Red cell exchange for rapid leukoreduction in adults with hyperleukocytosis and leukostasis.

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.

A simulation-based comparison of centralized and point-of-care supply chain strategies for autologous cell therapy.

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.

Scalable Manufacturing of CAR T cells for Cancer Immunotherapy.

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.

Humanized CD19-Targeted Chimeric Antigen Receptor (CAR) T Cells in CAR-Naive and CAR-Exposed Children and Young Adults With Relapsed or Refractory Acute Lymphoblastic Leukemia.

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.

Clinical development of natural killer cells expressing chimeric antigen receptors.

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.

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

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.

Engineered T cells: the promise and challenges of cancer immunotherapy.

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.

NKG2D expression by CD8+ T cells contributes to GVHD and GVT effects in a murine model of allogeneic HSCT.

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.