Points to Consider Response with Clinical Protocol, July 6, 1990

Abstract

Severe combined immunodeficiency (SCID) due to deficiency of the purine metabolic enzyme adenosine deaminase (ADA) is a fatal childhood immunodeficiency disease. Immune reconstitution by transplantation with HLA-identical bone marrow is the treatment of choice. For patients not candidates for bone marrow transplantation, we propose to attempt immune reconstitution by using infusions of autologous T lymphocytes expanded in tissue culture and genetically corrected by insertion of a normal ADA gene using retroviral-mediated gene transfer. The vector is LASN, in which the human ADA gene is promoted by the LTR while the Neo^R gene is driven by the SV40 early gene promoter. The packaging line is PA317. The protocol is designed to have two parts. In Part 1, autologous gene-corrected T lymphocytes would be infused repeatedly in low numbers in order to build an immune repertoire of T cells and also to obtain information as to how long gene corrected T cells survive in vivo. In Part 2A, the gene-corrected T cells would be selected in G418 and/or 2′deoxyadenosine and reinfused into the patient at monthly intervals for approximately 6 months. The goals would be essentially the same as in Part 1. In Part 2B, the number of gene-corrected T cells would be escalated in half-log increments to the predicted therapeutic level (probably around 1 × 10⁹/kg). 1–3 × 10⁹/kg gene-corrected cells would be infused several times and the patient would be monitored in order to determine if significant clinical improvement has occurred. ADA Deficiency is a fatal genetic disease that often results in death within the first years of life. The disease is characterized by a loss of immune cells (the lymphocytes) in the body and this results in a profound immunodeficiency, called Severe Combined Immunodeficiency (SCID). The disease is caused by a defect in one of the genes that is required for the proper functioning of the T lymphocytes. The treatment of choice is a matched bone marrow transplantation. But for those patients who are not candidates for bone marrow transplantation, we propose to attempt to provide immune protection by using gene therapy. The procedure would be to remove T lymphocytes from patients who are on PEG-ADA, grow the T cells in tissue culture, insert a normal ADA gene into them using a process called retroviral-mediated gene transfer, and then return the gene-corrected cells to the patient. The protocol is designed to have two parts. In Part 1, low numbers of gene-corrected T lymphocytes would be given to the patient repeatedly in order to build up the immune system and also to obtain information as to how long gene-corrected T cells survive. In Part 2A, a selection procedure would be used to increase the number of gene-corrected T cells making substantial amounts of the ADA enzyme. These enriched cells would then be given to the patient monthly for approximately 6 months. In Part 2B, the number of gene-corrected T cells would be escalated to the predicted therapeutic level (probably around 1 billion gene-corrected T cells per kilogram body weight of the patient). Then, 1 to 3 billion gene-corrected T cells per kilogram would be infused several times and the patient would be monitored in order to determine if significant clinical improvement has occurred.