CAR T cells in solid tumors: challenges and opportunities
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CAR T cells in solid tumors: challenges and opportunities
CAR T cells in solid tumors: challenges and opportunities. CAR-modified T cells have super-physiological properties and have the function of “living medicine”, which can not only prove the immediate effect after expression in T cells, but also prove its long-term effect [3].
In order to carry out CAR engineering in T cells, the cells must be cultured so that they can be used for transduction and expansion. In this process, transduction may use a variety of methods, but gene transfer must be established to continue to express CAR in clonal expansion and durable T cells (Figure 1) [4].
Taking into account the principle, CAR can target antigens expressed on the cell surface, CAR can target a variety of T cell subgroups, T cell progenitor cells and other immune cells, especially natural killer (NK) cells [5]. Establishing immune reactivity against specific antigens is not the only therapeutic goal of smarter CARs, and these cells are designed to not only trigger engineered T cell activation and function. Importantly, CARs with significant potential and signal quality can regulate the expansion and perseverance of T cells, as well as the strength of engineered T cell activation in the cancer microenvironment. These characteristics strongly change the efficacy and safety of T cells that target cancer.
According to biological and molecular studies, CAR delivery has a broader functional role than the transduced T cell receptor (TCR). In TCR, the signal transduction ability that is usually modified by the affinity of the TCR for the target antigen is that the transduced T cell receptor The central factor of the body determines the fate of T cells [6]. Although flexibility is related to the dynamic range of the engineered CAR, and is very promising and ideal, CAR can only recognize markers located on the cell surface. On the other hand, CARs induce target cell death without relying on MHC molecules [7]. Considering their impact on T cell specificity as well as potency and safety, we discuss here targeting and signaling the ownership of engineered CARs.
In this review, procedures involving T cell expansion and collection of this cell subset are discussed. In general, based on the modular nature of chimeric antigen receptors, CAR is developing rapidly and has shown remarkable ability to be effectively used in a wide range of immunotherapy [8].
CAR structure
CAR contains an extracellular antigen recognition domain, which consists of a monoclonal antibody fragment that recognizes a specific protein on the cell membrane of cancer cells (such as EGFR on solid tumor cells or CD19 on B cells) and a T cell receptor (TCR) signal. Trigger CART cell activation and function [9, 10].
The first generation of CAR T cells contain an intracellular domain derived from the TCR CD3ζ chain, which induces the cytotoxic effect of T cells on targeted cancer cells, but cannot promote the expansion of CAR T cells in vivo after reinfusion.
On the other hand, the second and third generation CAR T cells contain additional costimulatory intracellular domains, which in turn enhances the potential of CAR T cells to grow, expand, and ultimately last in the patient (Figure 2) [11 ,12,13].
CAR T cell engineering
When a human primary T cell transduction protocol was developed, CAR began to be studied in various ways. In the past decade, almost all CAR research has been based on the use of retroviral vectors, such as γ-retroviral vectors and lentiviral vectors [14]. Although retroviral vectors can stimulate insertional tumorigenesis in human cells, T cells appear to be much less sensitive to these transformations. Transposases that support the integration of any vector have begun to be evaluated in the field of CAR therapy [15]. Although the advantages and disadvantages of commonly used vectors have not yet been clarified, the ratio is closely related to the range of CAR expression, silence over time, ease of engineering, and safety. However, the transformation of T cells due to insertional mutagenesis is still unclear. It has been confirmed so far; the direct integration of the vector into the safe region of the genome can eventually lead to long-term CAR expression without the risk of insertional mutagenesis [16].
Alternative strategies that are independent of transgene integration, using RNA electroporation or cell surface coupling, in turn lead to transient CAR expression and CAR T cell persistence limitation for more than 7-14 days [3]. The remarkable properties of transient CAR-expressing T cells that may require multiple infusions to produce an acceptable tumor response may attenuate normal tissue damage or prevent T cells from accumulating to levels that support the risk of cytokine storm.
In this regard, another important aspect of CAR metastasis is the recipient, and recognizes which T cells (such as CD4+, CD8+αβT cells and γδT cells) are superior to other types of T cells to achieve the best tumor suppression effect [17, 18].
CAR’s intracellular signal transduction pathway
As noted, the first engineered receptor that exhibited significant T cell stimulating ability was a chimeric molecule between CD3-ζ or Fc receptor γ and CD8, CD4, CD25 or CD16, which stimulated and Phosphatidylinositol and tyrosine kinase signal cascades related to calcium influx. Murine antibody hapten-specific scFv was added to these fused extracellular parts of human leukemia T cells [19, 20], these parts are described as T bodies and can acceptably promote cell lysis.
Although the increase of the CD3-ζ chain is sufficient to support the cytolytic function of cytotoxic T cell (CTL) lines, it has been found that the basic signal intensity that exhibits cytotoxic activity is lower than that of other types of functions [21]. Once the researchers can effectively transduce human primary T cells, they will notice that CD3-ζCARs cannot stimulate the violent release of cytokines after recognizing the target antigen and improve the growth of T cells.
Therefore, a second-generation CAR containing CD3-ζ chain and costimulatory receptor cytoplasmic domain (such as CD28 and 4-1BB) was designed. In various types of models using mouse or human T cells, the second-generation CAR has shown the ideal function compared with the first-generation CAR [23,24,25]. The main feature of dual-signal receptors is to support the strong potential and perseverance of T-signals, thereby ensuring that T cells have overall superior efficacy.
In one study, although the researchers found no significant difference in the therapeutic activity of CD19-specific CAR based on CD28 and 4-1BB, they described that T cells expressing CD19-BB CAR aggregated at a higher level, which may be related to the antigen. Irrelevant approach [27]; on the other hand, in other models, citation differences are not recognized [28].
It seems that more comprehensive research is needed, noting that these studies must focus on the differences between chimeric receptors within any given category. For example, various CD28/CD3ζCARs suggest that the potential of interleukin 2 secretion is different [29, 30]. In addition, the specific position of the target epitope, its concentration and the affinity of CARs, and other topological effects of the CAR structure can modify CAR signaling.
The third-generation CARs contain two different costimulatory domains in their cytoplasmic part and a special activation domain in their cytoplasmic part. They have shown greater ability to treat solid tumors in a variety of mouse models [31 , 32]. Although the first clinical study using CD20-specific CD28/4-1BB/CD3ζ did not reveal the desired response, these results should not be diminished by the therapeutic importance of these “three-tier” chimeric receptors [33 ].
In general, it is hoped that more research will be conducted to gain a more comprehensive understanding of the optimal CAR signal transduction to improve persistent T cell activity and viability, reduce premature mortality, rapid failure or uncontrolled progression .
Recognition of tumor-associated antigens, expression levels and sensitivity to CAR T cells
The main difference between solid tumors and blood diseases is that detecting the ideal target antigen is more complicated (Figure 3). Unlike hematological malignancies where cancer cells usually express specific and single markers, solid tumors usually do not express a tumor-specific marker. Generally, in solid tumors, it is more common to recognize tumor-associated antigens (TAA), regardless of the increased expression of markers such as CEA, ERBB2, EGFR, GD2, mesothelin, MUC1 and PSMA on cancer cells.
It should be noted that the expression of these markers in the natural tissues of the human body is also very low [34, 35]. There is no doubt that in the absence of tumor antigen specificity, the risk of significantly increasing non-tumor toxicity on the target significantly increases. This catastrophic toxicity occurred in patients receiving Her2-CAR T cell metastatic CRC [36] and patients receiving GD2-CAR T cell therapy with neuroblastoma [37]. According to reports, these disappointing events highlight the value of identifying safe TAA, because even a low specific antigen ratio can produce significant toxicity.
In addition, these responses also indicate that there is a close relationship between the linking affinity of CAR and its related safety and efficacy. An in vivo study showed that compared with CARs with nM affinity, using ICAM-1 specific CAR T cells with μM affinity has a low level of side effects and is more effective [38, 39].
In addition, studies have shown that CARs with lower affinity exhibit low levels of fatigue and promote proliferation in the body. In this regard, other studies have shown that GUCY2C-specific CAR T cells (a receptor that is approximately 95% expressed in metastatic CRC) are not only immune to aggressive cancer mice but also in human xenograft models. Safe and effective [40].
In conclusion, the abnormal or over-expressed antigens on tumors expressed on normal tissues must be carefully evaluated in order to describe them as target antigens for solid tumor therapy.
In the last decade, various experimental groups have used immunoproteomics to recognize TAAs using autoantibodies against immunogenic antigens that are functionally expressed on the cytoplasm or on the surface of cancer cells [41]. These target antigens may be completely unrecognized proteins, known as neoantigens, or wild-type mutant peptides called neoepitopes [42].
PSMA1, LAP3, ANXA3 and maspin are one of the TAAs recognized by proteomics and are considered to be biomarkers of CRC [43]. Neoantigens can also be identified by DNA or RNA sequencing, and whole-exome screening can also be used to study somatic mutations in cancer [44, 45]. Studies based on the use of melanoma whole-exome sequencing [46] and glioblastoma multiforme (GBM) samples have shown multiple mutant epitopes in these patients [42]. For the prediction of neoantigens, whole-exome sequencing was performed in PDA patients, and it was found that a greater number of neoantigens and a greater number of CD8+ TILs together contributed to the improvement of survival rate [47]. Some studies have evaluated the potential of CD40 agonists to improve the immunity of T cells to solid tumors, and found that CD40 agonists can enhance the response of T cells to immunogenic tumor antigens [48].
In this regard, in the PDA model, chemotherapy combined with CD40 agonists showed the infiltration process of T cells and the neoantigen-specific response as well as tumor suppression [49]. These studies using new epitopes indicate that tumors can trigger a secondary immune response to previously unknown markers, and endogenous immunity associated with neoantigens may regulate tumor progression. These findings highlight the importance of adoptive T cell therapies, such as CAR-based treatments.
Although a large number of studies have confirmed that new epitopes have the potential to recognize pre-existing TCR reactivity, the detection of new epitopes and the use of CAR T cells to target these epitopes may circumvent the subject’s importance because CAR acts as The MHC-dependent receptor.
CAR T cell therapy in solid tumors: latest developments
Considering the numerous methods that enable tumors to suppress T cells, the number of cell engineering and combination therapies that can be examined clinically is unlimited. In this regard, it is very interesting to carefully study reliable preclinical models of treatment combinations before clinical translation. Although our focus is not on CAR-based trials, in this section, we briefly evaluate the latest research on CAR T treatments for solid tumors and briefly discuss their efficacy and important targeted surface markers (Figure 4) (Table 1 and 2).
As cited, solid tumors tend to show high levels of antigenic heterogeneity. According to research, tumors usually only have cell divisions that strongly express the target antigen, and there is usually a risk that the target antigen is destroyed and cleared from cancer cells [50].
Although this event has been confirmed with leukemia cells after CD19-CAR T cell infusion, the process involved has not been well established [51]. However, a study investigated a specific mutation in the form of CD19 that lost a specific epitope targeted by CD19-based CAR T cells [52].
In clinical trials using EGFRvIII-specific CAR to treat GBM, CAR T cell administration can inhibit EGF/EGFRvIII receptor expression and seem to enhance T cell resistance, but infusion has been proven to be non-toxic and effective [53]. In addition, in the GBM model, CAR T cell-based IL13Rα2 expands in vivo and releases various cytokines, but it has shown an inhibitory effect on IL13Rα2 expression in recurrent tumors [54].
Breast Cancer
After recognizing tMUC1 on triple-negative breast cancer (TNBC) cells MUC28z CAR T cells, MUC28z CAR T cells are a specifically composed chimeric antigen receptor containing CD28 and CD3ζ domains, which can amplify granzyme B, IFN- γ and other types of Th1 secreted cytokines and chemokines.
In this study, a single dose of MUC28z CAR T cells greatly reduced the proliferation and survival rate of TNBC tumors in a xenograft model [60]. Other studies have shown that CD27 or 4-1BB co-stimulated, self-enriched NKG2D CAR redirecting T cells have anti-cancer function against TNBC tumors [61]. Other studies have shown that CAR-T cells based on HRG1β can successfully inhibit the proliferation of breast cancer through HER family receptors, and can provide attractive treatments to overcome cancer resistance to HER2-based targeted therapy [62 ].
Meanwhile, Munisvaradass et al. It was found that human anti-HER2 CAR T cells showed an ideal targeting effect in breast cancer cells overexpressing HER2 and triggered cell death [63]. In addition, the recognition of mesothelin by special CAR T cells has been described as a promising immunotherapy target for breast cancer treatment [64].
Prostate cancer
Prostate Stem Cell Antigen (PSCA) and Prostate Specific Membrane Antigen (PSMA) are commonly used to target chimeric antigen receptors to achieve appropriate therapeutic effects in prostate cancer (PC) [107]. Anti-PSMA CAR T cells show strong ability to human PC cells, and show strong expansion and cytotoxic potential in PC cells [28, 65]. Clinical trials conducted by Junghans et al. [66] and Slovin et al. [67] approved the safety and effectiveness of PSMA-directed CART cells in PC.
Kidney cancer
According to reports, carboxyl anhydrase IX (CA-IX) expressed in various types of kidney cancer has been regarded as a new target for CAR T cell therapy. CA-IX is a kind of metalloproteinase, usually involved in the catalysis of carbon dioxide hydration [13, 68], and it can be used in renal cell carcinoma and several normal tissues (including gastric mucosal epithelium, small intestinal epithelium and duodenum) The key antigen, biliary tree is moderately expressed [69]. In addition, hypoxic conditions may lead to the expression of CA-IX in a variety of tissues [70]. It has been found that the first generation of CAIX-CAR T cells targeting renal cancer cells are involved in the secretion of high levels of cytokines in relation to their cytotoxic function [71].
Stomach Cancer
Recent studies have shown that bispecific Trop2/PD-L1 CAR-T cells can significantly reduce the growth of gastric cancer through intratumoral injection, and its inhibitory effect is more significant than that of Trop2-specific CAR-T cells. These findings indicate that the new bispecific Trop2/PD-L1 CAR-T cells participate in the blocking effect of Trop2/PD-L1 and checkpoints on gastric cancer, thereby promoting CAR-T cells in gastric cancer and other types of solid tumors. Cytotoxicity [72]. In addition, it has been confirmed that after injection of mesothelin-CAR T cells containing mesothelin scFv, CD3ζ, CD28 and DAP10 intracellular signaling domain (M28z10), the death of gastric cancer cells is triggered and the growth of tumors is significantly inhibited [73] . According to other studies, using claudin18.2-CAR T cells [74], NKG2D-CAR T cells [75], folate receptor 1 (FOLR1)-CAR T cells [76] and HER2-CAR T cells [77] can be Think of it as a new treatment method for gastric cancer. In a recent study, Jung et al. showed that the use of ICAM-1 CAR T cells alone or in combination with the chemotherapy drug paclitaxel or CAR T cells can change the release of IL-12, which is expected to greatly improve ICAM- 1 A promising approach for patients with high-grade gastric cancer [78].
Pancreatic cancer
Studies have confirmed that in pancreatic cancer, CAR T cells expressing CXCR2 are more effectively transferred to the microenvironment containing IL-8 and IL-8. As a result, CAR T cells expressing CXCR2 have greater anti-tumor activity against pancreatic tumor xenografts that are recognized as expressing αvβ6 [79]. In addition, it has been proved that B7-H3.CAR-T cells can treat pancreatic ductal adenocarcinoma in vitro and in orthotopic and metastatic xenograft mouse models. Interestingly, when we want to target tumor cells that express PD-L1 constitutively, costimulation of 4-1BB supports lower PD-1 expression in the generated T cells and higher anti-tumor activity [80 , 81].
In addition, phase I clinical studies in patients with hepatocellular carcinoma, pancreatic cancer, and colorectal cancer have shown the inhibitory effect of CD133-CAR T cells on the metastatic potential of these cells [82]. In addition, other types of pancreatic cancer CAR T cell therapy target antigens include CD24 [83], PSCA [84], CEA [85], MUC-1 [86], mesothelin [87], FAP [88] and Her- 2 [89] It is well known and is currently being studied in preclinical and clinical trials.
Lung cancer
The treatment of receptor tyrosine kinase-like orphan receptor 1 specific (ROR1)-CAR T cells supports strong anti-tumor activity in the human lung cancer A549 cell line. Importantly, ROR1-CAR T cells infiltrate cancer tissues and eradicate multiple layers of tumor cells [90]. Similarly, after expressing and releasing cytokines such as perforin, granzyme B, IFN-γ and TNF-α, EGFRvIII-CART specifically and effectively identifies and kills A549-EGFRvIII cells. On the other hand, studies have shown that EGFRvIII-CART cells can significantly reduce the transfer of mouse A549-EGFRvIII cells, and can effectively prolong the survival time of mice without any side effects [91]. Similarly, it has been confirmed that CAR T cell-based mesothelin [92], erythropoietin-producing hepatocellular carcinoma A2 (EphA2) [93], PSCA and mucin 1 [94] can produce ideal therapeutic effects in lung cancer . Recently, a group of researchers suggested that the use of PD-L1-CAR T in non-small cell lung cancer (NSCLC) may have anti-tumor cytotoxic activity against PD-L1high and EGFRmut NSCLC, and to some extent lead to patient recovery (PD -L1+) NSCLC [95]. On the other hand, Chen and his colleagues introduced delta-like 3 (DLL3) as an attractive target for the treatment of small cell lung cancer (SCLC). They showed that DLL3, which targets only antibodies and CAR-T cells or with PD-1 inhibition, can kill DLL3 tumor cells, including H82, H196 and H446 cell lines [96].
Liver Cancer
The application of CAR-T therapy in the treatment of liver cancer has just begun to be studied, and more research is needed. However, the efficacy of CAR-T cell-based CEA [97], glypican-3 [98], mucin-1, epithelial cell adhesion molecules and carcinoembryonic antigen [99] has been confirmed in the treatment of liver cancer. Glypican-3 (GPC3) antibody combined with CART therapy may be a useful method for the treatment of liver malignancies. Liu and his colleagues found that the use of 32A9 monoclonal antibody/CAR T cells can kill (GPC3 +) HCC cells in vitro and regress liver xenograft tumors in vivo [100]. Another study showed that GPC3/CAR T cells expressing IL15/21 can promote the anti-tumor response of T cells to HCC [101].
Colorectal cancer
Studies have found that chimeric antigen receptor T cell therapy may be an effective treatment for colorectal cancer. Overall, in colorectal cancer, NKG2D [102], CD133 [82], GUCY2C (Guarnate cyclase 2C) [40] and TAG-72 [103] are the most promising treatment targets. The main target antigen. Humbach et al. Studies have shown that mesenchymal stem cells (MSC) engineered to release IL-7/12 cytokines increase the resistance of CAR T cells to colorectal cancer cells by changing the inflammatory effects of Th2 to Th1/17 executive structures in the tumor environment. Tumor activity [104]. Based on previous evidence, increased Doublecortin-like kinase 1 (DCLK1) expression in human colorectal tumors is associated with higher mortality. A recent report showed that DCLK1 targeted CAR-T therapy effectively eradicated primary and metastatic colon cancer cells [105].
CAR T cell therapy challenges to solid tumors
This section discusses the basic challenges of CAR T cell therapy in solid tumors and useful strategies to enhance the therapeutic effect. The challenges listed below are the most important obstacles that interfere with cell therapy and affect the effectiveness of the treatment, depending on the tumor type, disease steps, and molecular markers.
Tumor antigen heterogeneity
One of the obstacles to the effectiveness of cell therapy against solid tumors is antigen heterogeneity, which weakens the detection of cancer cells by T cells and reduces the impact of CART therapy. Since the most useful target of CAR engineering is tumor-associated antigen (TAA), the diversified expression of TAA by different types of tumor cells is a major obstacle. In addition, due to the diversity of malignant cell antigens, it is difficult to identify tumor cell-specific antigens. Different antigen expression levels at various tumor sites may impair the function of CAR T cells at tumor sites [108].
So far, a variety of methods have been used to support the identification of CAR T cells targeting multiple TAAs, including co-expression of multiple CARs on a single T cell, programmable CAR expression, the possibility of temporary regulation of target antigens, and the use of various In CAR T cells, the expression of each chimeric receptor relative to a specific antigen and the expression of chimeric receptors that include two or more antigen recognition domains lead to the identification of multiple antigens by a single receptor [109]. On the other hand, targeting cancer stem cells closely related to tumor heterogeneity is one of the methods to eliminate tumor heterogeneity. For example, CD133 is a tumor stem cell marker that is overexpressed in many solid tumors and is now considered a target tumor marker for CAR-T cells [13].
Delivery and infiltrate into tumor tissue
In solid tumors, CAR-T cell therapy is more limited than in hematological tumors, because CAR-T cells return to the bloodstream and lymphatic system, so they come into contact with blood tumor cells more, and in solid tumors, CAR- T cells may not be able to penetrate the tumor tissue through the vascular endothelium [110]. The existence of a series of mechanisms in tumor tissues reduces the secretion of vascular-related factors. For example, the overexpression of endothelin B receptors in cancer tissues down-regulates the level of ICAM-1, thereby preventing T cells from escaping from blood vessels [111].
On the other hand, the migration of CAR-T cells in solid tumors depends on the regulation of chemokines such as ligand 11 and 12 chemokines [112]. However, these chemokines are less expressed in tumor tissues. In short, due to the lack of expression of chemokines involved in the penetration of T cells into tumor tissues, and the presence of dense fibrotic matrix in solid tumors, the ability of CAR to migrate and invade tumor cells is reduced [71]. The identification of solid tumors requires the transition of cells from the blood to the cancer site, and various abnormalities will occur, thereby roughly preventing T cell infiltration [113, 114]. It has been proposed that local administration of CAR T cells is more effective than systemic administration in tumor-restricted sites.
In glioblastoma, intracranial transport has been proven to be safe and has acceptable anticancer effects [115]. In preclinical studies of human pleural malignancy, intrapleural transport of CAR T cells is more effective than systemic administration. Effective [116]. Through further genetic variation of T cells or the use of CAR T cells in combination with oncolytic viruses, an in-depth understanding of the process of improving or eliminating the entry of T cells into tumors is expected to provide opportunities to increase the transport of CAR T cells [117]. Or other methods, which ultimately enhanced the inflammatory response at the tumor site [118].
CAR T cells can be modified to express chemokine-specific receptors, especially CCR2 and CCR4, which must be overexpressed by tumors to support their effective contact with tumor cells (Figure 5) [119]. Rather than conventionally transforming T cells into a special cancer chemokine profile, a more acceptable method is to convince tumors to release chemokines, and CAR T cells previously responded to chemokines. An oncolytic virus has been used to transport the chemokine CCL5 to tumor cells.
CAR-T cells usually express RANTES receptors, such as CCR1, CCR3 and CCR5 receptors. In some preclinical studies, the combination of oncolytic viruses expressing CCL5 and engineered CAR T cells can effectively promote their viability and tumor Clearance rate [118, 120]].
Immunosuppressive tumor microenvironment
Another important challenge for effective targeting of solid tumors with CAR T cell therapy is the immunosuppressive tumor environment. Unlike many hematological malignancies that lack local immunosuppressive pathways, solid tumors can be strongly infiltrated by different cell types that support tumor growth, angiogenesis, and metastasis [121]. Regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC) and M2 tumor-associated macrophages (TAM) are the most important immunosuppressive cell types in the tumor environment [122, 123].
In addition to tumor cells, these cells also promote tumor growth and proliferation by producing growth factors, local cytokines and chemokines in solid tumors (including VEGF, IL-4, IL-10 and TGFβ). Immune checkpoint molecules (such as CTLA-4 and PD-1) can also reduce anti-tumor immunity [120, 124]. Generally, a tumor microenvironment with multiple cells and inhibitors can limit the impact of CAR T cell therapy. A lot of research has focused on enhancing CART cell function by modifying its metabolic profile to improve cell activity in a hostile environment. Generally, tumors are often described by high levels of adenosine and reactive oxygen species (ROS), which disrupt the T cell response (Figure 5) [125, 126].
Likewise, tumors show elevated extracellular potassium levels, thereby significantly attenuating TCR-driven Akt-mTOR phosphorylation and subsequent effector activity. T cell engineering aims to increase the expression of potassium channels to prepare for greater potassium efflux, thereby successfully eliminating this inhibition and enhancing T cell function in TME [127]. Studies have shown that in TME, the destruction of immunosuppressive cells is usually necessary for the high level of efficacy of CAR T cells. For the purpose of suppressing regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), the combination of inhibitory antibodies and gene manipulation can improve the efficacy of T cell therapy in animal models (Figure 5). [128, 129].
On the other hand, cancer-associated fibroblasts (CAF), which include the most common types of TME cells and highly express fibroblast activation protein (FAP), play a crucial role in shaping the immunosuppressive microenvironment and releasing ECM proteins to attenuate toxicity The role of. T cell penetration. Interestingly, the application of FAP-specific CART to reduce the activity of CAF cells or to engineer new types of CAR T cells designed to secrete ECM degrading enzymes can significantly increase their potential to transport and lyse tumors [130]. Otherwise, the operation of CAR T cells to secrete the pro-inflammatory cytokine IL-12 may modify TME and ultimately enhance macrophage recruitment and function [131].
Many organizations have tried to improve CART cell activity by using ACT in combination with TME modulators. One promising treatment that shows acceptable efficacy in tumors is the use of checkpoint inhibitors, which target the PD-1/PD-L1 or CTLA-4 pathway (Figure 5) [132, 133]. In this case, by improving the preparation of tumor-specific T cells, checkpoint blockade can be improved, and it can be reasonably combined with the adoptive spread of CAR T cells, and under normal circumstances, the risk of toxicity can be increased. On the other hand, specific CART cells are engineered to release anti-PD-L1 antibodies against PD-1 and LAG3 through CRISPR [134, 135].
Although anti-CTLA-4 antibody can increase the endogenous T cell response to cancer, the relevant mechanism of its promotion of CAR T cell response is still unclear. In addition, anti-CTLA-4 antibodies can trigger an immune response in an extracellular manner after the reduction of CTLA-4+ Treg cells, which may help CAR T cells [136].
Future directions and conclusions
The development of CAR T cell therapy is a promising treatment option for patients with advanced malignant tumors, especially blood diseases. The progress of CAR T cells reflects the fusion of knowledge from various scientific fields; however, so far, success has been limited to B cell abnormalities.
The progress of this treatment approach to solid tumors will require an improved plan based on the understanding of the obstacles associated with TME and tumor heterogeneity, which emerges from complex logic tools and high-importance models .
These methods will benefit from our ability to create transgenic T cells to support new desired activities, help them target solid tumor cells and persist and function in a hostile environment.
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