Autologous CAR T itself is the patient's own cell, there is no problem of rejection, why even invisible? The reason is that in CAR, scFV in CAR structure is derived from mouse, a heterologous protein and can cause immune response, and antibodies against CAR may be one of the reasons for the poor effect of CAR in some populations.
Therefore, in the following article, in order to avoid the immune response to CAR, the stealth technology is adopted to insert CART cells with invisible wings, which can remove tumor cells more efficiently.
The core content of this article is about a new study designed to reduce the immunogenicity of chimeric antigen receptor (CAR-T) cells by using "invisible" transgenic technology, and thus to enable them to evade the host immune response. Here is a summary of the key points:
1. Background: CAR-T cell therapy has improved treatment outcomes for patients with hematologic malignancies. However, the patient developed humoral and cellular immune responses to non-self components of CAR T cells (such as the FMC 63-based α CD19 single-chain variable fragment derived from the mouse monoclonal antibody), which may limit the persistence and success of CAR T cells.
2. Methods: The investigators implemented a one-time approach to prevent rejection of engineered T cells by expressing a transgene for a viral inhibitor (TAPi) and shRNA for class II MHC transcription activator (CIITA), while reducing the surface expression of antigen presentation and MHC molecules.
3. Results: The combination of EB virus TAPi and shRNA against CIITA reduced class MHC I and II in the surface of α CD19 "invisible" CAR T cells in vitro and in vivo. CAR T cells expressing the stealth transgene to evade allogeneic and autologous anti-CAR responses were confirmed by mixed lymphocyte response testing and IFN γ ELISpot testing with T cells from patients previously treated with autologous α CD19 CAR-T cells.
4. Conclusion: Studies suggest that the proposed invisible transgene may reduce the immunogenicity of autologous and allogeneic cell therapy. Furthermore, patient data showed that patients who received multiple autologous FMC 63-based α CD19 CAR-T cell infusions significantly increased anti-CAR T cell responses.
5. Implications: This study highlights the increased anti-CAR response in patients receiving multiple CAR T cell doses, which requires consideration of reducing the immunogenicity of autologous CAR T cells and current efforts to develop allogeneic products that avoid clearance by the host immune system.
6. Research Limitations: Despite providing promising results, the authors note that more patient data are needed to establish a correlation between lack of response and CAR T cell rejection.
7 Funding and ethical approval: The study was funded by NIH and NCI and approved by MGH IACUC, and human T cells involved were collected under the IRB exemption protocol or with written informed consent.
Is a good idea, but can't help but think of reduced MHC expression, will it not be recognized and cleared by NK cells? After all, NK's famous function is to remove cells with decreased MHC expression.
In the case of CAR T cells, reducing the expression of class MHC I and class II molecules may:
-Reduce inhibitory signals in NK cells: NK cells may receive less inhibitory signals, which may increase the killing potential of NK cells to CAR T cells.
-Increased activation signal of NK cells: If CAR-T cells express certain stress-induced ligands on their surface, this may increase the activation signal of NK cells.
However, according to the content of the documents provided, although the "invisible" CAR T cells used in the study, decreased the expression of class MHC I molecules, no significant increase in the killing activity of NK cells was observed. This could be because other mechanisms regulating NK cell activity are operating or because the surface markers of CAR T cells are insufficient to activate NK cell killing function.
In addition, CAR T cells that decreased the expression of class MHC I molecules by EBV TAPi triggered significantly reduced NK cell killing or degranulation (degranulation) compared to β 2M knockout T cells. This suggests that while reducing expression of class MHC I molecules, the mechanism through TAPi may maintain some degree of NK cell inhibition and reduce NK cell-mediated killing.
Overall, the effects of reduced antigen presentation and expression of class MHC II molecules on NK cell recognition and killing of CAR-T cells are complex and may be influenced by multiple factors, including the expression levels of other molecules on the surface of CAR-T cells and the specific configuration of NK cell receptors.
Since T cells do not express MHCII, why do they suppress the expression of MHCII?
T cells usually do not express class MHC II molecules, which is true. Class MHC II molecules are mainly expressed on dedicated antigen-presenting cells (such as dendritic cells, macrophages, B cells, etc.), which are responsible for presenting exogenous antigens to CD4 + T cells. However, in some cases, T cells may also express class MHC II molecules, especially during activation or certain pathological states.
Inhibition of expression of class MHC II molecules may be due to the following considerations:
1. Avoid non-specific activation: Although T cells usually do not normally express MHC II, T cells may upregulate MHC II expression in some cases, such as chronic activation or inflammatory states. Through inhibition of MHC II expression, reduced CAR T cells can nonspecifically activate other immune cells, thereby reducing potential immune-related adverse events.
2. Reduced immunogenicity: In allogeneic CAR A-T cell therapy, even low levels of MHC II expression may increase the risk of CAR-T cells being recognized by the host immune system. Reducing MHC II expression by using shRNA against CIITA could further reduce the immunogenicity of CAR T cells and reduce the host immune response to CAR T cells.
3. Improve efficacy and safety: By reducing the expression of MHC I and class II molecules, CAR T cells may more effectively evade the surveillance and clearance of the host immune system, thus improving efficacy. Meanwhile, reducing immunogenicity may also reduce the toxic side effects associated with CAR-T cell therapy.
4. Objective: In the study, MHC II expression may be suppressed to explore its effects on CAR T cell function and immunogenicity, and to assess the potential of this method to improve the efficacy of CAR T cells.
5. Technical strategies: When developing "invisible" CAR T cells, researchers may have chosen strategies that target both MHC I and class II molecules to achieve maximum immune escape. Such a strategy may help to provide wider applicability in different clinical applications and disease states.
In conclusion, although T cells generally do not express class MHC II molecules, inhibition of MHC II expression in CAR T cell therapies may help to improve efficacy, reduce toxic side effects, and reduce the risk of CAR T cells being cleared by the host immune system. The choice of this strategy may be based on a deep understanding of CAR T cell immunogenicity and function and an exploration to improve the safety and efficacy of CAR T cell therapies.
In CAR-T cell therapy, a usual concern is to focus on the possible host immune response, triggered by the exogenous part of the CAR protein (e. g., scFv derived from mice). This immune response may target the non-human portion of the CAR protein, resulting in the clearance of CAR-T cells and thereby reducing efficacy. Therefore, the strategy of targeting CIITA using TAPi and shRNA in studies aimed to reduce the surface expression of MHC molecules to reduce the immunogenicity of CAR T cells and improve their persistence in the host.
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