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EBMT 2020 Annual Meeting - Large-scale access to marketed CAR T-Cells

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Cellular Therapy & Immunobiology Working Party (CTIWP)

Cell Therapy Day - Monday 31 August, 14:30-15:50H – Auditorium 4

This year’s Cell Therapy Day features four sessions across Monday, with ten expert speakers covering a variety of subjects from biotechnological developments, law and ethics, and integration of care and research to modern developments in immunogenetics and immunology. However, our preview in today’s newsletter is on session CTD3: large-scale access to marketed CAR T-Cells.

In the first session, Dr Elad Jacoby of the Sheba Medical Center, Ramat Gan, Israel, will explore the process of collecting autologous mononuclear cells (MNC) for industry-manufactured CAR-T cells. “The first step in the production of CAR T-cells for patients is the collection of non-mobilised peripheral blood lymphocytes through leukapheresis,” he explains.

CAR T-cell therapies are currently approved for heavily pre-treated patients, after failing two lines of previous treatment. Moreover, some patients are referred with rapidly growing tumours. Both factors may significantly limit lymphocyte numbers and function. Also, the presence of a high number of leukaemic blasts or a high proportion of monocytes in the leukapheresis product may affect the final CAR T-cell product and patient outcome.

Dr Jacoby explains: “Thus, there is a delicate balance between the need for disease control and the desire to start production with untouched lymphocytes.  In this talk, I will discuss factors affecting the timing of leukapheresis relative to previous and planned therapies and current recommendations, such as timing of lympho-depleting agents. I will also cover the specific challenges of leukapheresis in the paediatric population receiving tisagenlecleucel for ALL, especially in younger patients, including venous access and cell requirements.”

In the second talk, Professor Ulrike Koehl (Director, Institute of Clinical Immunology
University of Leipzig, and University Hospital Leipzig, Germany) will a
ddress bottlenecks in CAR T-cell manufacturing.

“The adoptive transfer of CAR T-cells and the successful remissions in B-cell leukaemia and lymphoma is attracting growing interest for the treatment of various malignant diseases,” explains Professor Koehl. “With further applications and increasing numbers of patients, the reproducible manufacture of high-quality clinical-grade CAR T-cells is becoming an ever-greater challenge. New processing techniques, quality-control mechanisms, and logistic developments are required to meet both medical needs and regulatory restrictions.”

He will explain that manufacturing of autologous cells for personalised medicine remains time consuming and expensive. “Preliminary results with automated manufacturing have given hope for improvement in both centralised and decentralised manufacturing units. However, a modular, open and transferable system with AI-mediated robotics and digital control as well as the respective automated documentation of all in-process parameters is still missing,” he says. “This means no system exists to address 100 times more patients, if we find that tumours can successfully be targeted.”

Furthermore, there are no harmonised rules for patient selection regarding the leukapheresis starting material, and surrogate markers are completely missing to predict production failure. “In several cases, failure in manufacturing appears because the patients are heavily pre-treated and this can significantly influence the fitness of the cells,” explains Professor Koehl. “Finally, there have been some observations that the relapses of the disease belong to a contaminating transduced leukaemic clone during the manufacturing process. In summary, improvement of manufacturing is necessary, along with systems to use allogeneic effector cells as an ‘off the shelf product’ to overcome bottlenecks in the future.”

In the final talk, the unique issue of management of “out-of-specification” (OOS) or “nonconforming” product will be covered by Dr Alexey Bersenev, Assistant Professor of Clinical Lab Medicine, Yale University and Facility Director, Cell Therapy Labs, Yale-New Haven Hospital, CT, USA.

“Regulatory approval and wide-spread clinical adoption of commercial autologous CAR-T cell therapy has brought this unique issue to our attention,” says Dr Bersenev. He will explain that, even though OOS is a new phenomenon for commercial CAR-T cell therapy industry, it is very well known as “nonconforming product release” in haematopoietic stem/progenitor cell (HPC) transplantation.

He says: “The CAR-T cell therapy industry can learn clinical aspects of OOS product management from the HPC transplantation field. Depending on what criteria is out of specification, CAR-T cell products could be safely released and administered into the patient. Examples of such OOS criteria could include cell viability, potency, dose and cellular composition. Currently, the CAR-T cell therapy field is accumulating data on the frequency of OOS events and their clinical and commercial impact.”