity matrix protocol to produce anti-CD19 CAR T-cells in eight days. Normal donor mononuclear cells were collected by leukapheresis and enriched for CD4 and CD8 cells by immunomagnetic bead selection in three stages. Enriched T-cells were activated with MACS GMP T Cell TransACT and cultured at 37°C with 5% CO 2 for 16-24 hours in media supplemented with 12.5mcg/L each of IL-7 and IL-15, and 3% heat-inactivated human AB serum. On day 1 of the process, activated T-cells were transduced with lentiviral vector encoding the anti-CD19 CAR (Lentigen, LTG1563) at a multiplicity of infection (MOI) of 7-10. On day 3, the cells were washed twice and the media volume adjusted to feed the expanding cells. The culture was again fed on day 5 by exchanging half the volume of spent media with fresh supplemented media. Media supplemented with cytokines alone was used for the remaining four washes on day 6, 7 and 8. Transduction efficiency and T-cell subset frequencies were assessed by flow cytometry on the MACSQuant-10 and CAR-T Express Mode package on days 3, 6 and 8. Subsequently, we performed ELISPOT assay for CAR T-cell potency testing and in-vivo efficacy testing in NSG mice bearing Raji B cell lymphoma. Results Refer to Table 1 for details on cell populations of interest for experiment number 1 and 2. The total number of CD3 T-Cells increased from 97% on day 0 to >99.5% on the harvest day (day 8). CD3 T-cells expanded 11.6- and 34.2-fold on day 8 when compared to day 0. Transduction efficiency of ~40% was observed in both experimental runs. Final CD19 CAR T-cells numbers ranged from 9.3-13.3 x 10e8 with viability of CD3+ cells >93% for both the runs. Day 3 of the culture is an important day since a clinical decision to proceed with lymphodepletion must be made to facilitate the fresh in and fresh out approach. Here we observed reliable transduction of T-cells on day 3 with an average efficiency of 15.9%. Day 3 data reliably provided information to proceed with lymphodepletion. A total of 100,000 CD19 CAR T-cells produced in experiment #1 were exposed to beads coated with CD19 protein, BCMA control protein, or T cell-activating beads coated with anti-CD3 and anti-CD28 antibodies in an ELISPOT plate. Spots in figure 1 represents individual CAR T-cells producing IFN-gamma. This novel ELISPOT assay shows high IFN-gamma by CD19 CAR T-cells in response to the target antigen or unspecific stimulation using CD3/CD28 beads. Subsequently, NSG mice received injections of 5x10e5 Raji B cell lymphoma cells stably expressing luciferase into the tail vein. One week later, 4 mice per group received individual i.v. injections of 4x10e6 CD19 CAR T-cells, 0.3x10e6 CD19 CAR T-cells, 4x10e6 mock-transduced CAR T-cells, or media. Survival curves in figure 2 represent survival of the mice after receiving the treatment with best survival seen with 4x10e6 dose. Conclusions In these experimental runs, we were able to generate CD19 CAR+ T-cells in a short eight-day manufacturing process. The final product characteristics (viability, transduction efficiency and doses) were comparable to clinical formulations. Further, point-of-care potency assay suggests high IFN-gamma production and elimination of CD19 tumor in the in vivo murine model. The point-of-care CAR T-cell production allows for shorter vein-to-vein time and offers dramatic reduction in the product cost. Lastly, the novel potency assay via ELISPOT testing allows for rapid and visual functional analysis of the CAR T-cell product. Figure 1 Figure 1. Disclosures Hardy: Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; American Gene Technologies, International: Membership on an entity's Board of Directors or advisory committees; InCyte: Membership on an entity's Board of Directors or advisory committees. Abramowski-Mock: Miltenyi Biotec: Current Employment. Mittelstaet: Miltenyi Biotec: Current Employment. Dudek: Miltenyi Biotec: Current Employment.

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Ascorbate Deficiency Is Associated with Severity of Cytokine Release Syndrome Following Therapy with Chimeric Antigen Receptor T-Cells

Blood ◽

10.1182/blood-2021-153929 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4801-4801

Author(s):

Ankit Kansagra ◽

Dheepthi P. Ramasamy ◽

Aishwarya Sannareddy ◽

Qing Ding ◽

Alexa Wilden ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Therapy ◽

Board Of Directors ◽

Advisory Committees ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T ◽

Low Serum

Abstract The therapy of hematologic malignancies has been revolutionized by the development of therapies using chimeric antigen receptor modified T-cells (CAR-T). However, CAR-T cell therapy is often associated with cytokine release syndrome (CRS), characterized by fevers, hypotension, and hypoxia, as well as immune effector cell-associated neurotoxicity syndrome (ICANS). Severe cases of CRS can result in significant morbidity and mortality. Although disease features such as tumor burden may predict for more severe CRS and ICANS, other clinical features and biomarkers predictive of CRS and ICANS remain lacking, with the exception of measurements of serum cytokines following cell infusion (PMID: 27076371, PMID: 24553386). Experimental models have implicated elaboration of inflammatory cytokines such as IL-1 and IL-6 by monocytes in the pathogenesis of CRS and ICANS (PMID: 29808007, PMID: 29808005). Accordingly, the severity and duration of CRS and ICANS can be mitigated in part by IL-6 receptor blockade with tocilizumab and treatment with corticosteroids such as dexamethasone. Recent work has implicated ascorbate in the regulation of the activity of TET enzymes in hematopoietic cells (PMID: 28825709, PMID: 28823558). Given that TET2 deficiency has been associated with increased elaboration of inflammatory cytokines such as IL-6 and IL-1 by macrophages (PMID 3026882, PMID: 28104796, PMID: 28636844), we reasoned that ascorbate deficiency might predict for more pronounced cytokine release in patients leading to more severe CRS or ICANS. We identified 13 patients receiving CAR-T cell therapy for hematologic malignancies at the University of Texas Southwestern. Plasma specimens were collected from patients at baseline prior to receipt of lymphodepleting chemotherapy and/or at two weeks following CAR-T cell infusion. Given the poor reliability of clinical ascorbate measurements due to oxidation, we used an optimized protocol incorporating a C13-labeled ascorbate internal standard to obtain highly precise serum measurements using liquid-chromatography mass spectrometry. The incidence and severity of CRS and ICANS was classified using standardized grading criteria as per the American Society for Transplantation and Cellular Therapy. We measured serum ascorbate in 7 baseline and 12 post CAR-T cell infusion specimens obtained from 13 patients, with a median age of 65 (range 53 to 77). The cohort included eight patients with diffuse large B-cell lymphoma and two patients with mantle cell lymphoma receiving CD19-targeted CAR-T cells, as well as three patients with multiple myeloma receiving BCMA-targeted CAR-T cells. Eight patients developed grade one CRS, three patients developed grade two CRS, and two patients did not develop CRS. One patient developed grade one ICANS, one developed grade two ICANS, and one developed grade three ICANS. Eight patients received dexamethasone for CRS or ICANS, and eight patients received tocilizumab. Five patients only received one dose of tocilizumab, while two received two doses and one received three doses. Taking all pre- and post-CAR-T cell infusion ascorbate measurements into account, a significant correlation was found between having low serum ascorbate levels and a higher maximal grade of CRS or ICANS (Figure 1A, r 2=-0.64, p=0.0039). Post-infusion ascorbate measurements also demonstrated a significant correlation between low serum ascorbate levels and higher maximal CRS or ICANS (Figure 1B, r 2=-0.78, p=0.0035), while there was no correlation between pre-infusion ascorbate measurements and CRS or ICANS. Finally, we noted a significant decrease in serum ascorbate levels when comparing pre-infusion to post-infusion specimens (Figure 1C, p=0.048), including five paired specimens. There was no significant correlation between serum ascorbate levels and the number of doses of tocilizumab or dexamethasone administered. Low serum ascorbate levels may be associated with an increased risk for developing severe CRS and ICANS following CAR-T cell therapy. Although follow-up studies with a larger cohort of patient are necessary to substantiate this correlation, these data provide preliminary evidence that serum ascorbate levels may serve as a useful biomarker to predict severity of CRS and ICANS. Furthermore, they suggest ascorbate supplementation as a promising future strategy to mitigate these common complications of CAR-T cell therapy. Figure 1 Figure 1. Disclosures Kansagra: Alynylam, Celgene/BMS, Cota Health, GSK, Janssen, Karyopharm, Oncopeptide, Pfizer, Takeda, Sanofi: Membership on an entity's Board of Directors or advisory committees. Anderson: Celgene, BMS, Janssen, GSK, Karyopharm, Oncopeptides, Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Awan: Abbvie: Consultancy; Dava Oncology: Consultancy; Johnson and Johnson: Consultancy; Incyte: Consultancy; BMS: Consultancy; Astrazeneca: Consultancy; ADCT therapeutics: Consultancy; Pharmacyclics: Consultancy; Janssen: Consultancy; Beigene: Consultancy; Merck: Consultancy; Gilead sciences: Consultancy; Cardinal Health: Consultancy; Verastem: Consultancy; MEI Pharma: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Kite pharma: Consultancy; Genentech: Consultancy. Madanat: Stem line pharmaceutical: Honoraria; Blue Print Pharmaceutical: Honoraria; Onc Live: Honoraria; Geron Pharmaceutical: Consultancy. Patel: Agios: Membership on an entity's Board of Directors or advisory committees; PVI: Honoraria; Celgene-BMS: Membership on an entity's Board of Directors or advisory committees. Sweetenham: EMA Wellness: Membership on an entity's Board of Directors or advisory committees.

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Evolution in Resource Utilization for Unique Toxicities Related to Chimeric Antigen Receptor T Cell Therapy from 2017 to 2020: A Database Review

Blood ◽

10.1182/blood-2021-154341 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4844-4844

Author(s):

Moazzam Shahzad ◽

Muhammad Salman Faisal ◽

Ernie Shippey ◽

Qamar Iqbal ◽

Laila Hashim ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

Board Of Directors ◽

Resource Utilization ◽

Chimeric Antigen Receptor ◽

Advisory Committees ◽

T Cell Therapy ◽

Car T ◽

Group 2 ◽

Group 1

Abstract Introduction: Chimeric antigen receptor T cell therapy (CAR-T) is a novel treatment that utilizes T cells by augmenting them using vector viruses to add antigens to target cancer cells. In 2017, FDA approved CD-19 CAR-T for relapsed/refractory diffuse large B-cell lymphoma and acute lymphoblastic leukemia patients ≤ 26yr old. Unique toxicities associated with CAR-T therapy include cytokine release syndrome (CRS) and immune effector cell-related neurotoxicity (ICANS). Lower-grade CRS and ICANS are managed with tocilizumab, an interleukin-6 antagonist, and steroids. Management of higher-grade CRS and ICANS requires intensive care unit (ICU) admission. Our understanding and management of CRS and ICANS continue to evolve. In this analysis, we conducted a retrospective review using the Vizient database® to investigate toxicity incidence and resource utilization among patients admitted for CAR-T therapy between 2017 and 2020. Methods: We used The Vizient® CDB database to analyze admissions for CAR-T infusion for patients over 18 years of age receiving FDA approved CD19 CAR-T axicabtagene ciloleucel (axi-cel) and tisangenlecleucel (tisa-cel) between 2017 to 2020. We compared patients who received CAR-T between October 2017 and March 2018 (group 1) to those who received CAR-T therapy between October 2019 and March 2020 (group 2). Due to the lack of diagnosis code for CRS or ICANS until 2021, surrogates billing codes such as fever, sepsis, dyspnea were used for CRS. In regards to ICANS, we used codes for febrile seizure, febrile convulsions, altered mental status, somnolence, and stupor. In addition, other adverse events such as weakness and nausea were also collected. Results: Eighty-one institutions had performed CAR-T in the period 2017 through 2020. The 2017-2018 period (group 1) included 215 patients, with a median age of 59 (49-68) years, while the CAR-T recipients in 2019-2020 (group 2) had 655 patients with a median age of 62 (52-69) years. Tisa-cel and Axi-cel was administered to 31% (n= 67) and 69% (n= 148) in group 1 and 26% (182) and 74% (n= 517) of group 2 patients respectively. The incidence of sepsis in group 1 was 18% vs. 13% in group 2, with an absolute difference of -5.8% (P value=0.04). Fever and dyspnea were the most common presentations of CRS present in 44.2% and 49% in group 1 and 35% and 28% in group 2, respectively. The incidence of fever decreased by 8.2% (p=0.02) in group 2 compared to group 1. The incidence of hypoxia was 24.7% vs. 20.5%, and the incidence of hypotension was 32.1% and 33.8% in groups 1 and 2, with no statistically significant difference between the two groups (p=0.64 and 0.19). The incidence of neurotoxicity decreased slightly in group 2 compared to group 1, but it was not statistically significant (P= 2723). Overall ICU utilization was 24.7 and 24.6% in both groups (p=0.9). The 30 days mortality in groups 1 and 2 was 6% vs. 3.7%. Tocilizumab utilization decreased by 20%, and dexamethasone or equivalent steroid usage decreased by 70% in group 2 compared to group 1. (Table 1) Conclusions: The incidence of CRS and ICANS among recipients of CAR-T remains high, with up to one-fourth of the patients requiring ICU, which has remained static. However, the general use of tocilizumab and steroids has decreased by 20% and 70%, respectively, possibly due to the implementation of consensus grading and operation protocols that may have increased awareness and judicious early interventions. Figure 1 Figure 1. Disclosures Mahmoudjafari: Incyte: Membership on an entity's Board of Directors or advisory committees; Omeros: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees.

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Checkpoint Inhibitors Augment CD19-Directed Chimeric Antigen Receptor (CAR) T Cell Therapy in Relapsed B-Cell Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2018-99-112572 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 556-556 ◽

Cited By ~ 29

Author(s):

Amanda M. Li ◽

George E Hucks ◽

Amanda M. Dinofia ◽

Alix E. Seif ◽

David T Teachey ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Advisory Committees ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

Abstract Abstract CAR T cell therapy in relapsed B-ALL can result in complete response (CR) rates of 80-90%, but relapse-free survival declines to 60% within the first 12-months due to both CD19-positive and negative relapses. CD19-positive relapses that occur during this time are largely due to early CAR T cell loss. We hypothesize that inhibiting the PD-1:PD-L1 (programmed cell death 1) checkpoint axis may decrease T cell exhaustion, thereby improving CAR T cell function and persistence. We report our single institution experience of the use of PD-1 inhibitors in patients with relapsed or refractory B lymphoblastic malignancies treated with CD19-directed CAR T cell therapy. Methods: Patients treated with CD19-directed CAR T cell therapy (murine CTL019 or humanized CTL119) at the Children's Hospital of Philadelphia who demonstrated repeated early CAR T cell loss or partial/no response to CAR T cell therapy received a PD-1 inhibitor starting no sooner than 14 days after CAR T cell infusion and after resolution of cytokine release syndrome (CRS) symptoms, with the possibility of repeated doses up to every 3 weeks. Results: Fourteen patients, ages 4-17 years, with heavily pretreated, relapsed B-ALL (n=13) or B lymphoblastic lymphoma (n=1), were treated with CD19-directed CAR T cell therapy (CTL019, n=4; or CTL119, n=10) in combination with pembrolizumab (n=13) or nivolumab (n=1). Three of 6 patients treated with CD19 CAR T cells in combination with a PD-1 inhibitor for early B cell recovery re-established B cell aplasia (a reflection of CAR T cell function) for 5-15 months, 2 of whom have persistent B cell aplasia with ongoing pembrolizumab therapy. Four patients started pembrolizumab for bulky extramedullary disease unresponsive to or relapsed after CAR T cells, with 2 partial and 2 complete responses seen. In one patient, significant CAR T cell proliferation was measured within days of starting pembrolizumab and in temporal correlation to radiographic disease response. In 4 patients who failed to achieve disease remission with initial CAR T cell infusion, no CRs were achieved with the addition of pembrolizumab, although partial responses were seen, and one patient progressed with CD19-dim/negative disease. CRS symptoms and fever typical of CAR T cell proliferative responses were observed in 3/14 patients within 2 days of starting pembrolizumab. Other early and delayed adverse effects associated with PD-1 inhibition were tolerable or reversible upon discontinuation, and including 1 case each of acute pancreatitis, hypothyroidism, arthralgias, urticaria, as well as 4 patients with grade 3-4 cytopenias. No grade 5 toxicities or graft-versus-host disease flares occurred. Two patients discontinued pembrolizumab for delayed adverse effects after multiple doses; both patients relapsed/progressed with CD19+ disease a few weeks after discontinuation. Discussion: T cell exhaustion or activation induced CAR T death (AICD) has been suspected to contribute to poor persistence of CAR T cells. We hypothesized that the PD-1 checkpoint pathway may be involved in CAR T cell exhaustion in some cases, which may be overcome by checkpoint inhibition. Here, promising responses were specifically seen in those with early B-cell recovery and bulky extramedullary disease. In contrast, PD-1 inhibition had partial, but no durable, effect in the four B-ALL patients with poor initial marrow response to CAR T cell therapy alone, suggesting a different mechanism such as AICD may be responsible for poor initial responses. No unexpected or fatal toxicities were seen. This cohort shows initial evidence that checkpoint inhibitors can be used effectively and safely with CAR T cell therapy in children with relapsed B-ALL, and that this strategy may augment CAR T cell effect and persistence. Disclosures Teachey: Amgen: Consultancy; La Roche: Consultancy. Callahan:Novartis Pharmaceuticals Corporation: Consultancy. Porter:Genentech: Other: Spouse employment; Novartis: Other: Advisory board, Patents & Royalties, Research Funding; Kite Pharma: Other: Advisory board. Lacey:Novartis Pharmaceuticals Corporation: Patents & Royalties; Tmunity: Research Funding; Parker Foundation: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding. June:Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Immune Design: Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Celldex: Consultancy, Membership on an entity's Board of Directors or advisory committees. Grupp:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Adaptimmune: Consultancy; University of Pennsylvania: Patents & Royalties. Maude:Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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