OP206 Expert Elicitation Of Probabilistic Distributions to Inform Survival Modelling of CD19 Chimeric Antigen Receptor T-Cell Therapies

2020 ◽  
Vol 36 (S1) ◽  
pp. 3-3
Author(s):  
Niamh Carey ◽  
Conor Hickey ◽  
Laura Mc Cullagh ◽  
Michael Barry
Keyword(s):  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Expert Elicitation ◽  
Cell Transplant ◽  
Major Advance ◽  
Cell Therapies ◽  
Risk Of Death ◽  
Car T Cell ◽  
Car T

IntroductionIn 2018, the National Centre for Pharmacoeconomics (NCPE) was commissioned to conduct a health technology assessment (HTA) of one of the first commercially available chimeric antigen receptor (CAR) T-cell therapies, tisagenlecleucel. CAR T-cells are a major advance in personalized cancer treatment, demonstrating promising outcomes in relapsed/refractory pediatric acute lymphoblastic leukemia (pALL). However, the results are based on short-term follow up, limiting their value in predicting long-term survival and leading to uncertainty about the most appropriate survival modeling method to employ. This study aimed to address these limitations by means of expert elicitation.MethodsAn expert elicitation method, the histogram technique, was employed. A predefined discrete numerical scale was presented in Microsoft Excel® and the expert was asked to place twenty crosses on a frequency chart. These crosses represented the expert's beliefs about the distribution of particular quantities. Each cross represented five percent of the probabilistic distribution. Individual distributions were then aggregated across experts using linear pooling.ResultsA total of seventeen experts were invited to take part; eight agreed to participate and five completed the exercise. Three experts did not consider tisagenlecleucel to be a “curative” therapy because patients had a higher risk of death, compared with the age- and sex-matched general population. The aggregated distributions indicated the five-year overall survival rate to be thirty-three percent (95% CI 8.65–56.88) in patients who do not receive a subsequent stem cell transplant and twenty percent (95% CI 2.38 -52.04) in those who do.ConclusionsThe results of this study will be used to calibrate CD19 CAR T-cell therapy survival estimates presented in HTA submissions to the NCPE to ensure more robust assessments. They will also be used to inform the construction of a de novo cost-utility model for examining the cost effectiveness of CD19 CAR T-cell therapies for relapsed/refractory pALL in the Irish healthcare setting.

scholarly journals Chimeric antigen receptor T cell therapy in cancer: Advances and challenges

2021 ◽  
Vol 3 (3) ◽  
pp. 46-47
Author(s):  
Yuanzheng Liang ◽  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Number Of Patients ◽  
Car T

Chimeric antigen receptor (CAR) T-cell therapy has drawn the most attention ever in the treatment of hematologic malignancies due to its impressive efficacy in heavily pretreated patients. However, the use of CAR T-cell therapy has just started in the field of solid tumor. Till now, four CAR T-cell therapies have been approved in the world, and an increasing number of patients will receive this expensive treatment. Thus, we will briefly talk about the advances and challenges in the adventure of CAR T-cell therapy

scholarly journals Implementation of a Standardized Assessment for Neurotoxicity in Patients Receiving Chimeric Antigen Receptor (CAR) T-Cell Therapies on an Inpatient Hematology Unit

2019 ◽  
Vol 25 (3) ◽  
pp. S432-S433
Author(s):  
Carolyn Stigge Harris ◽  
Kathryn Torres-Nicolas ◽  
Jennifer Peterson ◽  
Selina Cervantes ◽  
Christina Golly ◽  
...  
Keyword(s):  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Standardized Assessment ◽  
Cell Therapies ◽  
Car T Cell ◽  
Car T

The pharmacist’s role in chimeric antigen receptor T cell therapy

2020 ◽  
Vol 26 (7) ◽  
pp. 1725-1731
Author(s):  
Jennifer P Booth ◽  
Carolyn L Kusoski ◽  
Julie M Kennerly-Shah
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Cell Transplant ◽  
T Cell Therapy ◽  
Hematopoietic Stem ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

The emergence and efficacy of chimeric antigen receptor (CAR) T cell therapy in previously incurable malignancies represents a promising paradigm shift in cancer care. However, it is not without significant clinical, operational, and financial considerations. Pharmacists should be prepared to fulfill the various roles in CAR T cell therapy provision including: policy development; electronic medical record build; patient and staff education; patient selection; procurement, storage, and handling; medication administration and supportive care; management of adverse reactions; and quality tracking. Our commentary provides an overview of the opportunities for pharmacy involvement in the implementation and maintenance of a CAR T cell therapy program with an emphasis on the importance of pharmacy involvement as part of a multidisciplinary approach to care. Although some institutions have dedicated a CAR T cell pharmacist to meet the demands of emerging CAR T cell therapy, we believe that clinical pharmacists practicing in hematopoietic stem cell transplant and hematology/oncology have the skills and training to fulfill the pharmacist’s role in CAR T cell therapy.

scholarly journals The Influence of Chimeric Antigen Receptor Structural Domains on Clinical Outcomes and Associated Toxicities

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 38
Author(s):  
Ashleigh S. Davey ◽  
Matthew E. Call ◽  
Melissa J. Call
Keyword(s):  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Rational Design ◽  
Antigen Receptor ◽  
Structural Domains ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Car T Cell ◽  
Car T ◽  
Used Cars

Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of B cell malignancies, improving patient survival and long-term remission. Nonetheless, over 50% of patients experience severe treatment-related toxicities including cytokine release syndrome (CRS) and neurotoxicity. Differences in severity of toxic side-effects among anti-CD19 CARs suggest that the choice of costimulatory domain makes a significant contribution to toxicity, but comparisons are complicated by additional differences in the hinge and transmembrane (TM) domains of the most commonly used CARs in the clinic, segments that have long been considered to perform purely structural roles. In this perspective, we examine clinical and preclinical data for anti-CD19 CARs with identical antigen-binding (FMC63) and signalling (CD3ζ) domains to unravel the contributions of different hinge-TM and costimulatory domains. Analysis of clinical trials highlights an association of the CD28 hinge-TM with higher incidence of CRS and neurotoxicity than the corresponding sequences from CD8, regardless of whether the CD28 or the 4-1BB costimulatory domain is used. The few preclinical studies that have systematically varied these domains similarly support a strong and independent role for the CD28 hinge-TM sequence in high cytokine production. These observations highlight the value that a comprehensive and systematic interrogation of each of these structural domains could provide toward developing fundamental principles for rational design of safer CAR-T cell therapies.

scholarly journals Genome Editing as a Vehicle to Drive Successful Chimeric Antigen Receptor T Cell Therapies to the Clinic

2021 ◽  
Author(s):  
Caitlin R Hopkins ◽  
Joseph A Fraietta
Keyword(s):  
T Cell ◽  
Genome Editing ◽  
Chimeric Antigen Receptor ◽  
Gene Editing ◽  
Antigen Receptor ◽  
Cell Therapies ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Specific Antigens

Chimeric antigen receptor (CAR) T cells have emerged as an effective therapy for patients with relapsed and refractory haematological malignancies. However, there are many challenges preventing clinical efficacy and thus broader translation of this approach. These hurdles include poor autologous T cell fitness, manufacturing issues and lack of conserved tumour-restricted antigens to target. Recent efforts have been directed toward incorporating genome editing technologies to address these challenges and develop potent CAR T cell therapies for a diverse array of haematopoietic cancers. In this review, the authors discuss gene editing strategies that have been employed to augment CAR T cell fitness, generate allogeneic ‘off-the-shelf’ CAR T cell products, and safely target elusive myeloid and T cell cancers that often lack appropriate tumour-specific antigens.

scholarly journals Evaluation and Management of Chimeric Antigen Receptor (CAR) T-cell-Associated Neurotoxicity

2020 ◽  
Author(s):  
L Nicolas Gonzalez Castro ◽  
Jorg Dietrich
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Tumor Antigens ◽  
Antigen Receptor ◽  
Cell Therapies ◽  
Car T Cells ◽  
Car T Cell ◽  
Specific Tumor ◽  
Car T

Abstract Adoptive cell therapies (ACT) are a group of cancer immunotherapies that involve the infusion of engineered immune cells targeting specific tumor antigens, with chimeric antigen receptor (CAR) T-cells at the vanguard of this revolution in cancer therapy. Several CAR T-cell products have been approved for the treatment of leukemia and lymphoma and many more are currently undergoing evaluation in clinical trials for the treatment of other liquid and solid malignancies. Despite their remarkable effectiveness, as with other immunotherapies, CAR T-cells are frequently associated with systemic and neurologic toxicity. There has been a major effort by many institutions to develop specific protocols to guide management of treatment associated toxicities (e.g., cytokine release syndrome, CRS). However, neurotoxic effects of CAR T-cell therapies are more difficult to evaluate and treat, not easily lending themselves to an algorithmic approach to diagnosis and management. Given the steadily expanding use of CAR T-cell therapies for various malignancies, it is of critical importance for neuro-oncologists to be familiar with the clinical presentation and management principles of CAR T-cell-associated neurotoxicity. Here we present key principles for the evaluation and management of patients affected by CAR T-cell associated neurotoxicity based on the most recent evidence.

OP136 Provision Of A Chimeric Antigen Receptor T-Cell Program: A Rapid Review

2019 ◽  
Vol 35 (S1) ◽  
pp. 31-31
Author(s):  
Niamh Carey ◽  
Marie Harte ◽  
Claire Gorry ◽  
Laura McCullagh
Keyword(s):  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Grey Literature ◽  
Antigen Receptor ◽  
Rapid Review ◽  
European Medicines Agency ◽  
Successful Implementation ◽  
Cell Therapies ◽  
Car T Cell ◽  
Car T

IntroductionThe recent European Medicines Agency (EMA) approval of chimeric antigen receptor (CAR) T-cell therapies, axicabtagene ciloleucel and tisagenlecleucel, means the imminent arrival of health technology assessment (HTA) submissions to HTA agencies. HTA requires identification of all resources and organizational impacts pertaining to an intervention. Rapid review is a form of knowledge synthesis that abbreviates certain methodological aspects of systematic reviews to produce information in a timelier manner. Considering the time-sensitive nature of CAR T-cell HTAs, the aim of this research was to conduct a rapid review to identify the institutional requirements for the provision of a CAR T-cell program.MethodsA Rapid Review protocol was developed and registered in PROSPERO. Electronic databases, EMBASE and MEDLINE, and grey literature were searched. All study designs published in English after the year 2000 were included. Studies pertained to the use of CAR T-cells in adult and pediatric patients with solid and hematological malignancies. No restrictions were placed on the comparators or study setting. Primary outcomes were organized into two categories: (i) resource use, (ii) processes relating to implementation of CAR T-cell programs. Secondary outcomes included associated costs of implementation and barriers to successful implementation. Screening, review, and extraction of relevant data was conducted by a single reviewer. Extracted data included publication details, population and setting, study characteristics, outcomes and outcome measures, and strengths and limitations of research. Data was synthesized by means of thematic analysis.ResultsResults indicate that the provision of a CAR T-cell program in Ireland will require the establishment of bespoke infrastructural support. This includes additional outpatient facilities, ICU resources, and nursing capacity. Close relationships will need to be formed between hematology, ICU and neurology.ConclusionsThe findings of this Rapid Review will inform the assessment of organizational impacts associated with the introduction of a CAR T-cell program, ensuring a robust HTA assessment.

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