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CAR T cell therapy for the treatment of solid tumors. The potential of immunotherapy as a cancer treatment option is evident from the remarkable response of certain leukemia patients to adoptive cell transfer using genetically modified autologous T cells expressing chimeric antigen receptors (CARs).
However, the vast majority of cancers, especially the more common solid cancers, such as breast cancer, colon cancer, and lung cancer, have no obvious response to CAR-T cell infusion. Solid cancer presents some powerful obstacles to adoptive cell transfer, including suppression of T cell function and suppression of T cell localization.
In this review, we discussed the current status of CAR T cell therapy in solid cancers, and are studying various concepts to overcome these obstacles, as well as methods aimed at improving the specificity and safety of adoptive cell transfer.
The production of chimeric antigen receptors (CARs) has revolutionized T cell-based immunotherapy for the treatment of certain cancers. Developed from the concept of adoptive immunotherapy using tumor-infiltrating lymphocytes (TIL), the T-cell receptor (TCR) of TIL recognizes tumor-associated antigens (TAA), and genetic modification of peripheral blood T lymphocytes with CARs is used in treatment Outstanding results have been produced in T cells [1,2]. TCR-modified cells have shown potential in immunotherapy, but their target antigen library is very limited, requiring major histocompatibility complex (MHC) to present immunity Processed antigen. On the other hand, CARs recognize a variety of antigens in a non-MHC environment, which broadens clinical applications compared with TCR-modified cells.
CAR consists of an antigen-specific region of a single-chain variable fragment (scFv) of an antibody fused to the signal chain of the TCR complex. More specifically, the basic structure of CAR consists of an extracellular scFv region connected to a hinge region, which allows flexibility. It can then be further connected to the transmembrane region, and most importantly, to the intracellular signaling part, which regulates the function, durability and overall efficacy of the CAR itself.
The ability to recognize antigens in an MHC-independent manner is advantageous because there are no human leukocyte antigen (HLA) compatibility issues between the donor and recipient. Although CARs can recognize targets such as glycolipids and cell surface proteins, their disadvantage is that they rarely recognize TCR antigens that can be processed by engineered TCRs, such as MAGE and NY-ESO-1 .
The first-generation CAR is composed of a single intracellular signal transduction chain of CD3ζ. However, because the MHC-antigen complex interaction in the normal TCR environment will co-stimulate T cells, further improvements in CAR design include the addition of secondary and tertiary intracellular signal transduction chains. These subsequent CARs plus one or two costimulatory domains (respectively in the second and third generation CARs) showed enhanced activity, durability and efficacy. There are great intergenerational and intra-generational variability between the second and third generation CARs, and a series of costimulatory domains (CD28, 41BB, OX40, CD27, ICOS, DAP10, LAT) have been tested. To make matters more complicated, the attributes of each co-stimulatory domain are also different in giving modified CAR T cells the ability to secrete cytokines, cytotoxicity, proliferation, memory development and even metabolism [4,5].
The success of CAR T cells in the treatment of hematological malignancies is impressive, especially in infants, reaching a clinical response rate of up to 90% in acute lymphoblastic leukemia (ALL) . This has led to a greatly expanded clinical trial of CARs for various hematology antigens, such as CD19, CD20, and CD22 (reviewed in Holzinger et al. ). However, the clinical efficacy of CAR T cells in solid tumors is far less desirable, with multiple toxic side effects and/or lack of treatment response [8-11]. At present, there are 81 active or planned clinical trials using CAR T cells against blood cancer, and only 51 trials for solid tumors (Table 1).
In solid tumors, CAR T cells have little clinical efficacy in hematological malignancies, and the factors necessary to improve their efficacy are currently being determined. There are many differences between hematological malignancies and solid tumors. Moreover, although each aspect is being studied separately, it seems likely that a modified combination will be needed to optimize CAR therapy for the latter indication. Hematological malignancies usually spread, so they lack many physical immunosuppressive factors that prevent adoptively transferred cells from reaching solid tumors. In addition, the target antigens present in hematological cancers are usually homogeneous and expressed in most (if not all) tumor populations. In contrast, the target antigens on solid tumors are usually heterologous, not only within a tumor, but also between primary and metastatic tumors.
Therefore, starting from the first step of treatment, CAR T cell therapy for solid tumors faces multiple obstacles, in which CAR T cells must encounter the correct chemotactic signal in order to be transported to the tumor in sufficient numbers. Abnormal vasculature prevents effective infiltration, and the physical barrier of surrounding stroma and infiltrating tumor immune cells also prevents adequate infiltration. Finally, a large number of immunosuppressive factors, such as checkpoint pathways, cytokines, and by-products of metabolic changes, have accumulated to seem to be almost impossible challenges for CAR T cells. This review will outline some of the issues related to CAR T cell therapy for solid tumors, as well as novel CAR T cell innovations that help solve these challenges (Figure 1 and Figure 2).
Delivery and penetration: chemotactic manipulation and breaking barriers
The first of the many obstacles encountered in the use of adoptively transferred cells is that they are difficult to migrate and penetrate sufficiently into the tumor to release their cytotoxic function. One factor in the high level of efficacy observed with CAR T cells against hematological malignancies may be that both tumor cells and effector cells have hematopoietic origin and therefore have a higher tendency to migrate to similar areas (such as bone marrow and lymph nodes).
On the contrary, it is known that solid tumors secrete chemokines. For example, CXCL12 and CXCL5 can inhibit the migration of T cells into the area [12,13], and the chemokine receptors present on T cells are usually not completely labeled with tumor chemokines Matching, which leads to the analysis of tumor chemokine characteristics , and genetic modification of CAR T cells to express appropriate chemokine receptors, which may allow a greater proportion of cells to home to the tumor. Indeed, it has been shown that T cells genetically modified to express CXCR2 migrate to a series of tumor cells expressing CXCL1 .
This effect has also been observed in mesothelioma and neuroblastoma xenografts using CAR T cells with CCR2b receptors [16,17] and Hodgkin’s lymphoma. CAR T cell lymphoma with CCR4 . In addition, because the surrounding stroma can also secrete different chemokines, the location of the tumor and the local “normal” cytokine environment may also determine the composition of chemokines and should be considered .
As an alternative method to change the chemokine receptors on CAR T cells, the secretion of chemokines in tumors can be adjusted to correlate with the chemokine receptors naturally present on CAR T cells. Direct injection of oncolytic adenovirus expressing RANTES and IL-15 into neuroblastoma tumors leads to increased CAR T cell infiltration and better tumor control . Similarly, the combination of EGFR-CAR NK-92 cells and oncolytic herpes simplex virus produced promising results and produced a metastatic preclinical model , and the work of our laboratory proved the extensive combination of CAR T cells and oncolytic viruses.
T cell infiltration and solid tumor eradication . However, this type of method is applied to primary liver cancer and primary liver cancer. It may be necessary to use metastatic disease, other viral vectors (such as vaccinia virus) or other methods of administration (such as cell delivery vehicles) [23,24]. The future aims to change the tumor microenvironment (TME) to make it essentially more work. T cells need to be accessible.
Before entering the immunosuppressive TME, another obstacle that CAR T cells may face is the physical barrier that prevents effective penetration into the tumor. Immunosuppressive myeloid cells can be attracted to the tumor microenvironment, thereby preventing T cell infiltration . Tumor fibroblasts and myeloid cells may also contribute to the development of pre-tumor fibrotic extracellular matrix, which may hinder T cell penetration.
Heparanase (HPSE) is the main enzyme that degrades heparin sulfate proteoglycan, and heparan sulfate proteoglycan constitutes most of the extracellular matrix. Since the loss of HPSE has been observed in T cells cultured in vitro, the overexpression of HPSE in CAR T cells or the use of CAR T cells targeting TAA’fibroblast activation protein’ to target the surrounding non-malignant matrix can overcome These physical barriers enhance the penetration of T cells into TME .
In addition, the antigens targeted by CARs are not limited to TAA. Targeting and destroying the vasculature will limit the blood flow to the tumor and nutrient supply, thereby hindering the development of the tumor, while at the same time enhancing the infiltration of T cells.
As shown by Chinasamy et al. , simultaneous targeting of tumor antigens and VEGFR-2 expressed on angiogenic endothelial cells and myeloid suppressor cells can eradicate B16 melanoma in mice and increase T cells to tumors. Of infiltration. In addition, CARs combined with ligands related to angiogenesis molecules (such as αvβ3, an integrin normally expressed on tumor vascular endothelium)  showed enhanced migration capabilities.
The combination of echistatin CAR T cells (targeting αvβ3 protein) and nanoparticles will increase the deposition of nanoparticles in tumors, indicating that it is possible to use CAR T cells targeting blood vessels to enhance drug delivery . Similarly, the use of anti-VEGFR methods that can secrete IL-12 CAR T cells leads to increased CAR T cell accumulation and tumor regression in multiple preclinical models . However, since tumor regression in this system depends on the presence of cytokines and CARs, the vasculature alone may not be enough to produce an effective anti-tumor response.
Prostate-specific membrane antigen (PSMA) is present on the endothelium of malignant prostate cells and some tumor vasculature, but not on the normal vasculature, making it an ideal target for immunotherapy. Application of PSMA-CAR T cells to a mouse ovarian tumor model can lead to tumor regression, but a complete response cannot be achieved due to the heterogeneous expression of PSMA on the tumor vasculature . This study shows that CAR T cells can induce anti-tumor responses without targeting tumor-limiting antigens, which suggests that it may be necessary to combine CAR T cells targeting the vasculature and targeting tumor-limiting antigens to achieve complete eradication. This method can enhance the efficacy of CAR T cells against solid tumors with heterologous or low-level antigen expression.
Fight against immunosuppression
The tumor microenvironment is composed of a variety of cellular and molecular components, which can reduce the effective anti-tumor immune function. This active coordination of immunosuppression can severely inhibit the effector functions of CAR T cells. However, it is worth noting that this effect is closely related to the tumor microenvironment, because removing CAR TILs from the tumor can restore its anti-tumor function . These data strongly indicate that appropriate suppression of immunosuppression or changes in immunosuppressive TME can rescue the under-functioning CAR T cells and restore their functions. It opens up a new therapeutic approach to improve CAR T cell function.
Immunosuppressive cytokines, such as TGF-β or IL-10 secreted by pre-tumor immune cells and tumor cells themselves, can keep immune activity away from powerful cytolytic reactions. In order to re-polarize the tumor microenvironment, “armoured” CAR T cells or “TRUCKs” (redirecting T cells that are used for universal killing of cytokines) have been studied in preclinical studies. These improved armored CARs and TRUCKS are designed to secrete pro-inflammatory cytokines, which can better function in the immunosuppressive microenvironment. In particular, even in the absence of exogenous IL-2, the co-expression of single-chain IL-12 on CAR T cells can lead to tumor regression by repolarizing the tumor microenvironment. This effect is mediated by changes in the number and function of myeloid cells in the tumor . In addition to repolarizing TME, constitutive IL-12 signaling also enhances the cytotoxicity of T cells and the secretion of cytokines, and enhances the resistance to Treg immunosuppression . TRUCKs that can provide a variety of cytokines and their potential to change TME deserve further exploration (summarized in Chmielewski and Abken ).
Checkpoint inhibitory proteins that are commonly used to regulate immune responses, such as PD-L1, are usually upregulated in tumors. When PD-L1 interacts with the receptor PD-1, the receptor is up-regulated on tired T cells and TILs, and T lymphocyte function is low. Our group has previously demonstrated that the efficacy of CAR T cells is enhanced when used with monoclonal antibodies against checkpoint molecules. The addition of anti-PD-1 antibody can reduce the myeloid-derived suppressor cell (MDSC) population infiltrated in TME and lead to a more effective CAR T cell anti-tumor response . After this study, we recently reported that blocking the PD-1 and CD73/adenosine pathways with specific adenosine 2A receptor antagonists can further enhance CAR T cell responses in vivo. Another recent study produced CAR T cells capable of secreting anti-PD-L1 antibodies, which exceeded the need for co-transferring anti-PD-L1 mAbs . In addition to significantly reducing tumor growth in a mouse model of humanized renal cell carcinoma, the increase in local secretion of anti-PD-L1 antibodies from CAR T cells increased the migration of adoptively transferred human NK into the tumor. NK cells have shown anti-tumor effects through ADCC and IFNγ stimulation to CD8+ T cells. Therefore, enhancing the infiltration of non-T cell anti-tumor immune subpopulations into TME through local antibody secretion can improve CAR T cell therapy.
Another way to combat immunosuppression is to generate new CARs that incorporate mutated or invalid cell surface dominant negative receptors (DNR), which can cover the inactivation signals encountered in TME. DNRs maintain the extracellular region of membrane receptors, but usually have mutations in the intracellular chain, leading to a lack of downstream signal transduction and subsequent loss of function . Therefore, DNRs are usually able to compete with their endogenous receptors for target ligands, and therefore cannot fully play the role of target/receptor binding. The use of DNR for immunosuppressive factors (such as TGF-β) makes the transduced EBV cells immunosuppressive (monitored by proliferation and cytokine secretion) [38,39]. Similarly, DNR used for PD-1 in CAR T cells also rescued the checkpoint’s role. Blocking and restoring effector function . Since PD-1/PD-L1 blockade is usually achieved by antibody blockade, due to its wide target range, it can cause autoimmune effects, so the use of PD-1 “insensitive” DNR T cells may overcome this problem .
Switching receptors provides another alternative method to circumvent immunosuppression. They contain the extracellular part of antibodies specific for immunosuppressive molecules (such as PD-1 or CTLA-4), which are fused with intracellular activation signaling molecules (such as CD28) to enhance the effector function of the cell [41, 42]. Compared with parent CAR T cells, CAR T cells with PD-1-CD28 conversion receptor have higher anti-tumor and anti-tumor efficacy. Interestingly, Liu et al.  also observed a decrease in other checkpoint inhibitors, namely the decrease in the expression of LAG3, TIM-3 and CEACAM1 and the increase in IL-2 signaling, which may indicate that the increase in function may be due to the overall” Younger”, less exhausted population. However, unlike DNR receptors, this effect depends on effective CD28 signaling, because mutant PD-1-CD28 CAR T cells show similar efficacy to CAR T cells, indicating that the addition of another signaling domain can further Enhance CAR T cell function. This is expected to reduce the immunosuppressive effect of TME and further enhance the cytotoxic function of CAR T cells.
In addition, endogenous modifications can eliminate inhibitory signaling pathways in T cells, which is expected to restart T cell functions. The latest study by Newick et al.  showed that the use of “regulatory subunit 1 anchoring destroyer” (RIAD-CAR) to inhibit Ezrin protein kinase A will lead to the up-regulation of CXCR3 and CD49D integrin (VLA-4). Enhance the transport of RIAD-CAR T cells to tumors and better migrate to CXCL10 in vitro. In addition, RIAD-CAR cells express higher levels of IFNγ and cytotoxicity when exposed to adenosine in vitro, and have higher resistance to immunosuppressive adenosine in the tumor microenvironment. Compared with CAR T cells alone, Enhance the anti-tumor response. Therefore, preventing T cell inactivation may increase T cell infiltration and promote a more effective response.
In addition, conditions that increase the acidity of TME may negatively affect T cell function within the tumor. This may be the result of increased glycolysis in cancer cells. This situation is called the “Warburg effect” and refers to the preferential use of glucose through glycolysis rather than oxidative phosphorylation. The former leads to acidification of the extracellular environment by increasing the production of lactic acid. This metabolic change observed in cancer cells (reviewed by Vazquez et al. ) also led to another immunosuppressive approach. Oxidative stress and increased reactive oxygen species . In addition, it is known that infiltrating tumor myeloid cells (such as MDSCs) secrete high levels of reactive oxygen species (ROS), which increases their immunosuppressive ability. CAR T cells easily succumb to the immunosuppression of oxidative stress. In oxidative stress, proliferation and cytotoxicity are greatly weakened. However, when the project is designed to secrete the antioxidant enzyme catalase (CAT) into the local environment, CAR-CAT T cells retain their anti-tumor function . In addition, in vitro analysis showed that the secretion of local catalase is sufficient to promote bystander action and restore the cytotoxic function of NK cells. The modification of the surrounding tumor microenvironment by metabolism-based therapies requires further research.
CAR T cells and drugs
The concept of combining CAR T cells in combination with other drugs opens up new therapeutic approaches. Most clinical drug treatments are performed without adoptive cell therapy; therefore, although there are many opportunities to combine current treatment methods with ACT, it still needs to be rationalized based on the understanding of drug: immune system interactions Choose medicine.
Recent work has shown that the best cell type for adoptive cell transfer is the cell that retains its memory/naive ability, which can promote proliferation and function in vivo to a greater extent . Similarly, the use of in vitro differentiation inhibitors (such as BET) inhibitor JQ1 can preferentially enhance the expansion of central memory and stem cell memory-like T cells. Compared with untreated CAR T cells, CAR T cells treated with JQ1 transferred in vitro have higher proliferation, persistence and increased cytokine secretion, and significantly improve the survival rate .
Lenalidomide, a derivative of lenalidomide, has shown impressive anti-tumor effects in patients with multiple myeloma . Similarly, when used in combination with CAR T cells, it will lead to increased infiltration of CAR T cells into tumor sites and an increase in IFNγ. On the contrary, although rapamycin (rapa) and other rapalos are commonly used as therapies to treat AKT/mTOR signal imbalance, combined with other cancer therapies, the effect of rapa on the effector T cell function is counterintuitive ; Change the differentiation of T cells, promote the expansion of Tregs, and prohibit the function of all effector T cells [51,52]. Therefore, by expressing the mutant anti-rapa mTOR (mTorRR) in CAR T cells (CAR.mTorRR), Huye et al.  were able to prove the continuous ability of secreting IFNγ. In addition, since target cells treated with rapa are more susceptible to CAR T cells, the addition of rapa improves the effectiveness of CAR.mTorRR T cells. Therefore, before using them in combination, the effect of cancer treatment drugs on CAR T cells must be determined first. The two-pronged approach of using two drugs to target tumors and CAR T cells has broad prospects.
CAR T cells can also be used as a vehicle for drug delivery in targeted therapy. Since systemic administration is not always sufficiently localized to target cells (and may produce off-target effects), Boice et al.  used the antigen specificity of CAR T cells to locally secrete soluble herpes virus into the mediator (HVEM). ). B-cell lymphoma cells that bind to the B and T lymphocyte attenuator (BTLA) receptors inhibit their proliferation. Therefore, CD19-directed CAR can eliminate its target cells. In addition, the HVEM:BTLA interaction strongly blocks the proliferation of target lymphoma cells, resulting in better therapeutic effects than CD19-CAR T cells alone. Utilizing the antigen-specific localization of CAR T cells and the flexibility provided by our ability to genetically alter the “content” or “guest” of these cells may lead to new ways of delivering tumor-specific antibodies/drugs to tumors or TMEs . In addition, compared with systemic delivery, local delivery by CAR T cells can reduce the large amount of antibodies/drugs required to properly saturate the target, and may result in less off-target effects on distant organs or tissues.
All-trans retinoic acid (ATRA) for the treatment of acute promyelocytic leukemia can induce the differentiation of immature medulloblasts, which is one of the key immunosuppressive factors in TME. In addition, as observed in preclinical models of pediatric sarcoma xenotransplantation, targeting the MDSC population infiltrated in TME may also affect the efficacy of CAR T therapy. Preclinical studies of ATRA therapy have shown that the differentiation of immunosuppressive immature bone marrow cells can restore the function of anti-tumor lymphocytes . Similarly, when combined with CAR T cells targeting GD2 antigen for osteosarcoma xenotransplantation, the frequency and function of tumor infiltration were reduced compared with mice treated with GD2-CAR T cells alone, thereby increasing overall The survival rate .
Enhance the specificity and safety of CAR T cell therapy
One of the main differences between hematological malignancies and solid tumors is the availability and heterogeneity of tumor antigens. One of the reasons why CAR T cells against B cell antigens have shown this success is due to the homogenous expression of the tumor antigen CD19 or CD20 on almost all tumor cells in a given patient (at least before treatment). Although the non-malignant cells of these patients also express CD19/CD20 antigens and are therefore easily killed by CAR T, the targeting/non-tumor effect can be controlled and is not life-threatening, just like other tumor antigens  . Therefore, new CAR goals are currently being explored.
Examples of novel targets include the type 1 insulin-like growth factor receptor (IGF1R) and tyrosine kinase-like orphan receptor 1 (ROR1) of sarcoma 57 and the L1 cell adhesion molecule (L1 CAM) of ovarian cancer . However, in all cases, there will still be low levels of expression on non-malignant tissues, so caution must be exercised before applying these CARs in clinical trials.
Efforts are currently being made to find alternative CAR designs that identify target antigens that are uniquely expressed on tumors and not present in all other normal tissues. Although the specificity and affinity of CAR are improving, the toxicity caused by the low level of target antigens on normal tissues is a problem that deserves further attention. Therefore, based on the presence or absence of two target antigens, multiple groups have adopted a variety of methods to reduce extra-tumor effects. Previous work in our laboratory focused on the synergistic effect of two separate CARs on two TAAs (folate binding protein and Her-2), and the anti-tumor effect is minimal when only one exists . Although most tumor cells share TAA with normal cells. In tissues, two unique TAAs are less likely to be expressed on normal tissues and tumor tissues. It has been reported that when co-cultured with tumor targets expressing dual antigens, the cytokine secreted by T cells expressing dual CAR is almost double that of CAR T cells expressing single CAR .
Another way to reduce unnecessary off-target effects is inhibitory CAR. Inhibitory CAR (iCAR) contains the extracellular signaling domain of the “normal” antigen that binds to the cytoplasmic region of PD-1 or CTLA-4, thereby promoting downstream inhibition in the presence of the iCAR target antigen . However, due to the failure of iCAR signaling in order to completely eliminate T cell function, further modifications, such as the inclusion of a suicide gene (reviewed in the literature by Minagawa et al. ) may help eliminate the undesirable toxicity.
Other strategies to reduce autoimmunity include separating the intracellular signaling domains “Signal 1” (CD3ζ) and “Signal 2” (co-stimulation) into different CARs that recognize two alternative target antigens. As the first and second generation CARs clearly show, the existence of the costimulatory domain greatly enhances the overall function of the cell. By separating two intracellular domains, CAR T cells can perform all functions only in the presence of two target antigens, thus limiting the existence of a single antigen .
Similarly, one of the latest developments in CAR technology also uses a “one-to-two” system, which relies on the specificity of CAR to transport the secondary hit point (“two”) to the tumor target (“one”). The SynNotch receptor consists of an extracellular CAR specific to the target antigen and then fused to a cleavable transcription domain in the cell. Binding to the target antigen results in Notch cleavage, and Notch induces downstream transcriptional activation of genes . There are many possibilities to induce genes. For example, a secondary CAR can ensure specific targeting of tumor tissues expressing two antigens. Other possible inducible genes include chemokines, checkpoint blocking antibodies or endogenous factors, which may promote the persistence, memory or anti-tumor function of T cells themselves.
The follow-up work of the same group further explored this concept. Recognizing the “tumor-localized antigen” on the main SynNotch receptor can help express the CAR of the tumor antigen. Therefore, the tumor antigen and the tumor-localized antigen are required to activate the SynNotch/AND gate circuit together. Prevent premature CAR T cell activation in the presence of a single antigen-expressing tumor cell .
The potential efficacy of CAR therapy has been verified in hematological malignancies, but the current success rate in solid tumors is very low. New cutting-edge designs for CAR T cells are currently being tested to overcome many of the challenges posed by solid tumors.
It is hoped that our increasing knowledge of the tumor microenvironment and the speed of technological progress will promote the development of CAR T cells that have been fully modified to combat the immunosuppressive properties of the tumor microenvironment and cause a fatal blow to solid tumors.
(source:internet, reference only)