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    Home > Biochemistry News > Biotechnology News > Nature In-depth Report: CAR-T therapy breakthroughs continue to be the most promising of these new targets

    Nature In-depth Report: CAR-T therapy breakthroughs continue to be the most promising of these new targets

    • Last Update: 2021-03-23
    • Source: Internet
    • Author: User
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    FDACAR-T,CD284-1BB。CD284-1BB,OX40、CD27T-(ICOS)。,CAR。

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    Uncovering toxicity mechanisms and solutions

    Two hallmark clinical toxicities associated with CAR-T cell therapy are cytokine release syndrome (CRS) and neurotoxicity, neither of which was predicted by animal models before clinical transformation.


    Both CRS and neurotoxicity are attributed to the rapid activation and expansion of T cells that secrete cytokines.


    Although neurotoxicity is clinically related to CRS, its mechanism seems to be different.


    Clinically, the main treatment method to overcome CRS is to use IL-6 receptor monoclonal antibody tocilizumab to block the cytokine feedback loop.


    In addition to IL-6 receptor blockers, other interventions are also under study.


    In some cases, neurotoxicity or CRS-related multiple organ failure can be fatal.


    Resistance mechanisms and solutions

    One of the common mechanisms associated with recurrence after CAR-T cell therapy is antigen loss (Figure 4, top).


    The most direct way to prevent antigen escape is to develop CARs that target other antigens.


    Antigen loss can explain some recurrences, but not all patients who relapse have antigen-negative problems, which indicates that there may be other factors that lead to drug resistance, such as CAR-T cell failure.


    With the development of immune checkpoint blocking technology, revolutionary changes have taken place in the field of tumor immunotherapy.


    At present, most of the experience in the field of CAR-T cell therapy is about the treatment of hematological malignancies, so the tumor microenvironment (TME) plays a much smaller role in the treatment.


    Innovative methods to enhance the transport of CAR-T cells and limit the anti-inflammatory cytokine and cytostatic effects in TME are also under development.


    Promising new targets and indications

    Promising new targets and indications

    Multiple myeloma

    The main target of CAR-T cell therapy for multiple myeloma is BCMA (NCT02658929, NCT02546167).


    The G protein-coupled receptor, GPRC5D, is another target of multiple myeloma, and its expression pattern on CD138+ multiple myeloma cells is independent of the expression of BCMA.


    Solid tumors: pan-cancer

    A major concern in the field of CAR-T cell therapy is its applicability beyond hematological malignancies.


    The B7-H3 (also known as CD276) immune checkpoint molecule has been a popular immunotherapy target in the past few years, and some promising clinical trials (NCT02982941, NCT02381314, NCT03406949, NCT02628535 and NCT03729596) use monoclonal antibodies Target the molecule.


    CAR-T cells targeting mesothelin have been widely used in many diseases such as pancreatic cancer, lung cancer and ovarian cancer in recent years.
    Preclinical models are promising, and some clinical trials are underway.
    Preliminary results show that mesothelin targeting CAR-T cells is safe and has anti-tumor activity, which is promising for the prospects of CAR-T cells in the treatment of solid tumors.
    More clinical studies are evaluating whether mesothelin-targeted CAR-T cell therapy can enhance T cell responses by combining immune checkpoint blockade.
    Recently, the early phase I results (NCT03907852) were published using CAR based on the mesothelin-targeted T cell receptor fusion structure (TRuC).
    Compared with traditional CAR-T cells, these CARs retain their cytotoxicity, but have the characteristics of lower cytokine release and higher efficacy.

    Solid tumors: brain cancer

    Brain tumors are still less responsive to the wave of immunotherapy.
    However, due to the unique physiological structure of the brain, CAR-T cell therapy has potential to treat brain tumors.
    Unlike macromolecules that are difficult to enter brain tumors due to the blood-brain barrier, T-cell and T-cell therapy can penetrate into the brain after intravenous infusion.

    The preliminary clinical trials of CAR-T cell therapy for glioblastoma targeted EGFRvIII, IL-13Rα2 and HER2 (also known as ERBB2), but the therapeutic effect was not good due to the loss of target antigen.
    In order to overcome the heterogeneity of target antigen expression often found in glioblastoma, a CAR-T cell based on chlorotoxin (CLTX) peptide was designed, even in the absence of other glioblastoma-related antigens It also has strong anti-tumor activity.
    CAR-T cell therapy targeting CLTX peptides may be promising because it may not have the problem of antigen heterogeneity found in previous targets.

    The disialylganglioside GD2 targeting CAR-T cells for neuroblastoma has been well tolerated in clinical trials.
    Studies have pointed out that GD2 targeting CAR-T cells may be effective for diffuse midline gliomas with histone H3 K27M (H3-K27M) mutations (a commonly fatal pediatric cancer).

    In addition, the cell surface heparan sulfate proteoglycan GPC2 has also been selected as a new target for neuroblastoma.
    GPC2 is highly expressed in neuroblastoma tissues, but not in normal children's tissues, and may also be an effective CAR-T cell target.

    Innovation made by CAR

    Innovation made by CAR

    Gene transfer

    One limitation of genetic recombination T cell therapy is the clinical use of viral vectors that are expensive and have a long production time.
    In addition, viral vectors have size limitations on the length of DNA that can be encoded (AAV is about 4kb, adenovirus is about 8.
    5kb, and lentiviral vector is about 10kb).
    In the past 10 years, transposons have been developed as a non-viral method to produce CAR-T cells.
    This gene transfer method is more economical than virus-based methods.
    Biotechnology company Poseida Therapeutics is currently conducting two clinical trials using piggyBac-based CAR-T cells [4,5].

    In addition, CRISPR-Cas9-based electroporation technology is used to transfer DNA sequences (>1kb) to specific locations in the genome of primary human T cells.
    However, it is worth noting that the current technology is still limited to large gene loads.
    In addition to changes in the delivery of genetic material, improvements in CAR-T cell manufacturing also involve the cultivation of T cells in vitro.
    Several research groups have worked to determine the cytokine mixture suitable for optimal growth conditions.

    Improve effector cell types

    The current production process usually uses heterogeneous T cells from patients (except for the separation of CD4+ T cells and CD8+ T cells in some cases).
    However, there is evidence that certain T cell subpopulations may be more effective than others.

    Clinical trials have used central memory T cells to produce CD28-based CD19 targeting CAR-T cells (NCT01318317 and NCT01815749).
    Preliminary results show that these cells are effective, but they may not have longer persistence compared with mass-produced CD19-targeted CAR-T cells.
    Other potential groups include γδ T cells.
    CD26highCAR-T cells have also been studied because of their superior functions in solid tumor models.

    There are currently several ways to make CAR-T cell products more like a "universal" drug (Figure 5).
    One is the split, universal and programmable (SUPRA) CAR, which has a zip system to regulate the response of T cells.
    This method is still an autologous cell product, but a CAR can sense and respond to multiple antigens.
    There is also a combination method that uses two different zip systems, one with the CD3ζ signal domain and the other with the costimulatory domain.
    Other potential universal CARs include a dimerization system based on biotin-binding immunoreceptors and switch modules with new epitope tags.

    Allogeneic CAR

    "Off-the-shelf" allogeneic CAR-T cell therapy is highly sought after, mainly to improve product standardization, patient waiting time, and logistics costs.
    However, there are two main obstacles to the use of allogeneic T cell therapy, namely, causing GvHD and rejection.

    Natural killer (NK) cells have been used as the basis for the development of allogeneic gene products due to their inherent anti-tumor activity.
    A new method is to extract NK cells from cord blood and transduce them with anti-CD19 CAR vectors.
    In order to improve the persistence of NK cells, the researchers will also add IL-15 transgene.

    CAR macrophages (CAR-M) can also cross-present antigens and activate T cells.
    Treatment of mouse lung metastasis and intra-abdominal cancer xenograft models with CAR-M effectively reduced tumor burden.
    In humanized mice, CAR-M can enhance T cell anti-tumor response, and single-cell RNA sequencing has shown the induction of pro-inflammatory tumor microenvironment.

    CAR has also been used to redirect immunosuppressed CD4+CD25+ regulatory T cells (Treg cells) as a potential therapy for autoimmune diseases and organ transplantation.
    The first clinical trial of CAR-Treg cells was approved in 2019 for the prevention of rejection after HLa-a2 mismatched kidney transplantation in patients with end-stage renal disease.
    In addition, some research groups have proven that using CAR-Treg cells in vivo can prevent allogeneic skin transplant rejection.
    CAR-Treg cells are also used to improve colitis.
    However, because it is difficult to purify this cell subset from traditional T cells, the production of CAR-Treg cells is still a focus of future clinical applications, and new purification methods are currently being explored.

    summary

    summary

    Since the first CAR-T cell therapy was approved by the FDA in 2017, a large number of clinical trials for different targets and different indications have been carried out.
    The results of these trials have revealed new mechanisms of efficacy, toxicity and resistance, and catalyzed new The search for targets, the elucidation of signal mechanisms and the application of new technologies.
    Innovations in CAR design, transduction methods, and selection of the best cell types will definitely improve and change the therapeutic effects of many different types of cancer.

    Reference materials:

    [1] Rebecca C.
    Larson & Marcela V.
    Maus.
    Recent advances and discoveries in the mechanisms and functions of CAR T cells.
    Nature Reviews Cancer (2021)

    [2] CAR T Cells: Engineering Patients' Immune Cells to Treat Their Cancers (Source: NATIONAL CANCER INSTITUTE official website)

    [3] Brentjens R, et al.
    Driving CAR T cells forward.
    Nature Reviews Clinical Oncology (2016)

    [4] Barnett, BE et al.
    piggyBacTM-produced CAR-T cells exhibit stem-cell memory phenotype.
    Blood (2016).

    [5] Poseida Therapeutics.
    Pipeline.
    https://poseida.
    com/pipeline/(2020).

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