June 23, 2021

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How T cell gene therapy treats immunodeficiency?

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How T cell gene therapy treats immunodeficiency?

How T cell gene therapy treats immunodeficiency?  In the past few decades, therapeutic T cells have been used in a variety of diseases with significant success, including the infusion of donor lymphocytes, virus-specific T cells and, more recently, CAR-T cell therapy.

T-cell gene therapy may provide a potential treatment for diseases that mainly affect the lymphatic area, and has been studied in the context of immune diseases and infectious diseases using a number of different gene modification techniques (see the figure below). In this review, we will discuss the clinical experience of genetically modified T cells, as well as preclinical studies of immunodeficiency (see table below)

How T cell gene therapy treats immunodeficiency? How T cell gene therapy treats immunodeficiency?

Previous clinical research

For most primary immunodeficiencies, allogeneic hematopoietic stem cell transplantation (HSCT) can provide curative treatment, with a good survival rate in the case of HLA-matched family donors; however, historically, in non-relative donations In the case of donors or mismatched donors, the results are worse. The use of autologous cells can eliminate the risk of allogeneic reactions and allow the use of less toxic conditioning regimens. Therefore, it has several advantages over hematopoietic stem cell transplantation from mismatched donors.

The occurrence of some primary immunodeficiencies is mainly due to defects in the T cell area, so the correction of the T cell population may improve the clinical symptoms of some of these diseases, such as CD40L deficiency, IPEX syndrome (immune disorders, polyneuropathy, intestinal Disease, X-linked), X-linked lymphocytosis, CTLA4 deficiency, and STAT1 loss of function and gain-of-function mutations.

About CD40 ligand

CD40 ligand is a T cell active protein. The receptor CD40 is expressed by antigen presenting cells, including B cells. CD40 plays an important role in the proliferation and differentiation of B cells. The interaction of CD40 and its ligands induces the formation of memory B cells, thereby producing Igm and other types of immunoglobulins. The defect of CD40 ligand expression on the surface of T cells is the basis of X-associated high Igm syndrome. This defect can cause low serum IgG, IgA and IgE seen in the laboratory, but normal or elevated Igm.

CD40L is mainly expressed in activated CD4+ T lymphocytes, partially activated CD8+ T cells, basophils, mast cells, and NK cells. The thymoma cell line EL-4 also expresses CD40L. CD3 monoclonal antibody can stimulate T cells to express CD40L.

In view of the need for precise expression of CD40L, emerging gene editing technologies provide this precision; the ability to locate the correction at the local CD40L locus should allow endogenous promoters and other regulatory elements to regulate the corrected gene. According to reports, the editing rate of CD4+ T cells in patients is as high as 35%. These cells correctly express CD40L when T cells are activated, and induce class switching recombination of B cells and produce IgG in in vitro experiments. The corrected T cells were stably transplanted into diabetic-severe immunodeficiency (NOD-SCID) γ (NSG) mice, which showed the recovery of spleen CD4+ T cells and a physiological CD40L expression profile.


X-linked polyendocrine disease and enteropathy with immune dysregulation syndrome (IPEX) is a rare genetic disease of the immune system caused by mutations in the human FOXP3 gene.

In IPEX patients, the functional defect of FOXP3 leads to the destruction of peripheral self-tolerance, which is considered to be the main and direct cause of autoimmunity in IPEX patients. Due to the nature and function of genes involved in the pathogenesis of IPEX, it can be considered an ideal target for T cell-based immunotherapy. The single gene nature of IPEX leads to autoimmunity with a single basic defective cell population, opening up a way for more direct and targeted treatments. Therefore, the use of FoxP3mut (scurfy) mouse IPEX model for adoptive Treg transfer research.

One of the first studies focusing on the pathophysiology of IPEX syndrome was the correction of the mouse scurfy phenotype; this is a mouse IPEX model. The adoptive transfer of wild-type Treg cells (CD4+CD25+) controlled the symptoms, while the transfer of CD4+CD25- cells did not, highlighting the importance and immunomodulatory ability of the Treg population in this disease model. Based on these results, different research groups over-applied FOXP3 to CD4+ T cells from healthy donors, and cultivated Tregs de novo by adding lentiviral genes.

X-linked lymphoproliferative disease (XL P)

X-linked lymphoproliferative disease (X-linked lymphoproliferative disease, XL P) is one of the six X-linked immunodeficiency diseases. Due to the Xq25 mutation, the patient cannot produce an effective immune response to EB virus infection. Causes lymphocyte proliferation. The clinical manifestations of XL P are diverse, including fulminant IM, gamma globulin abnormalities, malignant lymphoma, aplastic anemia, etc. Hematopoietic stem cell transplantation or bone marrow transplantation is currently the only treatment for XL P. At present. A gene SH2 D1A (DSHP) related to XL P has been cloned, and its encoded protein SAP can interact with SLAM (CDw150) to regulate B cell proliferation. It is speculated that the pathogenesis of XL P is due to genetic defects after EBV infection. TH1 and TH2 are caused by an imbalance in the immune response.

Efforts have been made to directly address the T-cell-dependent clinical manifestations of XLP1, using genetically corrected adoptive T cell transfer in SAP-deficient mice, while restoring the patient’s T cell function in vitro. Here, previous scientists proved that in vivo and in vitro, the transfer of SAP-corrected T lymphocytes can correct the humoral and cytotoxicity defects in SAP-deficient mouse models. We have observed that after T cell-dependent antigen challenge, the functional humoral immunity is completely restored through the formation of reproductive centers and specific antibody responses, and both of these are not present in SAP-deficient animals.

The long-term persistence of autologous genetically modified T cells, and the persistence of the resulting clinical benefits, also need to be determined. In addition to previous clinical trials that have demonstrated the continued existence of genetically modified T cells, it has now been determined that specific T cell subsets can maintain the T cell compartment, namely stem cell-like memory T cells (TSCM) and central memory (TCM) cells. Scientists have reported that after slow transduction and amplification, genetically modified naive cells are preserved with TSCM and TCM phenotypes, supporting the view that SAP/modified patient cells may persist. This method is now being translated into clinical trials.

Familial hemophagocytic syndrome (HLH)

Researchers from Beijing Daopei Hospital used gene sequencing methods to detect the following six primary types of patients with refractory viral infectious diseases, including hemophagocytic syndrome (HLH), chronic active Epstein-Barr virus infection, and EBV-related lymphoma. The main related gene mutations of hemophagocytic syndrome, including perforin gene (PRF1), UNC13 homologous protein 4 gene (UNC13D), synaptic fusion protein 11 gene (STX11) and synaptic fusion protein binding protein 2 gene (STXBP2), SH2 domain protein 1A gene (SH2D1A), X-linked inhibitor of apoptosis protein gene (XIAP). HLH and chronic EBV active infection are diagnosed according to the diagnostic criteria of the International Organization and Cell Association, and the diagnosis of EBV-related lymphoma is diagnosed according to the diagnostic criteria of WHO (2008).

Results: In 25 patients with refractory viral infectious diseases, including virus-related hemophagocytic syndrome (HLH), chronic active Epstein-Barr virus infection (CAE), and EBV-related lymphoma, the above six genes were detected and 13 One patient has a genetic mutation. The patient and its detection are as follows.

Conclusions: 1. Genetic immunodeficiency is one of the causes of refractory viral infections and related HLH and lymphoma. Genetic testing is a strong evidence to help confirm the diagnosis of such diseases to avoid misdiagnosis and wrong treatment. 2. Whether the age of onset, clinical manifestations and severity of patients with different genetic immunodeficiency is related to the location of the immunodeficiency gene mutation and other factors that may be combined deserve further discussion.

Future strategies and applications

With the increase in our experience and understanding of genetically modified T cell transfer, more and more lymphocyte populations are genetically modified. As a means to improve durability, specific immunophenotypes have aroused people’s interest.

TSCM cells are a group of T memory cells with long-term survival ability, accounting for 2-3% of the human circulating T cell pool. 77,78 Their definition is the expression of CD95 and IL2Rb in the CD45RA+CD62L+ naive cell range, and this population has been shown to not only contain the transcriptional characteristics of naive and central memory cells, but also continue to be in a dynamic state. Compared with other T cell subgroups, these cells continue to show stronger proliferation ability, can rapidly proliferate and cell turnover under antigen stimulation, and have the ability to rebuild a complete memory T cell spectrum in in vivo and in vitro systems.

Adoption therapy based on Treg cells has only recently been translated into clinical trials. Some studies have been conducted to investigate the immunotherapy effect of Treg cells in solid organ transplantation (to avoid rejection) or hematopoietic stem cell transplantation (to prevent GVHD).

Only a few studies have studied Treg therapy for autoimmune diseases. In T1D, research initially focused on the combination of hematopoietic stem cell transplantation and Treg therapy. A phase I trial showed that autologous infusion of polyclonal Treg cells expanded in vitro is well tolerated, and is compatible with sustained Treg lifespan and long-term stability. The C-peptide level is about 90%. Although the number of published trials is currently limited, the results so far have paved the way for wider applications, including the use of in vitro expanded allogeneic antigen presentation CD4+CD25+Tregs to treat solid organ transplants, and the use of polyclonal Tregs to treat themselves Immune disease. The correction of the Treg segment may also have a place in the future PID gene therapy methods, because the correction of Treg is the most important, such as CTLA4 haploid dysfunction, there is a strong Treg-mediated immune disorder, leading to lymphocyte proliferation, Autoimmune cell disease and lymphocytic infiltration of non-lymphatic organs.

Sum up:

Adoptive transfer of genetically modified T cells has been used as an experimental treatment strategy for the treatment of malignant tumors, infectious diseases and immune diseases for more than 20 years. In some cases, it has very good results. Strong security. In fact, there are now licensed CAR-T cell products all over the world, and the next-generation products are already in development trials.

T cell gene therapy may provide treatment options for some immunodeficiencies, because partial correction of T cells will improve the clinical phenotype, but the continued existence of corrected cells in the body is still a problem.

We have learned a lot from previous research, and now we can combine specialized manufacturing solutions with new gene editing tools, which may lead to a more complex, effective and long-lasting therapy suitable for a range of immune disorders Diseases and primary immunodeficiency.

(source:internet, reference only)

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