Expansion of Lymphocytes for Cell-Based Therapeutics

Abstract SCI-48

Adoptive transfer of T cells can lead to targeted and long-lived anti-tumor or anti-infective activity and can also modulate alloreactivity. T cell therapies have been used in both autologous and allogeneic settings. Donor-derived cytotoxic specific T lymphocytes (CTLs) have already proved highly effective in preventing or treating viral infections and Epstein-Barr virus (EBV) lymphomas developing after allogeneic hemopoietic stem cell transplant while T cells expanded ex vivo with CD3/28 beads have enhanced immune reconstitution after autologous stem cell transplantation. Clinical responses have also been observed following T cell therapy in patients with melanoma, lymphoma or nasopharyngeal cancer. Although successes have been obtained, these studies have also provided insights into the requirements for more effective cellular immunotherapy, which may be obtained by genetic modification of T cells. Approaches under evaluation in the clinic include transfer of artificial T cell receptors to target tumor cells, transfer of genes to render T cells resistant to tumor evasion mechanisms and transfer of a suicide gene that can be activated should adverse effects occur to allow the cell to be destroyed on exposure to a specific signal. The suicide gene strategy using the herpes simplex viral thymidine kinase (Tk) gene allows ablation of infused donor T cells if they induce graft-versus-host disease after allogeneic HSCT and has reached phase III clinical trial. In all these adoptive T cell immunotherapy strategies, broader application is limited by suboptimal persistence of transferred T cells, and by the complexity of current manufacturing techniques. Current research focuses on defining the optimum type of cell for transfer and the ex vivo selection and expansion procedures that favor long term persistence, since broader applicability will require ex vivo expanded T cells to show clinical activity and to have robust manufacturing processes and a clinical distribution paradigm. Strategies for simplifying and accelerating manufacture of T cell products have included the use of artificial antigen presenting cells expressing co-stimulatory ligands to provide a rapid source of antigen and optimized costimulation; bioreactors to grow cells in a closed system; and cytokine combinations to optimize cell growth and survival. Integration of these multiple approaches will be required to determine the best cell type and culture conditions for generating T cells for subsequent adoptive transfer into a complex immune network.