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A breakthrough new strategy for tumor immune cell therapy
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A breakthrough new strategy for tumor immune cell therapy.
In the past 20 years, cell therapy, including CAR-T and TCR-T therapies, has undergone earth-shaking changes from conceptual verification trials to thousands of registered clinical trials.
In 2017, the US Food and Drug Administration ( FDA ) approved two CAR-T therapies for the first time, namely tisagenlecleucel ( Kymriah® ) and Axicabatagene ciloleucel ( Yescarta® ) for the treatment of acute lymphoblastic leukemia and diffuse large B cell respectively Lymphoma.
So far, 5 CAR-T therapies have been approved. As a revolutionary biotechnological product in cancer treatment, cell therapy demonstrates the outstanding potential of conquering cancer in the future.
However, CAR-T-based cell therapy for solid tumors still has many challenges, such as how to overcome drug resistance, how to solve tumor heterogeneity, how to overcome the immunosuppressive tumor microenvironment ( TME ), and how to avoid TME .
These problems need to be solved urgently to maintain the persistence of cell exhaustion.
At present, new concepts and strategies for the treatment of solid tumor cells are emerging.
These advances include better target selection through the transfer of tumor-associated antigens to personalized tumor-specific neoantigens, and enhancement of T cell production by breaking the matrix barrier.
Transport, and regenerate depleted T cells by targeting the immunosuppressive mechanism in TME.
Although there are still major challenges, it is believed that due to the maturity of T cell engineering, target selection and T cell delivery technology, cell therapy will soon lead and revolutionize cancer immunotherapy again.
New progress in CAR-T cell therapy for hematoma
In addition to the currently approved CAR-T cells targeting CD19 for lymphocytic leukemia and lymphoma, some new targets are emerging.
In hematology, the most abundant pipeline for new targets is multiple myeloma.
Some members of the signal transduction lymphocyte activation molecule ( SLAM ) family are being used as potential targets, including SLAMF7 ( CD319, CRACC, CS-1 ) and SLAMF3 ( CD229, Ly9 ).
SLAMF7 and SLAMF3 are evenly expressed on tumor cells of untreated and chemotherapy-resistant multiple myeloma patients.
CAR-T cells targeting either antigen have shown highly effective killing effects in both in vitro and in vivo experiments. Therefore, SLAMF7 CAR-T cells have now entered clinical trials.
CD37 is a four-pass transmembrane protein ( TSPAN26 ), which plays a role in cell membrane organization and co-signaling, regulates cell adhesion, migration and proliferation, and provides pro-survival and pro-apoptotic signals.
In preclinical animal models, CD37 CAR-T cells are as effective as CAR19. An early clinical trial ( NCT04136275 ) is currently underway to explore CD37 CAR-T cells for CD37+ hematological malignancies.
The following table lists some other new target antigens of CAR-T cells in multiple myeloma, B-cell and T-cell malignancies, and acute myeloid leukemia ( AML ).
Another aspect of the current breakthrough in CAR-T therapy for hematological malignancies is the structural modification of CAR, including adding binding domains with different affinities and different antigen binding, testing different hinges to connect antibodies and transmembrane domains, and optimizing Different costimulatory domains ( 4-1BB, CD28, GITR, CD27 ), combined with mutations in the signal domain to regulate signal strength.
Secondly, based on gene editing, test different immune effector cells to replace traditional T cells, including γδ T cells, NK cells and general CAR-T cells. In addition, different gene delivery technologies can be used to engineer CAR-T cells.
Third, CAR-T cells are further modified by additional transgenes to express cytokines to stimulate CAR-T cell functions and maintain their continuity, knock out checkpoint molecules through gene editing, and control CAR expression through a “switch” mechanism. Fourth, the strategy of designing CAR-T cells to improve safety and reduce drug resistance.
From TIL to TCR-T
Some characteristics of solid tumors that are different from hematomas pose significant challenges to the development of effective adoptive cell therapy.
First, the high heterogeneity of solid tumors makes it difficult to find ideal targets for all tumor cells. Targeting a single tumor antigen usually leads to antigen loss or more aggressive clonal recurrence.
Secondly, even if a large number of T cells are adoptively transferred, most solid tumors are difficult to infiltrate.
In addition, there are multiple immunosuppressive mechanisms in TME , which make it difficult for T cells to fully exert their functions .
TIL may have some unique advantages in the treatment of solid tumors.
First, TIL is composed of T cells with multiple TCR clones and can recognize a series of tumor antigens.
Therefore, compared with other adoptive cell therapies ( such as CAR-T and TCR-T ), TIL may be able to deal with tumor heterogeneity.
More advantages. Consistent with this, TIL shows better clinical efficacy than CAR-T in solid tumors with high mutation burden ( such as melanoma ).
Secondly, after being stimulated by tumor antigens in vivo, TIL is often mainly composed of effector memory T cells ( Tem ), whose surface expresses chemokine receptors, such as CCR5 and CXCR3.
Together with tumor-specific TCR, TIL can be easily localized to tissues expressing antigens, including tumors, after being transferred to patients.
Finally, targeted toxicity is rarely reported in TIL therapy, which may be due to the negative TCR selection of TIL during the early development of T cell immunity.
Between 2011 and 2020, there were 79 clinical trials of TIL treatments, including 22 TIL products, some of which showed encouraging results.
TCR-T immunotherapy technology activates the host’s immune system through effective interaction with MHC, especially class II molecules, which are specifically recognized by TCR-T cells and CAR-T cells.
TCR-T cells can recognize tumor-specific antigens in cells, while CAR-T cells mainly recognize specific antigens on the tumor surface.
This makes TCR-T cells more effective in tumor treatment.
Compared with CARs, TCRs have some structural advantages in T cell-based therapies. For example, there are more subunits in the receptor structure ( 10:1 ), and immune receptors are based on tyrosine-based activation motifs ( ITAMs). ) More ( 10:3 ), less dependence on antigen ( 1:100 ), and more costimulatory receptors ( CD3, CD4, CD28, etc. ).
TCRs with a low MHC affinity range ( 10 4 -10 6 M -1 ) can effectively activate T cells. On the contrary, CARs require a higher affinity range ( 10 6 -10 9 M -1 ).
In addition, compared with TCR, CARs recognize tumor antigens with certain disadvantages, such as extra-tumor toxicity.
Improve the effectiveness of CAR-T cells
At present, many engineering strategies have been explored in CARs to overcome obstacles in TME, including armed CAR-T to enhance the penetration of CAR-T cells into tumors, and gene editing tools ( such as CRISPR/Cas9 ) from CAR-T cells Remove immune checkpoint molecules to avoid exhaustion.
Some studies have explored the delivery technology of CAR-T cells. In preclinical studies in animal models, local injection of CAR-T cells into the pleura showed significantly better disease control and survival than intravenous injection of CAR-T cells.
In addition, local administration of CAR-T cells can not only control local diseases, but also promote the effective removal of tumors outside the chest.
This therapeutic effect depends on early CD4+ T cell activation, and is associated with a higher intratumoral CD4/CD8 cell ratio and CD28-dependent CD4+ T cell-mediated cytotoxicity.
Two phase I clinical trials were aimed at malignant pleural mesothelioma ( NCT02414269 ) and triple-negative breast cancer ( NCT02792114 ), using intrathoracic and systemic administration, respectively.
A total of 41 patients ( 4 patients received repeated doses ) received intrathoracic treatment, and 10 patients ( 1 patient received repeated doses ) received systemic therapy.
There are no CAR-T cell problems, no adverse events of grade 3 or above, and no targeted non-tumor toxicity. A phase II follow-up trial on intrathoracic administration is ongoing.
Recently, a new generation of CAR has been developed, named M28Z1XXPD1DNR CAR, which expresses the PD-1 dominant negative receptor on the surface of CAR-T cells to overcome the inhibitory effect of PD-L1 on tumors.
The new generation of CAR-T cells show enhanced in vitro cytotoxicity and in vivo tumor killing effects, prolonging the survival time of animal models.
Compared with traditional CAR-T cells, M28Z1XXPD1DNR CAR-T cells are more potent, the dose of CAR-T cells is lower, and their function in the body lasts longer.
Clinical trials using this CAR started in September 2020 for patients with mesothelioma ( NCT04577326 ).
Guiding CAR-T cells to actively regulate the cytokine environment in TME is another effective strategy to enhance curative effect.
Recently, it has been reported that making CAR-T cells produce IL-15, or the combination of IL-15 and IL-21 or IL-23 can improve the persistence and anti-tumor ability of CAR-T cells through an autocrine mechanism.
Similar effects have been observed for CAR-T cells that produce IL-18 or targeted delivery of IL-2 and TNF-a to tumors through oncolytic viruses, both of which have the ability to participate in innate and endogenous adaptive immune responses.
Additional effect. Similarly, the expression of CD40L on CAR-T cells can enable antigen-presenting cells to recruit endogenous tumor-targeting T cells.
The reduction of CAR-T cell metastasis to the tumor site may be caused by the mismatch of chemokine receptors on CAR-T cells and the abnormal expression of chemokines in the tumor.
Therefore, in order to promote delivery to tumors, CAR-T cells can be converted to express chemokine receptors that match the chemokine profile of a specific tumor.
The expression of CCR2b allows CAR-T cells to migrate to CCL2-expressing tumors.
Similarly, a recent study combined IL-8 receptor expression with CXCR1 or CXCR2 to increase the persistence of CAR-T cells and their ability to deliver to tumor sites.
In addition, it is conceivable that some of these strategies can be combined to “customize” CAR-T cell products to suit the specific conditions of each tumor entity.
Improve the safety of CAR-T cells
Cytokine release syndrome ( CRS ) is a systemic inflammatory response and the most common acute toxic response to CAR-T cell therapy. There are several factors that affect the incidence and severity of CRS, including tumor burden, CAR-T cell dose, in vivo expansion, and regulation of lymphocyte consumption.
Currently, many strategies are working to improve the safety of CAR-T cells.
Suicide gene has the ability to control apoptosis engineered cells. Herpes simplex virus thymidine kinase ( HSV-TK ) is being studied in CAR-T cells. However, it is not clear whether HSV-TK is potentially immunogenic.
Another less immunogenic method is the inducible safety switch caspase9 ( iCasp9 ), which contains a modified human caspase9 fused to the FK506 binding protein.
The induction of iCasp9 depends on the use of AP1903, which is a dimerization chemical inducer, which activates caspase molecules to cause cell apoptosis.
Inhibitory CARs ( iCAR ) can be used on T cells to control toxicity to healthy tissues. iCAR is composed of an antigen-specific single-chain antibody that is only expressed in normal cells.
It has a strong acute inhibitory signal. Although the activation receptor participates at the same time, it can still limit the activation of T cells.
The combination of CAR-T and BsAb can also improve tolerance. For example, CAR is designed to bind to fluorescein isothiocyanate ( FITC ), while FITC is not a target but a universal binding, and BsAb binds FITC to the target.
Therefore, in the absence of BsAb, CAR-T will not be activated and can be adjusted by the dose of BsAb.
Finally, combined target antigen recognition is another way to improve tolerance.
In this case, T cell activation depends on the co-activation of two different CARs, one is related to CD3 transduction, and the other is related to the costimulatory receptor CD28 or 4-1BB.
Cell therapy has achieved great success in the treatment of hematological malignancies. However, solid tumors still need to face huge challenges, and further breakthroughs in technology and methods are needed to have a chance of success.
The personalized neoantigen-oriented TCR-T, TIL, bispecific or trispecific engineered CAR-T cells and the combined application with checkpoint inhibitors have become a promising new therapy.
From the perspective of safety, the introduction of suicide genes, inhibitory CARs, the combination of CARs and BsAbs, and the combination of target antigens are some new research methods that may change the future development prospects of solid tumor patients.
The further development and breakthrough of these methods in the future will completely change the current model of cancer treatment.
1.New targets and technologies for CAR-T cells. Curr Opin Oncol. 2020 Sep;32(5):510-517.
2. Next generation chimeric antigen receptor T cells: safety strategies to overcome toxicity. Mol Cancer. 2019 Aug 20;18(1):125.
3. Engineered TCR-T Cell Immunotherapy in Anticancer Precision Medicine: Pros and Cons. Front Immunol. 2021;12: 658753.
4. Perspectives of tumor-infiltrating lymphocyte treatment in solidtumors. BMC Med. 2021 Jun 11;19(1):140.
A breakthrough new strategy for tumor immune cell therapy
(source:internet, reference only)