Considerations in T Cell Therapy Product Development for B Cell Leukemia and Lymphoma Immunotherapy

Fesnak, Andrew D.; Hanley, Patrick J.; Levine, Bruce L.

doi:10.1007/s11899-017-0395-9

Cited by 11 publications

(8 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since, for the time being, cellular therapy products that have obtained marketing authorization are being manufactured and released by pharmaceutical stakeholders, starting with leukapheresis products collected in hospitals, the applicability of the method is limited to quality control of the starting material, with variability inherent to such collections [26]. For example, target cell number of CD3+ T cells is one of the criteria for collecting starting material for CAR T-cell manufacturing.…”

Section: Discussionmentioning

confidence: 99%

Validation of a flow cytometry-based method to quantify viable lymphocyte subtypes in fresh and cryopreserved hematopoietic cellular products

et al. 2021

View full text Add to dashboard Cite

Background aims: Adoptive cellular therapy with immune effector cells (IECs) has shown promising efficacy against some neoplastic diseases as well as potential in immune regulation. Both inherent variability in starting material and variations in cell composition produced by the manufacturing process must be thoroughly evaluated with a validated method established to quantify viable lymphocyte subtypes. Currently, commercialized immunophenotyping methods determine cell viability with significant errors in thawed products since they do not include any viability staining. We hereby report on the validation of a flow cytometry-based method for quantifying viable lymphocyte immunophenotypes in fresh and cryopreserved hematopoietic cellular products. Methods: Using fresh or frozen cellular products and stabilized blood, we report on the validation parameters accuracy, uncertainty, precision, sensitivity, robustness and contamination between samples for quantification of viable CD3+, CD4+ T cells, CD8+ T cells, CD3ÀCD56+CD16+/À NK cells, CD19+ B cells and CD14+ monocytes of relevance to fresh and cryopreserved hematopoietic cellular products using the Cytomics FC500 cytometer (Beckman Coulter). Results: The acceptance criteria set in the validation plan were all met. The method is able to accommodate the variability in absolute numbers of cells in starting materials collected or cryopreserved from patients or healthy donors (uncertainty of 20% at three different concentrations), stability over time (compliance over 3 years during regular inter-laboratory comparisons) and confidence in meaningful changes during cell processing and manufacturing (intra-assay and intermediate precision of 10% coefficient of variation). Furthermore, the method can accurately report on the efficacy of cell depletion since the lower limit of quantification was established (CD3+, CD4+ and CD8+ cells at 9, 8 and 8 cells/mL, respectively). The method complies with Foundation for the Accreditation of Cellular Therapy (FACT) standards for IEC, FACT-Joint Accreditation Committee of ISCT-EBMT (JACIE) hematopoietic cell therapy standards, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Q2(R1) and International Organization for Standardization 15189 standards. Furthermore, it complies with Ligand Binding Assay Bioanalytical Focus Group/American Association of Pharmaceutical Scientists, International Council for Standardization of Hematology/International Clinical Cytometry Society and European Bioanalysis Forum recommendations for validating such methods. Conclusions: The implications of this effort include standardization of viable cell immunophenotyping of starting material for cell manufacturing, cell selection and in-process quality controls or dosing of IECs. This method also complies with all relevant standards, particularly FACT-JACIE standards, in terms of enumerating and reporting on the viability of the "clinically relevant cell populations."

show abstract

Section: Discussionmentioning

confidence: 99%

Validation of a flow cytometry-based method to quantify viable lymphocyte subtypes in fresh and cryopreserved hematopoietic cellular products

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Scaling up with automation may address these issues by delivering therapies to patients more quickly. Companies have developed automated cell bioprocessorsfor example, the CliniMACS Prodigy (Miltenyi Biotech), WAVE Bioreactor (GE Life Systems) and G-Rex flask (Wilson Wolf Manufacturing) [44]. While most commercial systems have limited processes capabilities, the CliniMACS Prodigy can perform all major unit operations in one devicefrom selection, stimulation and gene delivery to expansion.…”

Section: Systems Thinking To Address Act Supply and Manufacturing Challengesmentioning

confidence: 99%

“…In addition to cost reduction, CliniMACS Prodigy was reported to reduce CAR-T production time from ≥13 days to 8 days [45]. However, these approaches require significant capital expenditure for purchase of the device and ongoing maintenance [44]. Moreover, scaling up product production might be challenging, as many devices would be needed to produce multiple doses in parallel [46].…”

Section: Systems Thinking To Address Act Supply and Manufacturing Challengesmentioning

confidence: 99%

Rethinking Cancer Immunotherapy by Embracing and Engineering Complexity

Chin

Gentleman

Coppens

et al. 2020

Trends in Biotechnology

View full text Add to dashboard Cite

The meteoric rise of cancer immunotherapy in the last decade has led to promising treatments for a number of hard-to-treat malignancies. In particular, adoptive T cell therapy has recently reached a major milestone with two products approved by the FDA. However, the inherent complexity of cell-based immunotherapies means that their manufacturing time, cost, and controllability limit their effectiveness and geographic reach. One way to address these issues may lie in complementing the dominant, reductionistic mentality in modern medicine with complex systems thinking. In this Opinion, we identify key concepts from complexity theory to address manufacturing challenges in cell-based immunotherapies and raise the possibility of a unifying framework upon which future bioprocessing strategies may be designed. HighlightsComplexity theory provides a conceptual framework in which biological and artificial networks may be designed or manipulated to intensify cell bioprocessing in cancer immunotherapies.Studies on T cell mechanobiology have revealed how physical parameters may be exploited to perturb intracellular networks as an effective way of controlling T cell fates for immunotherapeutic applications.Systems biology-based computational models open up the potential to predict cues needed to guide T cell differentiation and reprogramming.Advances in immunomodulatory biomaterials, microfabrication and wearable medical technologies raise the possibility of scaling up point-of-care deployment of immunotherapies.

show abstract

“…This class of cell therapy has shown significant clinical efficacy in treating hematological malignancies, but less success in killing solid tumors. 2 Cell therapies are also being applied to treat a variety of other pathologies, such as diabetes, 3,4 neurodegenerative disease, 5 and graft versus host disease, 6 and general challenges exist in the field related to reproducible production of therapeutic products, 7,8 significant costs for individualized treatments, and quality control. 9 I think it is instructive to look at the challenges overcome by the pharmaceutical industry, developing small-molecule therapeutics, as the fields of organic and analytical chemistry matured.…”

Section: The Promise Of Cell Therapiesmentioning

confidence: 99%

Technologies for the Directed Evolution of Cell Therapies

Carlo

2019

SLAS Technology

View full text Add to dashboard Cite

The next generation of therapies is moving beyond the use of small molecules and proteins to using whole cells. Compared with the interactions of small-molecule drugs with biomolecules, which can largely be understood through chemistry, cell therapies act in a chemical and physical world and can actively adapt to that world, amplifying complexity but also the potential for truly breakthrough impact. Although there has been success in introducing targeting proteins into cells to achieve a therapeutic effect, for example, chimeric antigen receptor (CAR) T cells, our ability to engineer cells is generally limited to introducing proteins, but not modulating large-scale traits or structures of cellular “machines,” which play critical roles in disease. Example traits include the ability to secrete compounds, deform through tissue, adhere to surrounding cells, apply force to phagocytose targets, or move through extracellular matrix. There is an opportunity to increase the efficacy of cell therapies through the use of quantitative automation tools, to analyze, sort, and select rare cells with beneficial traits. Combined with methods of genetic or epigenetic mutagenesis to create diversity, such approaches can enable the directed cellular evolution of new therapeutically optimal populations of cells and uncover genetic underpinnings of these optimal traits.

show abstract

Considerations in T Cell Therapy Product Development for B Cell Leukemia and Lymphoma Immunotherapy

Cited by 11 publications

References 67 publications

Validation of a flow cytometry-based method to quantify viable lymphocyte subtypes in fresh and cryopreserved hematopoietic cellular products

Validation of a flow cytometry-based method to quantify viable lymphocyte subtypes in fresh and cryopreserved hematopoietic cellular products

Rethinking Cancer Immunotherapy by Embracing and Engineering Complexity

Technologies for the Directed Evolution of Cell Therapies

Contact Info

Product

Resources

About