Abstract
Background aims
The most widely accepted starting materials for chimeric antigen receptor T-cell manufacture
are autologous CD3+ T cells obtained via the process of leukapheresis, also known
as T-cell harvest. As this treatment modality gains momentum and apheresis units struggle
to meet demand for harvest slots, strategies to streamline this critical step are
warranted.
Methods
This retrospective review of 262 T-cell harvests, with a control cohort of healthy
donors, analyzed the parameters impacting CD3+ T-cell yield in adults with B-cell
malignancies. The overall aim was to design a novel predictive algorithm to guide
the required processed blood volume (PBV) (L) on the apheresis machine to achieve
a specific CD3+ target yield.
Results
Factors associated with CD3+ T-cell yield on multivariate analysis included peripheral
blood CD3+ count (natural log, ×109/L), hematocrit (HCT) and PBV with coefficients of 0.86 (95% confidence interval [CI],
0.80–0.92, P < 0.001), 1.30 (95% CI, 0.51–2.08, P = 0.001) and 0.09 (95% CI, 0.07–0.11, P < 0.001), respectively. The authors’ model, incorporating CD3+ cell count, HCT and
PBV (L), with an adjusted R2 of 0.87 and root-mean-square error of 0.26 in the training dataset, was highly predictive
of CD3+ cell yield in the testing dataset. An online application to estimate PBV using
this algorithm can be accessed at https://cd3yield.shinyapps.io/cd3yield/.
Conclusions
The authors propose a transferrable model that incorporates clinical and laboratory
variables accessible pre-harvest for use across the field of T-cell therapy. Pending
further validation, such a model may be used to generate an individual leukapheresis
plan and streamline the process of cell harvest, a well-recognized bottleneck in the
industry.
Key Words
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References
- The basic principles of chimeric antigen receptor design.Cancer discovery. 2013; 3: 388-398
- Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia.New England Journal of Medicine. 2018; 378: 439-448
- Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma.New England Journal of Medicine. 2019; 380: 45-56
- Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma.New England Journal of Medicine. 2017; 377: 2531-2544
- Guideline on the clinical use of apheresis procedures for the treatment of patients and collection of cellular therapy products.Transfusion Medicine. 2015; 25: 57-78
- Moderate and severe adverse events associated with apheresis donations: incidences and risk factors.Transfusion. 2010; 50: 478-486
- Building blocks for institutional preparation of CTL019 delivery.Cytotherapy. 2017; 19: 1015-1024
- Apheresis therapy in children: an overview of key technical aspects and a review of experience in pediatric renal disease.Journal of clinical apheresis. 2013; 28: 36-47
- Autologous lymphapheresis for the production of chimeric antigen receptor T cells.Transfusion. 2017; 57: 1133-1141
- Lymphocyte apheresis for chimeric antigen receptor T-cell manufacturing in children and young adults with leukemia and neuroblastoma.Transfusion. 2018; 58: 1414-1420
- Factors affecting lymphocyte collection efficiency for the manufacture of chimeric antigen receptor T cells in adults with B-cell malignancies.Transfusion. 2019; 59: 1773-1780
- Evolution of MNC and lymphocyte collection settings employing different Spectra Optia® leukapheresis systems.Vox sanguinis. 2017; 112: 586-594
- Feasibility of leukapheresis for CAR T-cell production in heavily pre-treated pediatric patients.Transfusion and Apheresis Science. 2020; 59102769
- Unstimulated apheresis for chimeric antigen receptor manufacturing in pediatric/adolescent acute lymphoblastic leukemia patients.Journal of Clinical Apheresis. 2020; 35: 398-405
- Current Challenges in Providing Good Leukapheresis Products for Manufacturing of CAR-T Cells for Patients with Relapsed/Refractory NHL or ALL.Cells. 2020; 9: 1225
- Management of “out of specification” commercial autologous CAR-T cell products.Cell and Gene Therapy Insights. 2018; 4: 1051-1058
- How to perform leukapheresis for procurement of the staring material used for commercial CAR T-cell manufacturing: a consensus from experts convened by the SFGM-TC.Bulletin du cancer. 2021; 108: 295-303
- Clinical utilization of chimeric antigen receptor T cells in B cell acute Lymphoblastic Leukemia: An expert opinion from the European society for blood and marrow transplantation and the American society for transplantation and cellular therapy.Biology of Blood and Marrow Transplantation. 2019; 25: e76-e85
- Management of Adults and Children receiving CAR T-cell therapy: 2021 Best Practice Recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA).Annals of Oncology. 2022; 33: 259-275
- Management of adults and children undergoing chimeric antigen receptor T-cell therapy: best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE).Haematologica. 2020; 105: 297-316
- Joint Task Force for Education and Certification. Calculations in apheresis.Journal of clinical apheresis. 2015; 30: 38-42
Terumo Corporation. Spectra Optia Apheresis System Operator's Manual. (2018). Terumo BCT: Lakewood, Colorado. URL: https://www.fda.gov/media/136838/download. Accessed 29 November 2022.
- Regression modelling strategies for improved prognostic prediction.Statistics in medicine. 1984; 3: 143-152
- Outcome modelling strategies in epidemiology: traditional methods and basic alternatives.International journal of epidemiology. 2016; 45: 565-575
- A heteroskedasticity-consistent covariance matrix estimator and a direct test for heteroskedasticity.Econometrica: journal of the Econometric Society. 1980; 48: 817-838
- Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD): the TRIPOD statement.Journal of British Surgery. 2015; 102: 148-158
- Evaluation of peripheral blood mononuclear cell collection by leukapheresis.Transfusion. 2019; 59: 1765-1772
- Low-Volume Leukapheresis in Non-Cytokine-Stimulated Donors for the Collection of Mononuclear Cells.Transfusion Medicine and Hemotherapy. 2018; 45: 323-330
- CAR-T cell therapies from the transfusion medicine perspective.Transfusion medicine reviews. 2016; 30: 139-145
- CAR T Cell Immunotherapy beyond haematological malignancy.Immune Network. 2022; 22e6https://doi.org/10.4110/in.2022.22.e6
- Mononuclear cell variability and recruitment in non-cytokine-stimulated donors after serial 10-liter leukapheresis procedures.Transfusion. 2005; 45: 445-452
- Lack of defined apheresis collection criteria in publicly available CAR-T cell clinical trial descriptions: comprehensive review of over 600 studies.Journal of Clinical Apheresis. 2022; 37: 223-236
- Poor stem cell harvest may not always be related to poor mobilization: lessons gained from a mobilization study in patients with β-thalassemia major.Transfusion. 2017; 57: 1031-1039
- Age-related decline in primary CD8+ T cell responses is associated with the development of senescence in virtual memory CD8+ T cells.Cell reports. 2018; 23: 3512-3524
- Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis.Immunity. 2016; 45: 389-401
- Naive T-cell deficits at diagnosis and after chemotherapy impair cell therapy potential in pediatric cancers.Cancer discovery. 2019; 9: 492-499
- Lingering effects of chemotherapy on mature T cells impair proliferation.Blood advances. 2020; 4: 4653-4664
- Rapid manufacturing of non-activated potent CAR T cells.Nature biomedical engineering. 2022; 6: 118-128
- Reducing Ex Vivo Culture Improves the Antileukemic Activity of Chimeric Antigen Receptor (CAR) T CellsLimited Ex Vivo Culture Improves CAR T-cell Immunotherapy.Cancer immunology research. 2018; 6: 1100-1109
- A feasibility and safety study of a new CD19-directed fast CAR-T therapy for refractory and relapsed B cell acute lymphoblastic leukemia.Blood. 2019; 134: 825
- Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas.Nature medicine. 2020; 26: 1878-1887
- Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia.Nature medicine. 2018; 24: 563-571
Article info
Publication history
Published online: December 11, 2022
Accepted:
October 24,
2022
Received:
May 3,
2022
Publication stage
In Press Corrected ProofIdentification
Copyright
© 2022 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.
