Pathobiology and treatment of patients with severe combined immunodeficiency

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Our projects in the area of severe combined immunodeficiency (SCID) and its treatment with allogeneic hematopoietic stem cell transplant (HSCT) and autologous gene therapy (GT) are aimed at testing various cellular therapy approaches to determine what approaches result in full immune reconstitution with the least toxicity. SCID is a disease in which children are born without T lymphocytes or T cells, which leaves them vulnerable to severe infection with common viruses and fungi that people with healthy immune systems handle without difficulty. T cells additionally are required for the function of B lymphocytes or B cells, which are the immune cells that make antibodies or immunoglobulin. The inability to make immunoglobulins, proteins in the blood that recognize bacteria and other microorganisms, leaves patients with SCID susceptible to severe infections. T cells and NK cells (which are also deficient in certain genetic types of SCID) are critical for control of oncogenic viruses, such as Epstein-Barr virus or human papillomavirus, and SCID patients are thus at risk of malignancy, particularly lymphoma. Thus, the goal of cellular therapy is to rescue patients with SCID from death due to opportunistic infection and prevent the development of cancer related to immunodeficiency. HSCT is the standard treatment for patients with SCID, and unlike patients with other diseases, HSCT may be performed without prior chemotherapy conditioning, yet still result in T cell reconstitution. We and others have shown however, that chemotherapy conditioning may enhance the longevity of T cell reconstitution, and for some genetic types of SCID, chemotherapy conditioning is required for correction of B cell numbers and/or function. The Conditioning SCID Infants Diagnosed Early (CSIDE) trial is aimed at studying the immune reconstitution of patients with SCID after allogeneic HSCT. The CSIDE study is a multi-institutional trial of HSCT for particular genetic subtypes of SCID that are known to require chemotherapy conditioning for full immune reconstitution (NCT03619551). We are enrolling patients with X-linked SCID (caused by genetic defects in IL2RG), JAK3 SCID (which signals downstream of IL2RG), and SCID caused by defects in RAG1 or RAG2 (which are important for T cell receptor and immunoglobulin gene rearrangement) on this study and randomizing patients to receive either of 2 conditioning regimens, that include busulfan given to achieve a low exposure (30 mg*h/L) or moderate exposure (60 mg*h/L). Dr. Pai and colleagues designed and opened this study, and she is the overall Protocol Chair. Currently there are 47 active sites in United States and Canada, with 30 IL2RG/JAK3 and 18 RAG1/RAG2 patients enrolled for a total of 48 patients. We successfully competed for extramural funding for this trial and also amended the protocol to have the primary endpoint changed to a global composite ranked score, driven by enrollment in the IL2RG/JAK3 arm. That arm is anticipated to meet the accrual target of 32 this year. The Pai lab is accumulating samples to perform B cell functional studies, including in vitro plasmablast generation in response to IL2RG/JAK3-dependent cytokines, immunoglobulin secretion, and other studies. In the area of GT, we are continuing a trial of GT for X-linked SCID, using a self-inactivating lentiviral vector with codon optimized transgene and elongation factor 1 alpha short (EFS) promoter, and low dose busulfan conditioning (targeted exposure 30 mg*h/L). This is a multi-institutional trial with Boston Children's Hospital as the lead trial site (NCT03311503). Dr. Pai continues as overall Protocol Chair after transitioning to NCI. A total of 18 patients have been enrolled study-wide. The Pai lab is accruing samples from the patients to examine B cell function, including IL2RG-specific cytokine response, in vitro Ig production, and other studies. Total accrual goal is 20 patients. We also have been using an in vitro cellular system to explore the effects of different mutations in IL2RG on function, including potential mutants that may exert a dominant negative effect when gene therapy is used to introduce a normal copy of the gene in the same cell.