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Abstract: We show that red cell exchange (RCE) treats hyperleukocytosis in acute leukemia. RCE provided similar leukoreduction to standard therapeutic leukoreduction and could be superior in patients with severe anemia or monocytic leukemias or when requiring rapid treatment., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background Aims: The selection between centralized and point-of-care (POC) manufacturing supply-chain network design is a crucial consideration in the autologous cell therapy (AuCT) industry, as each approach offers its advantages and disadvantages., Methods: This study uses a simulation-based approach to compare and examine the two strategies using the supply chain for chimeric antigen receptor T-cell therapy manufacturing as an exemplar. When does it make sense to use one manufacturing strategy over another? Currently, major manufacturers in the AuCT industry use centralized supply-chain strategies predominantly in practice. The simulation results explain the reasons for this choice. To enhance the competitiveness of the POC strategy, two operation rules are proposed and tested with the simulation. The study uses key performance indicators such as cost, fulfillment time, service level, and resource utilization to provide generic guidelines based on the findings., Results: The results have revealed that (i) the centralized supply-chain strategy has a significant advantage at current demand levels of a few thousand products per year; (ii) "optimal capacity" exists for the POC strategy that minimizes the cost of goods and (iii) allowing part-time labor and order transshipment can significantly increase the competitiveness of the POC strategy., Conclusions: This study may be useful in helping commercial manufacturers make informed decisions about their manufacturing approach to enhance their competitiveness in the market and to ensure a high level of patient benefit., Competing Interests: Declaration of Competing Interest Bruec L. Levine reports personal fees from Akron, Avectas, Immuneel, Immusoft, In8bio, Ori Biotech, Oxford Biomedica, ThermoFisher Pharma Services, UTC Therapeutics, Vycellix and is a co-founder and equity holder in Tmunity Therapeutics (acquired by Kite Pharma) and Capstan Therapeutics, outside the submitted work. Andrew D. Fesnak reports a relationship with Achieve Clinics that is outside the scope of the submitted work. There is no conflict of interest for other co-authors., (Published by Elsevier Inc.)

Purpose: CD19-targeted chimeric antigen receptor (CAR)-modified T cells demonstrate unprecedented responses in B-cell acute lymphoblastic leukemia (B-ALL); however, relapse remains a substantial challenge. Short CAR T-cell persistence contributes to this risk; therefore, strategies to improve persistence are needed., Methods: We conducted a pilot clinical trial of a humanized CD19 CAR T-cell product (huCART19) in children and young adults with relapsed or refractory B-ALL (n = 72) or B-lymphoblastic lymphoma (n = 2), treated in two cohorts: with (retreatment, n = 33) or without (CAR-naive, n = 41) prior CAR exposure. Patients were monitored for toxicity, response, and persistence of huCART19., Results: Seventy-four patients 1-29 years of age received huCART19. Cytokine release syndrome developed in 62 (84%) patients and was grade 4 in five (6.8%). Neurologic toxicities were reported in 29 (39%), three (4%) grade 3 or 4, and fully resolved in all cases. The overall response rate at 1 month after infusion was 98% (100% in B-ALL) in the CAR-naive cohort and 64% in the retreatment cohort. At 6 months, the probability of losing huCART19 persistence was 27% (95% CI, 14 to 41) for CAR-naive and 48% (95% CI, 30 to 64) for retreatment patients, whereas the incidence of B-cell recovery was 15% (95% CI, 6 to 28) and 58% (95% CI, 33 to 77), respectively. Relapse-free survival at 12 and 24 months, respectively, was 84% (95% CI, 72 to 97) and 74% (95% CI, 60 to 90) in CAR-naive and 74% (95% CI, 56 to 97) and 58% (95% CI, 37 to 90) in retreatment cohorts., Conclusion: HuCART19 achieved durable remissions with long-term persistence in children and young adults with relapsed or refractory B-ALL, including after failure of prior CAR T-cell therapy., Competing Interests: David M. BarrettTravel, Accommodations, Expenses: Therakos David T. TeacheyConsulting or Advisory Role: SobiResearch Funding: Novartis, Beam Therapeutics, NeoImmuneTech Colleen CallahanConsulting or Advisory Role: NovartisSpeakers' Bureau: Peerview Susan R. RheingoldEmployment: OptiNoseStock and Other Ownership Interests: OptiNoseConsulting or Advisory Role: PfizerResearch Funding: Pfizer Richard AplencExpert Testimony: Vorys Pamela A. ShawPatents, Royalties, Other Intellectual Property: I am part of a patent owned by UPenn and currently licensed to Novartis for an algorithm that predicts severe cytokine release syndrome for the CART 19 therapy. I receive 10% of the licensing fees Edward PequignotPatents, Royalties, Other Intellectual Property: As part of Penn's role in the FDA-approval of CAR-T therapy, and for my part as an employee of Penn involved in their research in CAR-T, I have received royalties of approximately $300 in US dollars over the past 2 years Jennifer L. BrogdonEmployment: Novartis Institutes for BioMedical ResearchStock and Other Ownership Interests: Novartis Institutes for BioMedical Research Donald L. SiegelResearch Funding: Tmunity Therapeutics IncPatents, Royalties, Other Intellectual Property: A patent, owned by the Trustees of the University of Pennsylvania, on which I am listed as an inventor is licensed to Alexion Pharmaceuticals. I receive royalties as stipulated in the University of Pennsylvania Faculty HandbookExpert Testimony: Regeneron Megan M. DavisLeadership: Cellares CorporationConsulting or Advisory Role: Tmunity Therapeutics IncResearch Funding: Tmunity Therapeutics IncPatents, Royalties, Other Intellectual Property: Novartis Institutes for Biomedical Research—royalties and milestones for patents/knowhow, Tmunity Therapeutics—royalties andmilestones from patents/knowhow Simon F. LaceyConsulting or Advisory Role: Gilead SciencesResearch Funding: Tmunity Therapeutics Inc, Cabaletta Bio, Novartis Institutes for BioMedical ResearchPatents, Royalties, Other Intellectual Property: Patents and IP related to CTL019 (Kymriah) assigned by the University of Pennsylvania to Novartis Elizabeth O. HexnerConsulting or Advisory Role: Blueprint Medicines, ABIM Subspecialty BoardResearch Funding: Blueprint Medicines, Tmunity Therapeutics Inc Gerald B. WertheimEmployment: Johnson & JohnsonStock and Other Ownership Interests: Johnson & Johnson Bruce L. LevineStock and Other Ownership Interests: Tmunity Therapeutics IncHonoraria: Novartis, TerumoConsulting or Advisory Role: Avectas, Ori Biotech, Vycellix, Immuneel Therapeutics, In8bio, Patheon/ThermoFisher Viral Vector ServicesResearch Funding: Tmunity Therapeutics IncPatents, Royalties, Other Intellectual Property: Intellectual property and patents in the field of cell and gene therapyTravel, Accommodations, Expenses: Avectas, Terumo Carl H. JuneLeadership: AC ImmuneStock and Other Ownership Interests: Celldex, Tmunity Therapeutics Inc, Cabaletta Bio, Carisma Therapeutics, DeCART Therapeutics, Bluesphere Bio, Cellares, ZIOPHARM Oncology, Decheng Capital, Posieda Therapeutics, VerismaHonoraria: PfizerConsulting or Advisory Role: Celldex, Viracta Therapeutics, Cabaletta Bio, Carisma Therapeutics, Kiadis Pharma, WIRB-Copernicus Group, Janssen OncologyResearch Funding: Novartis, Tmunity Therapeutics IncPatents, Royalties, Other Intellectual Property: IP licensed to Novartis; Royalties paid to University of Pennsylvania, Office of Naval Research; IP and patent royalties, IP licensed to Tmunity Stephan A. GruppConsulting or Advisory Role: Novartis, Jazz Pharmaceuticals, Janssen, Cellular Biomedicine Group, TCR2 Therapeutics, Humanigen, Roche, Adaptimmune, Alimera Sciences, Cabaletta Bio, CRISPR Therapeutics/VertexResearch Funding: Novartis, Kite/Gilead, Servier, Jazz Pharmaceuticals, VertexPatents, Royalties, Other Intellectual Property: UPenn Toxicity management patentExpert Testimony: Juno Therapeutics Shannon L. MaudeConsulting or Advisory Role: Novartis, Wugen IncResearch Funding: NovartisTravel, Accommodations, Expenses: Novartis, Kite, a Gilead company, Wugen IncNo other potential conflicts of interest were reported.

As of April 2021, there are five commercially available chimeric antigen receptor (CAR) T cell therapies for hematological malignancies. With the current transition of CAR T cell manufacturing from academia to industry, there is a shift toward Good Manufacturing Practice (GMP)-compliant closed and automated systems to ensure reproducibility and to meet the increased demand for cancer patients. In this review we describe current CAR T cells clinical manufacturing models and discuss emerging technological advances that embrace scaling and production optimization. We summarize measures being used to shorten CAR T-cell manufacturing times and highlight regulatory challenges to scaling production for clinical use., Statement of Significance ∣: As the demand for CAR T cell cancer therapy increases, several closed and automated production platforms are being deployed, and others are in development.This review provides a critical appraisal of these technologies that can be leveraged to scale and optimize the production of next generation CAR T cells.

Both natural killer (NK) cells and T cells demonstrate potent antitumor responses in many settings. NK cells, unlike T cells, are not the primary mediators of graft-versus-host disease (GVHD). Redirection of T cells with chimeric antigen receptors (CAR) has helped to overcome tumor escape from endogenous T cells. NK cells expressing CARs are a promising new therapy to treat malignancy. Clinical biomanufacturing of CAR NK cells can begin with NK cells derived from many different sources including adult peripheral blood-derived NK cells, cord blood-derived NK cells, cell line-derived NK cells, or stem cell-derived NK cells. Manufacturing protocols may include isolation of NK cells, activation, expansion, and genetic modification to express the chimeric antigen receptors. Clinical trials have tested both unmodified and CAR NK cells with encouraging results. The next stage in clinical development of CAR NK cells represents a highly exciting new frontier in clinical cell therapy as well as understanding basic NK cell biology. The purpose of this review is to provide the reader with a fundamental understanding of the core concepts in CAR NK cell manufacturing, specifically highlighting differences between CAR T cell manufacturing and focusing on future directions in the field., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Autologous Chimeric Antigen Receptor (CAR) T cell manufacturing involves the modification and expansion of T cells obtained by apheresis collection from a patient. The mechanism of apheresis collection and the specific clinical features seen in these patients combine to generate apheresis products with high variability of content. Manufacturers often attempt to minimize this variability such that processes can be standardize in accordance with Good Manufacturing Practices (GMP). Such standardization improves efficiency and helps to ensure robustness of the overall process. Apheresis product variability can negatively impact T cell manufacturing success. Patient and collection driven variability often leads to non-T cells entering the apheresis product. Many of these cells can directly or indirectly impair T cell activation and expansion, decreasing the manufacturing success rate. Therefore, patient driven variability observed in apheresis products, must be mitigated through downstream processing. T cell enrichment is one step in the manufacturing cycle that can reduce process variability by generating more uniform downstream material. However, current T cell enrichment methods have limitations. Much of this type of variability can be avoided by collecting patients earlier in their disease or treatment course, this is not current, widespread or standard practice. While variability poses challenges to successful CAR T cell manufacturing and mitigation strategies can be successful, more work is needed in this area.

Background Aims: Autologous cell therapy (AuCT) is an emerging therapeutic treatment that is undergoing transformation from laboratory- to industry-scale manufacturing with recent regulatory approvals. Various challenges facing the complex AuCT manufacturing and supply chain process hinder the scale out and broader application of this highly potent treatment., Methods: We present a multiscale logistics simulation framework, AuCT-Sim, that integrates novel supply chain system modeling algorithms, methods, and tools. AuCT-Sim includes a single facility model and a system-wide network model. Unique challenges of the AuCT industry are analyzed and addressed in AuCT-Sim. Decision-supporting tools can be developed based on this framework to explore "what-if" manufacturing and supply chain scenarios of importance to various cell therapy stakeholder groups., Results: Two case studies demonstrate the decision-supporting capability of AuCT-Sim where one investigates the optimal reagent base stocking level, and the other one simulates a reagent supply disruption event. These case studies serve as guidelines for designing computational experiments with AuCT-Sim to solve specific problems in AuCT manufacturing and supply chain., Discussion: This simulation framework will be useful in understanding the impact of possible manufacturing and supply chain strategies, policies, regulations, and standards informing strategies to increase patient access to AuCT., (Copyright © 2019 International Society for Cell and Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Based on laboratory and clinical research findings and investments in immunotherapy by many institutions in academia, government-funded laboratories, and industry, there is tremendous and deserved excitement in the field of cell and gene therapy. In particular, understanding of immune-mediated control of cancer has created opportunities to develop new forms of therapies based on engineered T cells. Unlike conventional drugs or biologics, the source material for these new therapies is collected from the patient or donor. The next step is commonly either enrichment to deplete unwanted cells, or methods to positively select T cells prior to polyclonal expansion or antigen-specific expansion. As the first generation of engineered T cell therapies have demonstrated proof of concept, the next stages of development will require the integration of automated technologies to enable more consistent manufacturing and the ability to produce therapies for more patients.

The immune system evolved to distinguish non-self from self to protect the organism. As cancer is derived from our own cells, immune responses to dysregulated cell growth present a unique challenge. This is compounded by mechanisms of immune evasion and immunosuppression that develop in the tumour microenvironment. The modern genetic toolbox enables the adoptive transfer of engineered T cells to create enhanced anticancer immune functions where natural cancer-specific immune responses have failed. Genetically engineered T cells, so-called 'living drugs', represent a new paradigm in anticancer therapy. Recent clinical trials using T cells engineered to express chimeric antigen receptors (CARs) or engineered T cell receptors (TCRs) have produced stunning results in patients with relapsed or refractory haematological malignancies. In this Review we describe some of the most recent and promising advances in engineered T cell therapy with a particular emphasis on what the next generation of T cell therapy is likely to entail.

In allogeneic hematopoietic stem cell transplantation (HSCT), controlling graft-versus-host disease (GVHD) while maintaining graft-versus-tumor (GVT) responses is of critical importance. Using a mouse model of allogeneic HSCT, we hereby demonstrate that NKG2D expression by CD8(+) T cells plays a major role in mediating GVHD and GVT effects by promoting the survival and cytotoxic function of CD8(+) T cells. The expression of NKG2D ligands was not induced persistently on normal tissues of allogeneic HSCT-recipient mice treated with anti-NKG2D antibody, suggesting that transient NKG2D blockade might be sufficient to attenuate GVHD and allow CD8(+) T cells to regain their GVT function. Indeed, short-term treatment with anti-NKG2D antibody restored GVT effects while maintaining an attenuated GVHD state. NKG2D expression was also detected on CD8(+) T cells from allogeneic HSCT patients and trended to be higher in those with active GVHD. Together, these data support a novel role for NKG2D expression by CD8(+) T cells during allogeneic HSCT, which could be potentially therapeutically exploited to separate GVHD from GVT effects., (© 2015 by The American Society of Hematology.)

Classically, recombination between immunoglobulin gene segments uses a pair of recombination signal sequences (RSSs) with dissimilar spacers (the "12/23 rule"). Using a series of different genotyping assays, four different kinds of atypical rearrangements were identified at the murine kappa locus: (1) V kappa to V kappa, (2) J kappa to J kappa, (3) V kappa to iRS, a heptameric sequence found in the J kappa C kappa intron, and (4) a possible by-product of a rearrangement between a V kappa and the hypothetical 12-RSS side of a pre-existing signal joint. The novel V kappa-V kappa structure prompted further characterization. Sequence analysis of 14 different V kappa-V kappa rearrangements cloned from murine splenocytes and hybridomas revealed a V kappa 4 family member as one participant in 13 rearrangements, but no rearrangements contained two V kappa 4 genes. The V kappa 4 partner in the V kappa-V kappa rearrangement exhibited more trimming of nucleotides at the V kappa-V kappa junction. A signal joint derived from the inversional rearrangement of two neighboring V kappas was also recovered. These data suggest that the V kappa-V kappa structures arise via RAG-mediated, intrachromosomal recombination.