What are other CAR cell therapies except CAR-T?
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What are other CAR cell therapies except CAR-T?
A chimeric antigen receptor ( CAR ) is a receptor protein that confers new abilities on immune cells to target specific antigenic proteins.
CAR-T cell therapy has made great achievements in hematological malignancies. In 2017, the U.S. Food and Drug Administration ( FDA ) approved the first two CAR-T therapies, tisagenlecleucel ( Kymriah® ) and axicabatagene ciloleucel ( Yescarta® ), for the treatment of acute lymphoblastic leukemia and diffuse large B-cell disease, respectively Lymphoma.
So far, six CAR-T therapies have been approved. As a revolutionary biotechnology product in cancer treatment, CAR-T cell therapy has shown great potential to conquer cancer in the future.
However, CAR-T cells still have some shortcomings, such as side effects, toxicity, T cell exhaustion, and show very low efficacy in the treatment of solid tumors.
At present, CAR-NK, CAR-NKT, CAR-macrophage (CAR-M), CAR-Treg, CAR-γδT and other new cell therapies with CAR technology as the core have emerged, showing broad prospects in immunotherapy .
CAR-Treg
Treg is a subset of T cells, accounting for 5-10% of the total number of CD4+ T cells, with the function of maintaining homeostasis and preventing autoimmunity, and is characterized by the co-expression of CD4, CD25, FOXP3 and low levels of CD127.
High levels of FOXP3 and demethylation of the Specific Demethylation Region ( TSDR ), a conserved region in the FOXP3 gene, are prominent features of Tregs.
Compared with TCR-Treg, CAR-Treg has some unique advantages: activation of these CAR-expressing T cells bypasses HLA restriction, increased specificity through activation of co-receptor signaling, and targeting flexibility of CARs ( any Soluble or surface polyvalent antigens can be used as targets ).
The most direct applications of CAR-Treg cells are GvHD and organ transplant rejection. Unlike most autoimmune diseases, there are very clear targets in transplantation, namely HLA molecules. In 2016, HLA-A2 CAR Treg cells were reported for the first time.
Studies have shown that HLA-A2-CAR-Treg cells inhibit the proliferation of Teff cells and prevent HLA-A2+PBMC-mediated GvHD in an immunodeficient NSG mouse model.
By identifying suitable target antigens, the application of CAR-Treg can be extended to more autoimmune diseases, such as autoimmune liver disease ( AILD ), type I diabetes, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease In addition, CAR Tregs have also been used to treat other diseases, such as hemophilia A, vitiligo, asthma, cardiovascular disease, and aging-related diseases.
CAR- γδT
γδ T cells are a subpopulation of innate T lymphocytes that contain a TCR consisting of γ and δ chains.
They constitute 0.5–5% of circulating T cells and exhibit less clonal expansion and TCR diversity than αβ T cells. Human peripheral blood γδT cells mainly express Vδ2 chain and Vγ9 chain, which are activated when they recognize phosphorylated antigen ( PAG ), and have strong anti-tumor cytolytic activity.
γδT cells exert their potent antitumor activity through different mechanisms and receptors: they secrete cytotoxic molecules, such as perforin and granzymes, or express apoptosis-inducing ligands, such as TNF-related apoptosis-inducing ligand (TRAIL ) and Fas ligand ( FasL ) to directly kill tumor cells.
Preclinical studies of CAR-γδT found that CD19-specific CAR-γδT cells enhanced killing of CD19+ tumor cells compared with negative CAR-γδT cells in vitro and reduced CD19+ leukemia xenografts in mouse models things.
Currently, some clinical studies are underway. CAR-γδT cells are expected to become a new type of γδT cell immunotherapy.
CAR- MAIT
Mucosa-associated invariant T cells ( MAIT ) are a distinct, evolutionarily conserved, innate-like T cell subset enriched in liver and mucosal tissues.
MAIT cells express a semi-invariant αβTCR that recognizes non-peptide antigens presented by the non-polymorphic MHC class I-related molecule MR1 .
As a nonclassical subset of cytotoxic T cells, MAIT cells secrete perforin, granzyme B , express TRAIL and FasL or produce pro-inflammatory cytokines such as IFN-γ , TNF , GM-CSF and IL-17 , Interacts with neutrophils, macrophages, and other effector T cells and displays potent cytotoxic activity.
MAIT cells have several favorable properties that make them excellent candidates for CARs.
First, they are abundant in human tissues, accounting for 45% of liver lymphocytes. They are also abundant in human adult blood, accounting for 10 percent of circulating T cells.
Second, MAIT cells have an intrinsic effector memory phenotype ( CD45RA-CD45RO+CD62LlowCD161+ ), which has the ability to rapidly generate an immune response upon activation.
Third, they have an intrinsic migratory ability to peripheral tissues due to high expression of tissue-homing markers ( CCR5, CCR6, CCR9, and CXCR6 ).
Given that MAIT cells are mainly found in the liver and mucosa-associated peripheral tissues, such as the lung, gastrointestinal tract, colon, and cervix, cancers occurring in these tissues may be more suitable for MAIT cell-based therapy.
Furthermore, since MAIT cells are MHC-independent, they are less likely to induce GvHD and thus have great potential as a platform for allogeneic immunotherapy development.
Preclinical studies have shown that CAR-MAIT targeting CD19 and HER2 exhibits similar cytotoxicity to its CAR-T counterparts, and in some cases significantly higher cytotoxicity, while having a better safety profile.
However, there are currently no registered clinical trials testing CAR-MAIT .
CAR-NK T
NKT cells are a subset of lipid- and glycolipid-reactive T lymphocytes that co-express markers associated with NK cells ( NKp46, NK1.1 ).
NKT cells play an important role in tumor immune surveillance and anti-tumor immunity. Unlike conventional T cells that recognize peptide antigens by MHC I or II, NKT cells recognize endogenous and exogenous glycolipids presented through the MHC I-like molecule CD1d.
iNKT cells possess several favorable properties, including potent antitumor functions through direct cytotoxicity or αβT cell cross-priming; a natural ability to efficiently transport to tumor sites;
and destroy TAMs and myeloid-derived suppressor cells (MDSCs) in a CD1d-dependent manner . ) inhibitory activity;
recognition and cytotoxic killing of TAMs by NKRs in a CD1d-independent manner; and no risk of GvHD due to lack of MHC involvement.
Currently, CAR-NKT cells targeting CSPG4, GD2, and CD19 have been developed, and CAR-NKT cells targeting GD2 and CD19 are undergoing clinical trials.
A Phase I clinical trial ( NCT03294954 ) has begun to test the efficacy and safety of anti-GD2 CAR-NKT cells in refractory neuroblastoma.
Preliminary results showed that the treatment of 10 selected patients was safe, including 1 complete remission, 1 partial remission, and 3 patients in stable condition.
CD19 CAR-NKT cells are being tested in a Phase I clinical trial ( NCT03774654 ) for safety and efficacy in relapsed and refractory B-cell malignancies.
CAR-NK
Compared with CAR-T, CAR-NK cells increase their cytotoxic ability and cytokine production through two other co-stimulatory molecules, namely NKG2D and CD244 ( 2B4 ).
Therefore, it has stronger tumor-specific targeting and cytotoxicity than CAR-T cells. CAR-NK cell therapy may become an alternative to CAR-T therapy in the future, because CAR-NK cells have several unique features beyond CAR-T as follows.
First, allogeneic NK cells are fairly safe for adoptive cell therapy ( ACT ) because they generally do not mediate GVHD.
In addition, NK cells only secrete small amounts of IFN-γ and GM-CSF, and do not produce IL-1 and IL-6 that initiate CRS.
Second, in addition to inhibiting cancer cells by recognizing tumor surface antigens through single-chain antibodies, NK cells can also inhibit cancer cells by recognizing various ligands through multiple receptors, such as natural cytotoxicity receptors (NKp46, NKp44, and NKp30 ) , NKG2D and DNAM-1 ( CD226 ).
Finally, NK cells are highly abundant in clinical samples and can be generated from peripheral blood ( PB ), umbilical cord blood ( UCB ), human embryonic stem cells ( HESC ), induced pluripotent stem cells ( IPSC ) and even the NK-92 cell line.
At present, in terms of clinical research, CD19-CAR-NK cells have a high response rate to hematological tumors. In addition to CD19, clinical studies of CAR-NK cells in lymphoma and leukemia also target CD7 ( NCT02742727 ) and CD33 ( NCT02944162 ).
Currently, several clinical trials of CAR-NK cells targeting hematological malignancies are underway.
There are also multiple studies in solid tumors that are in the initiation or recruiting stages.
CAR-M
In view of the success of CAR-T cell therapy and the development potential of CAR-NK cells, researchers have generated great interest in the development of CAR macrophages ( CAR-M ) for tumor immunotherapy.
The emergence of CAR-M has opened up a new possibility for the treatment of solid tumors: modifying human macrophages with specific CARs to improve the phagocytic activity and antigen presentation of macrophages to tumors.
An important reason why CAR-T is ineffective in treating solid tumors is that it is difficult for T cells to enter tumor tissue.
This is because the physical barrier formed by the extracellular matrix ( ECM ) of solid tumors prevents T cells from entering tumor tissue.
ECM is produced by highly ordered fiber molecules, glycoproteins and other macromolecules, and its synthesis and degradation are mainly regulated by matrix metalloproteinases (MMPs ) and tissue inhibitors of metalloproteinases ( TIMPs ), and macrophages are an important source of MMPs .
Currently, on the clinical front, two clinical trials based on the CAR-M strategy have been approved by the FDA.
The first is drug candidate CT-0508 from CARISMA Therapeutics, which treats patients with relapsed/refractory HER2-overexpressing tumors with an anti-HER2 CAR-M (Phase I clinical trial ) .
The other is Maxyte’s MCY-M11, which uses mRNA to transfect PBMCs to express mesothelin-targeted CARs ( including CAR-M ) for the treatment of patients with relapsed/refractory ovarian cancer and peritoneal mesothelioma, and is currently recruiting volunteers Conduct phase I clinical trials.
CAR-Neutrophils
Neutrophils, characterized by CD11b + CD16+CD66b+ , constitute 50-70% of circulating lymphocytes and play a fundamental role in the innate immune response.
Neutrophils also accumulate in many types of tumors, constituting a significant fraction of tumor-infiltrating cells.
Considering the similarity and common innate antitumor response of neutrophils and macrophages, neutrophils may also exhibit enhanced tumor suppressor activity after CAR engineering.
Previous studies have shown that neutrophils engineered to express HIV-specific chimeric immunoreceptors ( CIRs ) containing the CD3ζ intracellular domain exhibit improved cytotoxicity against tumor cells transfected with the HIV envelope.
However, because neutrophils are resistant to genetic modification and have a short lifespan, there are currently no registered clinical trials testing CAR-specific neutrophils.
CAR-HSPC
Hematopoietic stem/progenitor cells ( HSPCs ), defined as CD34+ cells, are critical for lifelong maintenance of hematopoiesis through self-renewal and differentiation into mature blood lineages.
Modification of human HSPCs by CAR provides long-term maintenance of antigen-specific cells of multiple hematopoietic lineages.
Transduced HSPCs will generate granulocytes and monocytes within 1-2 weeks, followed by NK cells within a few months and possibly T lymphocytes over a longer period of time.
CAR expression by these cells may enable durable antitumor immunity through a mix of constantly generated effector cell types.
CB- derived HSPCs were transduced with anti -CD19 CAR and then differentiated into myeloid or NK cells.
They observed that myeloid cells generated from anti- CD19 CAR- modified HSPCs exhibited specific cytotoxicity against CD19- positive tumor cells in vitro.
In vivo experiments also showed that CAR HSPCs could generate multi-lineage CAR- modified cells that could be detected in bone marrow, spleen, and peripheral blood in xenograft models. However, there are currently no registered clinical trials testing CAR- specific HSPCs .
CAR-iPSCs
To generate an unlimited supply of T cells for CAR technology that establishes long-term immune memory and avoids the depletion that occurs during in vitro expansion of primary T cells, one approach is to use human induced pluripotent stem cells (iPSCs) as starting material .
The possibility of obtaining iPSCs from almost any somatic cell, the accessibility of unlimited iPSC production, and the feasibility of genetic modification of iPSCs make them an attractive cell source for CAR technology.
Fate Therapeutics has developed two CAR iPSC-derived T cell products, FT819 and FT873. In FT819, a novel anti-CD19 CAR carrying CD3ζ and CD28 co-stimulatory domains was inserted into both alleles of the TRAC gene to achieve uniform CAR expression and eliminate the possibility of GvHD by inactivating the TCR .
FT819 has shown promising results in an in vitro B-ALL xenograft model and is currently the first iPSC-derived T-cell therapy to undergo clinical investigation (NCT04629729 ) .
references:
1. New cell sources for CAR-based immunotherapy. Biomark Res. 2023; 11: 49.
2. Chimeric antigen receptor natural killer (CAR-NK) cell design and engineering for cancer therapy. JHematol Oncol. 2021; 14: 73.
3. Natural Born Killers: NK Cells in Cancer Therapy. Cancers (Basel). 2020 Jul 31;12(8):2131
4 . CAR-macrophage: A newimmunotherapy candidate against solid tumors. Biomed Pharmacother. 2021 Jul;139:111605.
What are other CAR cell therapies except CAR-T?
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