The currently researched adoptive T-cell therapy has been able to avoid this problem to some extent. However, ATC currently has certain limitations. In solid tumors, it is necessary to overcome the inherent heterogeneity of tumor cells and the complexity of the tumor microenvironment (TME).
Tumors are generally ineffective for traditional anti-tumor drugs in primary drug resistance, progression, and relapse resistance, and the side effects of cytotoxic drugs are large and do not distinguish tumors from autologous cells. The currently researched adoptive T-cell therapy has been able to avoid this problem to some extent. However, ATC currently has certain limitations. In solid tumors, it is necessary to overcome the inherent heterogeneity of tumor cells and the complexity of the tumor microenvironment (TME). Despite the long road ahead, the recent breakthrough in this therapy has opened up a new world of cancer treatment.
In solid tumors, the interaction between tumor cells and immune cells is very obvious. In short, the immune system plays a dual role in the tumor environment. First, it can provide cells expressing CD4+ and CD8+ as well as cytokines to exert anti-tumor effects. At the same time, it can activate regulatory T cells and immunosuppression. Sex cytokines provide shelter for tumors. Let's start with the simplest and original T cell therapy. As the research progresses, we will review the history of adoptive T cell therapy in solid tumors.
T cell reinfusion - initial exploration
For advanced patients with traditional cancer treatment failure, it is natural to try to break the blocking of the immune system by tumor cells. The concept of adoptive cell therapy (ACT) has emerged, in which immune cells are infused into patients. Enhance anti-tumor ability. T cells are able to find and settle in tumors by "walking and patrolling" in the blood. In theory, T cells can be expanded in vitro to achieve clinically desirable quantities while providing a more durable anti-tumor effect. The benefit of T-cell reinfusion is clearer than antibody treatment - antibodies do not cross the blood-brain barrier (BBB) and do not consistently achieve effective anti-tumor concentrations in solid tumors. But the disadvantages are also obvious, such as the expensive and complex autologous T cell production process. (The good news is that the production process is greatly simplified and more functional treatments are being explored.
The initial treatment of this therapy was the study of tumor infiltrating lymphocytes (TIL), the first ACT reperfusion cells. The initial method was to isolate TIL from tumor cells, expand in vitro with IL-2, and then return to lymphocytes in advanced melanoma patients (Dr. Rosenburg, 1988, published on NEJM). The results were surprising: TIL was able to recognize intracellular tumor antigens through the interaction of MHC-I and soluble T cell receptors (TCRs). The patient's clinical response rate was 50-70%, and even 22% of patients completely contracted the tumor. Recently, a "homing navigation" that directs T cells to detect tumors has been added to the TIL to allow more T cells to converge.
TIL is a surprise for malignant melanoma, and another T cell therapy, cytotoxic T cells (CTL), is developing in virus-associated tumors. Similarly, CTL can be isolated from peripheral blood, expanded/specifically conferred to the patient in vitro, and returned to the patient with the tumor-derived polypeptide on the MHC-I of the CTL so that it can "lock" and activate it. The T cell receptor (TCR) allows T cell proliferation and produces anti-tumor properties. For example, CTLs specific for cytomegalovirus (CMV) have entered the exploratory phase of clinical trials for the treatment of glioblastoma.
Both TIL and CTL are first-generation T-cell therapies, providing a star hope for immunologists, but their widespread use is a problem. The main limiting factor is the difficulty in isolating and expanding T cells, because the T cell content in tumors is relatively low, and the current therapeutic prospects of TIL are mainly limited to malignant melanoma. Although CTLs are slightly wider than TIL, their recognition of tumor-associated antigens (TAAs) is MHC-restricted, which is indeed a big problem, because one of the ways in which CTL's old rival tumor cells evade immune recognition is to alter MHC and tumor antigens. expression. Escape the "immune check".
Second generation T cell therapy - T cell engineering
How to transform T cells to make it more effective and specific to identify tumor-associated antigens? There are two methods: one is to directly transform the T-cell's "probe" that binds to the tumor antigen - TCR, and the second is to directly install a new "probe" on the T-cell - chimeric antigen receptors (CAR) .
These engineered T cells were first reinfused to patients. In 2006, remodeled T cells bind to CD3 molecules and activate T cells to kill tumors. For example, T cell TCR specifically recognizes NY-ESO-1. This tumor antigen allows 60% of synovial cell sarcoma patients to regress tumors. This method of course has a lot of limitations. First, the effectiveness of treatment depends on the affinity of the TCR and the antigen it recognizes. If the TCR shows a lower affinity, or the tumor down-regulates MHC expression, these T cells have no effect. Secondly, there is a great diversity in the arrangement of human HLA alleles. It is almost impossible to engineer T cells for each individual, and it is unlikely that a transgenic TCR library will be produced for patient matching. Also, some studies have found that the a and b subunits that are transferred into T cells mismatch with their own TCR. Solutions to these problems include changes in the structure of the TCR, induction of differentiation of γδT cells or hematopoietic stem cells into T cells, or knockdown of endogenous TCRs.
Of course, other scientists have chosen to directly bypass the "probe" TCR-MHC restriction, directly artificially added a chimeric antigen antibody - CAR to T cells. CAR is an artificial fusion: the fusion of the antigen recognition region and the internal signaling region (usually the TCR chain), the idea is to allow the T cells with CAR to activate the T cells while recognizing the tumor antigen. The benefits of this CAR are obvious because it recognizes antigens that are not restricted by MHC. CAR-T was first used in hematological malignancies. The most successful outcome is the identification of CAR19 in CD19. There are now 27 clinical trials to study CD19 CAR-T in the treatment of hematological malignancies. However, in solid tumors, CART progress is limited. Most solid CARs have only transient anti-tumor activity.
Relocating T cells to tumor cells by "latent" T cells in tumors is actually a force that cannot be ignored in cancer therapy. Many studies have tried to "wake up" these sleepy warriors. Some bi-directional antibody platforms allow T cells to reorient tumor antigens: for example, by singling single-chain variable fragments (ScFv) one by one, called tandem ScFv (TanFv), which provides the simplest The antigen recognizer, in turn, meets the flexibility to identify different targets. This tandem ScFv can be designed into any adjacent antigen that we want to target and activate the immune response. For example, a Bispecific T-cell Engagers called BiTE can simultaneously target the CD3 molecule of TCR and a tumor-specific antigen. To date, a clinical Phase 1 trial of BiTE (CD3/EpCAM) called MT110 has been completed.
What is the difficulty of immunotherapy for solid tumors?
First, solid tumors have highly heterogeneous tumor antigens, which makes it easy to escape surveillance of the immune system. In addition, the solid tumor can form an inhibitory tumor microenvironment inside, making it difficult for immune cells to break.
For the former difficulty, we can try a "multi-weapon combination": the CARs that will be able to recognize multiple tumor antigens are connected in series, called tandem CAR (TanCAR), and each TanCAR cell can recognize the specific antigen of the carried CAR. It is also possible to recognize both antigens at the same time, and when the two antigens are recognized, a synergistic effect is generated to activate T cells. The scientists later further engineered this TanCAR, which carries both the recognition of tumor antigens and the antigens that recognize the tumor microenvironment.
For the latter difficulty, everyone also tried some solutions. One of the causes of the inhibitory microenvironment of tumors is that there are some inhibitory cytokines, such as TGF-β and IL10. For TGF-β, a TGF-β receptor is found to allow T cells to fight TGF-β. Inhibition. In addition, there are some studies that attempt to convert inhibitory signals into stimulatory signals. For example, some researchers have artificially synthesized a molecule that contains the extracellular Th2 anti-replication cytokine IL4 and fuses it into the cell. On the Th1 proliferation-promoting cytokine IL17, such binding can improve the survival rate of mice in EBV-positive mouse tumor experiments.
In addition, in neurological tumors, how T cells with anti-cancer function cross the blood-brain barrier BBB is also a problem. Some researchers have allowed T cells to express cytokine receptors on the surface, which helps T cells to find the source of the tumor and "homing." There are currently clinical phase 1/2 studies enrolling patients with metastatic malignant melanoma who are given a TIL that expresses CXCR2 (which is a cytokine receptor) and the nerve growth receptor NGFR.
The future direction of T cell therapy
To summarize, T cell therapy has evolved from the initial “collection-amplification-return” to T cells engineered to patients, and is inhibitory and heterogeneous for solid tumors. Sexual conquer has also made some progress. Combining the screening of tumor-specific antigens with CAR technology is undoubtedly one of the key points; in addition, the combination of card control point treatment inhibitors, vaccines and antibodies with T cells to find the optimal combination is also one of the development directions.
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