The Landscape of Early Clinical Gene Therapies outside of Oncology.

The field of cell and gene therapy (GT) is expanding rapidly and there is undoubtedly a wave of enthusiasm and anticipation for what these treatments could achieve next. Here we assessed the worldwide landscape of GT assets currently in early clinical development (clinical trial phase 1/2 or about to enter clinical trial). We included all gene therapies, i.

Transfer of gene-corrected T cells corrects humoral and cytotoxic defects in patients with X-linked lymphoproliferative disease.

Background: X-linked lymphoproliferative disease 1 arises from mutations in the SH2D1A gene encoding SLAM-associated protein (SAP), an adaptor protein expressed in T, natural killer (NK), and NKT cells. Defects lead to abnormalities of T-cell and NK cell cytotoxicity and T cell-dependent humoral function. Clinical manifestations include hemophagocytic lymphohistiocytosis, lymphoma, and dysgammaglobulinemia.

T-cell gene therapy for perforin deficiency corrects cytotoxicity defects and prevents hemophagocytic lymphohistiocytosis manifestations.

Background: Mutations in the perforin 1 (PRF1) gene account for up to 58% of familial hemophagocytic lymphohistiocytosis syndromes. The resulting defects in effector cell cytotoxicity lead to hypercytokinemia and hyperactivation with inflammation in various organs.

Objective: We sought to determine whether autologous gene-corrected T cells can restore cytotoxic function, reduce disease activity, and prevent hemophagocytic lymphohistiocytosis (HLH) symptoms in in vivo models.

Thymus transplantation for complete DiGeorge syndrome: European experience.

Background: Thymus transplantation is a promising strategy for the treatment of athymic complete DiGeorge syndrome (cDGS).

Methods: Twelve patients with cDGS underwent transplantation with allogeneic cultured thymus.

Objective: We sought to confirm and extend the results previously obtained in a single center.

Cord blood T cells mediate enhanced antitumor effects compared with adult peripheral blood T cells.

Unrelated cord blood transplantation (CBT) without in vivo T-cell depletion is increasingly used to treat high-risk hematologic malignancies. Following T-replete CBT, naïve CB T cells undergo rapid peripheral expansion with memory-effector differentiation. Emerging data suggest that unrelated CBT, particularly in the context of HLA mismatch and a T-replete graft, may reduce leukemic relapse.

Towards gene therapy for EBV-associated posttransplant lymphoma with genetically modified EBV-specific cytotoxic T cells.

Epstein-Barr virus (EBV)-associated posttransplant lymphoma (PTLD) is a major cause of morbidity/mortality after hematopoietic stem cell (SCT) or solid organ (SOT) transplant. Adoptive immunotherapy with EBV-specific cytotoxic lymphocytes (CTLs), although effective in SCT, is less successful after SOT where lifelong immunosuppression therapy is necessary. We have genetically engineered EBV-CTLs to render them resistant to calcineurin (CN) inhibitor FK506 through retroviral transfer of a calcineurin A mutant (CNA12).

Optimization of methodology for production of CD25/CD71 allodepleted donor T cells for clinical use.

Background Aims: Immunotherapy with allodepleted donor T cells improves immunity after T cell-depleted hematopoietic stem cell transplantation. We developed a methodology for selective depletion of alloreactive T cells after activation with host antigen-presenting cells by targeting T cells up-regulating CD25 and CD71. Combined depletion of these cells yields a pool of allodepleted donor T cells with antiviral properties with minimal capacity to cause graft-versus-host disease.

Simultaneous generation of multivirus-specific and regulatory T cells for adoptive immunotherapy.

Previous studies have established that adoptive immunotherapy with donor-derived virus-specific T cells can prevent/treat viral complications post-stem cell transplant and regulatory T cells show promise as inhibitors of graft-versus-host disease. On the basis of flow cytometric analysis of upregulation of activation markers after stimulation with viral peptide pools, we have developed a rapid and clinically applicable protocol for the simultaneous selection of virus-specific T cells (after stimulation with peptide pools for the immunodominant antigens of cytomegalovirus, Epstein-Barr virus, and adenovirus) and regulatory T cells using CD25 immunomagnetic selection. Using tetramer staining, we detected enrichment of CD8 T cells recognizing peptide epitopes from cytomegalovirus and Epstein-Barr virus antigens after CD25 selection in 6 of 7 donors.

Anti tumour necrosis-alpha therapy increases the number of FOXP3 regulatory T cells in children affected by Crohn's disease.

Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. Its pathogenesis is not completely understood, though the prevailing model is that the intestinal flora drives a strong intestinal T helper 1 (Th1)/Th17 type immune response and inflammation in the genetically susceptible host. This leads to overly aggressive T-cell responses to normal bacteria causing tissue damage.

Unexpected role of surface transglutaminase type II in celiac disease.

Background & Aims: In celiac disease (CD), transglutaminase type II (TG2) has 2 fundamental roles: (1) as the autoantigen recognized by highly specific autoantibodies and (2) the modifier of pathogenic gliadin T-cell epitopes. It follows that inhibition of TG2 might represent an attractive strategy to curb the toxic action of gliadin. Here we studied the validity of this strategy using the organ culture approach.

Gliadin as a stimulator of innate responses in celiac disease.

In celiac disease (CD) we have the prototype of an immune mediated response dominated by the activation of the adaptive immune system and in particular of CD4+ HLA class II restricted T cells. Various seminal studies have established the precise mechanism of how antigen (prolamine) specific activation of CD4+ mucosal T cells occurs. Thus, CD is a condition in which T cells and their activation is the essential hinge in the pathogenic process.

Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease.

Background: The adaptive immune system is central to the development of coeliac disease. Adaptive immune responses are, however, controlled by a preceding activation of the innate immune system. We investigated whether gliadin, a protein present in wheat flour, could activate an innate as well as an adaptive immune response in patients with coeliac disease.