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What is TCR-T cell therapy different from CAR-T Immunotherapy?
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What is TCR-T cell therapy different from CAR-T Immunotherapy?
At present, tumor immunotherapy is in the ascendant, and one of the most effective treatment strategies is adoptive cell transfer therapy (ACT) .
Chimeric antigen receptors (CARs) and engineered T-cell receptors (TCRs) have been the mainstay of adoptive T-cell immunotherapy in recent years.
TCR-engineered T cells express tumor antigen-specific receptors whose alpha and beta chains are cloned from high-quality, high-affinity antigen-specific T cells .
TCR molecules belong to a superfamily of immunoglobulins and consist of two covalently bound polymorphic subunits , each antigen-specific , which are associated with at least four different types of signal transduction chains. In order to activate T cells,there must be an interaction between the TCR and the major histocompatibility complex (MHC)
The strength of the interaction between TCRs and pMHC (peptide-MHC) determines the fate of immature thymocytes and is critical for the survival of naive T cells .
Therefore, 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 intracellular tumor-specific antigens, while CAR-T cells mainly recognize specific antigens on the tumor surface . This makes TCR-T cells more effective in tumor therapy.
At present, some new technologies and tools are being applied to TCR-T, which helps to improve the efficacy and safety of TCR-T therapy. TCR-T cell therapy is showing great potential for anti-tumor therapy.
Comparison of CAR-T and TCR-T
In ACT therapy, both TCR-T and CAR-T cells have been successfully used in the clinical treatment of solid tumors. CARs contain tumor antigen-targeted single-chain antibodies, a transmembrane domain, and an intracellular activation domain of CD3ζ. In this way, the engineered CAR can recognize specific tumor-associated antigens, and the CAR can bind to untreated tumor surface antigens without MHC treatment.
While first-generation CAR-T cells exhibited limited expansion and relatively short persistence, “second-generation” CAR-Ts incorporate the co-stimulatory receptors CD28, 4-1BB/CD137, and OX40. The addition of these costimulatory receptors to the CD3ζ domain of CAR-T cells promotes more robust and durable T cell responses. Third-generation CARs simultaneously bind two co-stimulatory signals (CD28 and 4-1BB) , which have better expansion and longer persistence than second-generation CARs.
In contrast, TCRs are alpha/beta heterodimers bound to MHC antigen complexes . Compared with TCRs, CARs recognize tumor antigens with certain disadvantages, such as off-tumor toxicity. Compared with CARs, TCRs have some structural advantages in T cell-based therapy , such as more subunits in their receptor structure (10:1) , immunoreceptor 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 (104-106M-1) can effectively activate T cells, whereas CARs require a higher affinity range (106-109M-1) .
Therefore, CAR-mediated cytotoxicity relies on higher densities of cell surface antigens. Furthermore, T cell/antigen interactions are initiated in the immune synapse (IS) structure, where TCR presents a ring-shaped region with peripheral LFA-1 adhesion, whereas CAR presents a diffuse LFA-1 distribution without a ring-shaped region. Therefore, TCR-IS signals slower but longer duration than CAR-IS . At the same time, CAR-T cells exhibit a faster killing function and migrate to the next tumor target (serial killing) , which is in sharp contrast to TCR-T cells for prolonged signaling and prolonged killing time.
TCR is one of the most complex receptors in the human body, and it contains six different receptor subunits that have a very wide range of functions in T cells.
Alterations in the TCR of tumor-infiltrating lymphocytes (TILs) significantly affect tumor-specific T cells. Among them, the change of TCR contributes to the proliferation of T cells, and the diversity of TCR is related to the anti-tumor effect.
TCR engineering of TILs is one of the best treatments for tumors. The TCR consists of alpha and beta chains bound to peptide-MHC ligands, the signaling subunits of the CD3 complex(ϵ, gamma, and delta),and the CD3ζ homodimer. All subunits, except CD3ζ, have extracellular immunoglobulin(Ig)domains. Based on these structures, new technologies utilizing engineered TCRs include ImmTAC, TRuCs, and TAC.
Immune mobilization monoclonal T cell receptor (ImmTAC)
ImmTACs were designed using engineered, soluble and affinity-enhanced monoclonal TCRs (mTCRs) . ImmTACs are essentially fusion proteins that combine an engineered TCR targeting system with single-chain antibody fragment (scFv) effector functions. In the construction of ImmTACs, TCRs are able to recognize peptides from intracellular targets presented by human leukocyte antigen (HLA) .
ImmTAC promotes T-cell-mediated effector functions by specifically targeting HLA-peptide complexes on the surface of tumor cells and through the interaction of scFv antibody fragments with CD3. ImmTAC also activated CD8+ T cells in a dose-dependent manner and could effectively redirect and activate effector and memory CD8+ and CD4+ cells.
ImmTAC exhibits a multifunctional response by secreting multiple cytokines, such as TNF-α, IFN-γ, IL-6, MIP1α-β, and IFN-γ-inducible protein 10.
In addition, the selection of suitable target antigens is the key to ImmTACs, and mass spectrometry technology and MHC multimer technology help to identify suitable antigens.
Notably, TCR-engineered T cells also exhibited unexpected on-target toxicity. Overall, ImmTACs have been shown to enhance the antitumor response of TCR-T cells, but their safety needs to be further investigated.
T cell receptor fusion constructs
T-cell receptor fusion constructs (TRuCs), an antibody-binding domain fused to a T-cell receptor subunit, are designed to efficiently recognize tumor surface antigens. TRuCs consist of specific antibodies targeting tumor-associated antigens fused to the extracellular N-termini offive TCR subunits(TCRα, TCRβ, CD3ϵ, CD3γ, and CD3δ)and HLA-independent target cell clearance ability, can be activated by the corresponding target cells.
Compared with second-generation CAR-T cells, this approach showed better antitumor effects. Furthermore, TRuCs govern the entire signaling machinery of the TCR complex, whereas CARs utilize only limited signaling from the isolated intracellular segment of CD3ζ.
T cell antigen coupling agent (TAC)
T-cell antigen coupling agents are another engineered TCR cells that induce more potent antitumor responses and reduce toxicity in an MHC-independent manner.
TAC chimeric proteins bind to the CD3 domain to form TCR/CD3 complexes and obtain more T cell responses.
The activity of TAC receptors is closely related to the choice of CD3 binding domain. For example, single-chain antibodies from OKT3 (muromonab-CD3) have lower cytokine production and cytotoxicity compared to UCHT1 , which may lead to substantially different functional outcomes.
Compared with second-generation CARs, TAC-engineered T cells not only facilitated greater post-adoptive infiltration of solid tumors, but also reduced T cell expansion and off-tumor toxicity in healthy tissues expressing the antigen.
Workflow of TCR-T Cell Therapy
To isolate therapeutic TCRs, antigen-specific T cells must first be isolated from the blood of patients or healthy donors and expanded in vitro with specific peptide antigens as well as cytokines such as IL-2 and IL-15 . This process requires prior identification of specific tumor-associated peptide targets that can be safely targeted to patients .
After the target antigen has been selected, different methods can be used to screen for TCRs with the desired high affinity and tumor specificity .
Preclinical safety testing is also necessary to ensure minimal off-target effects and cross-reactivity of isolated high-affinity TCRs.
Viral vectors are commonly used to genetically modify autologous patient T cells to express a validated therapeutic TCR, which is then infused back into the patient.
Identify target antigens
Melanoma antigen 1 (MART-1) recognized by T cells is the first tumor-associated antigen targeted in TCR-T clinical trials. Following this breakthrough, TCR-T therapies targeting multiple tumor antigens have been developed, including MAGE-A3, MAGE-A4, GD2, mesothelin, gp100, MART1, AFP, CEA, NY-ESO-1, and TCR-T therapy with viral peptides derived from HPV and EBV .
Among them, NY-ESO-1 has been proved to be one of the most promising targets of TCR-T cells, and has achieved success in the treatment of synovial sarcoma with an objective response rate of 67%.
Ideal TCR-T target antigens exhibit the following characteristics:
(1) the ability to induce an immune response;
(2) associated with driving tumor phenotypes to reduce the risk of antigen loss and tumor immune evasion;
(3) the ability to act on tumor stem cells Expressed to promote permanent tumor eradication.
Methods for the identification of tumor-associated antigens
High-resolution mass spectrometry (MS) has been shown to be the most powerful high-throughput method to facilitate the direct identification of HLA-I-binding peptides from tumor cells.
In this method, HLA-I/peptide complexes are isolated from tumor tissue or cell lines by immunoprecipitation (IP), followed by extensive washing and application of an acidic elution buffer, from HLA-I molecules and antibodies for IP Binding peptide antigens were isolated in .
This strategy allows the identification of thousands of validated peptide targets per tumor sample and has been used to identify glioblastoma(GB), melanoma, renal cell carcinoma(RCC)and colorectal cancer (CRC ) among others. HLA-I ligands.
Methods for the identification of tumor neoantigens
Although MS-based techniques can be used to identify neoantigens, they are more difficult to identify due to their relatively low abundance and the limited sensitivity of MS, especially for tumor samples of limited size.
However, the development of next- generation sequencing technologies has helped to identify and localize such tumor targets.
Whole-exome DNA sequencing, combined with computational prediction algorithms, allows the identification of specific genetic alterations in cancer cells that can generate mutated peptides that can be presented on tumor HLA-I molecules.
All somatically mutated genes can be analyzed in silico to predict potential high-affinity epitopes that may bind to a patient’s individual HLA-I molecule for recognition by T cells.
HLA-I peptide binding prediction algorithms are continually updated and improved with the use of large databases of MS-eluted peptides, and other prediction algorithms attempt to account for biological variables associated with the complexity of intracellular processes.
Another frequently used method is tumor RNA sequencing , which allows selection of neoantigens with the highest transcriptional expression.
It is worth noting that although these prediction methods generally show very good accuracy in identifying presented and highly immunogenic neoantigens, they generally predict a higher number of neoantigen targets than the actual number of true targets1 to 2 orders of magnitude.
The discovery of neoantigens by trogocytosis is a new method that has emerged in recent years.
Trogocytosis is a biological phenomenon that occurs during cell association, in which cells share and transfer membranes and membrane-associated proteins. Li et al. found that T cell membrane proteins specifically translocate to tumor target cells that present cognate HLA-I/peptide complexes.
Taking advantage of these T cell-target cell interactions, they created a neoantigen discovery system by co-incubating T cells expressing tagged orphan TCRs with cognate target cells.
By transferring fluorescent labels from T cells to target cells, the method enables the isolation of these target cells and the sequencing of cognate TCR ligands to create neoantigen libraries.
Isolation of tumor-specific T cells and TCRs
Using HLA-I multimers, single-cell TCR sequencing, or antigen-negative humanized mice, tumor-reactive T cells and TCRs can be identified from autologous, allogeneic, or xenogeneic cell banks.
Using the HLA-I multimer method , antigen-specific CD8+ T cells can be directly isolated by multimer staining and flow cytometry sorting .
These polyclonal T cells were subjected to homologous peptide recognition and antitumor function testing prior to isolation of paired full-length TCR sequences.
Using a highly sensitive PCR-based single-cell TCR analysis method (TCR-SCAN) , TCRs with high affinity and specificity can be obtained.
Another approach utilizes humanized mouse TCR gene repertoires that do not develop T cell clonal deletion or tolerance that arises in humans.
To this end, Li et al. constructed transgenic mice using the entire human TCR α/β locus and a chimeric HLA-A2 transgene to achieve the isolation of human TCR against human TAA.
Single-cell sequencing approaches represent a more promising approach to high-throughput isolation of tumor-specific TCR-encoding genes.
Using RNA bait libraries targeting each individual V and J element within the TCRα and TCRβ loci, TCR-encoding genomic elements can be selectively isolated from sheared genomic DNA(gDNA)fragments for subsequent paired-end deep sequencing.
This enables the identification of antigen-specific TCRs from human material or from oligoclonal T-cell populations of TCR-humanized mice.
Naive T cells can also serve as a TCR source for TCR-T therapy. TAA and neoantigen-specific T cells can be derived and expanded from low-frequency precursors in the peripheral blood of cancer patients and can be re-infused or used as a source of antigen-specific TCRs.
Since cancer patients often exhibit immunosuppression or dominant T-cell tolerance, the original sequence of an HLA-I-matched healthy donor also represents a reliable source due to its enormous diversity of TCR sequences that theoretically T cells have Any antigen specificity, including tumor neoantigens.
High-throughput technology platforms have been developed to find original sequences for rapid and efficient identification of rare but therapeutically valuable TCRs for personalized adoptive T-cell therapy.
Cloning of TCR
Most TCR-based gene therapy approaches rely on in vitro transduction of T cells with viral vectors , the earliest vectors used for gene therapy being adenoviruses .
However, due to their inability to integrate the transgene into the host genome, TCR expression is lost during T cell proliferation.
In addition, the immunogenetic properties of adenovirus also limit its application as a gene therapy vector.
In contrast, retroviruses have shown greater promise as gene transfer vehicles because they can infect a wide variety of cells and have the ability to insert transgenes into the host genome , resulting in stable expression of ectopic TCR α/β chains.
Retroviral vectors derived from gamma-retroviruses such as mouse leukemia virus (MLV) have been widely used for gene transfer into human T cells. This approach has been used to deliver a variety of genes, including suicide genes, TCRs, and CARs.
The main disadvantage is that they cannot transduce non-proliferating target cells, which precludes the use of quiescent T cells in TCR-T therapy. In addition, retroviral insertional mutagenesis may cause potential side effects.
Recently, lentiviral vectors (LVs) have gained more attention as gene transfer vehicles because they can deliver genes into dividing and non-dividing cells . Various techniques, such as Golden Gate cloning and LR cloning, are commonly used to construct vectors for insertion of TCRα/β genes.
Adeno-associated virus (AAV)is another widely used viral vector. Compared with adenoviral vectors, AAV has lower immunogenicity and broader cell tropism , so it has been widely used in tumor gene therapy.
To facilitate transgene integration, self-complementary AAV vectors (scAAV)make AAV independent of complementary strand synthesis in host cells , and scAAV is more effective than traditional AAV in preclinical models.
At the same time, some non-viral gene editing methods have also been developed. mRNA electroporation has been shown to achieve transient TCR and CAR expression, thereby minimizing the risk of persistence of viral components. Clinical data suggest that both mRNA-modified TCR-T and CAR T cells are viable and safe, with no clear evidence of off-target toxicity to normal tissues.
However, lack of sustained TCR expression may limit efficacy, requiring repeated infusions. In addition, the non-viral Sleeping Beauty retrotransposon system was also used for the transduction of TCRs and CARs.
Gene editing can specifically and efficiently insert large gene fragments into target cells through homology-directed repair (HDR) .
TCR-T cells developed using CRISPR/CAS9 have been shown to specifically recognize tumor antigens in vitro and induce productive antitumor responses in vivo.
Validation method of TCR
Following TCR cloning, extensive preclinical validation is required to demonstrate the specificity and safety of engineered TCR-T cells.
Validation included assessing the affinity of the TCR by titrating cognate peptide antigens, and measuring the killing of a panel of HLA-I-matched tumor cell lines .
If no such tumor cell line exists, target cells can be transduced to express the relevant antigen and associated HLA-I molecules. Neoantigens can also be expressed in autologous antigen-presenting cells to assess the antigenic reactivity of TCRs.
Safety testing includes testing the ability of candidate TCR-Ts to recognize HLA-I-matched primary tissue to ensure that no normal tissue is targeted, resulting in possible off -target toxicity .
In at least two clinical trials of TCR-T cell therapy, cross-reactivity to normal brain and heart cells has occurred, resulting in patient death.
These trial results underscore the importance of extensive safety testing of TCRs before entering clinical trials.
Security of TCR-T
ACT of TCR-T cells has shown high tumor killing, but some serious adverse events have also been reported in some clinical studies.
Optimizing TCR affinity in engineered T cells is critical, and receptor affinity can determine the safety and efficacy of T cell therapy.
In terms of efficacy, affinity TCR interactions are sufficient to activate T cells, but strong affinity is required to maintain T cell expansion.
In phase I/II ACT clinical trials, low-affinity engineered T cells showed safer properties, but their antitumor responses were weaker.
By recognizing the TCR-pMHC interaction of T cells, engineered T cells can be divided into high-affinity and low-affinity types .
In addition, some techniques have also been developed to improve the security of TCR-T. Safety switch mechanisms based on engineered T cells are an attractive strategy.
The thymidine kinase gene derived from herpes simplex virus type I (HSV-TK) is one of the most common suicide genes.
Although HSV-TK has shown safety in cell-based immunotherapy, introduction of phosphorylated nucleoside analogs is required.
Another safer inducible T cell safety switch is called inducible caspase-9 (iC9) .
iC9 is a modified human FK-binding protein that can be activated by the small molecule compound AP1903, a process dependent on the mitochondrial apoptotic pathway.
The iC9 suicide gene was less immunogenic and elicited a reduced immune response against the transgenic cells. An iC9-based safety switch has been shown to have more potential for cell therapy than previous suicide genes.
Clinical status of TCR-T cell therapy
As of August 9, 2021, there are 175 ongoing studies using TCR-T therapy on ClinicalTrials, of which 71 are TAA-specific or neoantigen-specific TCRs, and 32 studies have been completed.
NY-ESO-1 is the most commonly targeted antigen and is expressed in a variety of cancers, including myeloma, melanoma, etc.
Other tumor testis-associated antigens, such as PRAME and MAGE proteins, as well as the melanoma differentiation antigens MART-1 and gp100, and more recently cancer drivers, such as WT1, KRAS, and TP53, are also popular TCR-T targets.
A total of 83 sponsors/collaborators initiated or participated in research on TCR-T cell therapy, including the National Institutes of Health (NIH) , government organizations, industry, and universities/academic institutions.
Currently, the National Cancer Institute (NCI) supports 53 TCR-T projects, accounting for 20% of all ongoing projects.
Of the 29 pharmaceutical companies developing TCR-T therapies, GlaxoSmithKline and Adaptimunime initiated the most clinical trials with 11 and 7, respectively.
Recently, a phase 1 clinical trial (NCT02858310) of TCR-T cells targeting human papillomavirus (HPV) -16 E7 protein in the treatment of metastatic HPV-associated epithelial carcinoma was reported .
In this study, 6 of 12 treated patients experienced objective clinical responses, with robust tumor regression observed.
This is a landmark clinical trial of TCR-T cell therapy, demonstrating that targeting viral antigens has favorable clinical outcomes in patients with virus-related cancers.
Other viral antigens explored as TCR targets include the HPV-E6 protein, antigens from Epstein-Barr virus (EBV) , and human endogenous retrovirus (HERV) targets such as HERV-E.
MART-1 and NY-ESO-1 TCR-T therapies targeting TAAs have also shown clinical efficacy in advanced melanoma, myeloma and non-small cell lung cancer.
The overall response rate (ORR) of completed TCR-T clinical trials was between 0 and 60%.
Notably, most of these TCR-T clinical trials enrolled only a small number of patients (2 to 25) , so the ORR may not be statistically accurate. Therefore, larger phase II and III clinical trials are needed to confirm the actual clinical efficacy of these TCR-T therapies.
Challenges and potential solutions of TCR-T cell therapy
Although TCR-T cell-based immunotherapy has shown some clinical efficacy in the majority of treated patients, it still faces many challenges in many fields.
These challenges include:
(1) immunotoxicity caused by targeting normal tissues;
(2) insufficient or transient TCR expression in engineered T cells ;
(3) T cell exhaustion and dysfunction;
(4) tumor immune escape ,
( 5) Most cancer patients lack effective tumor-specific antigens as targets.
Overcoming these challenges will be the key to greater clinical success in the future.
Discovery of new targets
Currently, there are very limited peptide antigen targets for effective and safe immunotherapy of TCR-T.
Most of the targets currently used are TAAs, which, although upregulated in tumor tissues, remain expressed at low levels in normal tissues, which may lead to autoimmune toxicity.
Therefore, neoantigens appear to be the safest targets for TCR-T cancer therapy.
However, the main challenges in the clinical development of neoantigens in TCR-T include:
(1) Neoantigen-forming mutations are largely individualized and vary among cancer patients, making it difficult to develop broadly applicable immunotherapies
(2) The expression of neoantigens in tumor tissues is often heterogeneous .
Nonetheless, reports in recent years have highlighted the emergence of immunogenic neoantigens that are widely shared by tumor cells, including mutated KRAS and TP53.
Numerous other studies have also demonstrated the immunogenicity of shared neoantigens that can be used to generate potentially therapeutic tumor-specific TCRs .
With the development of next-generation sequencing technologies, especially single-cell DNA sequencing, transcriptome sequencing, and well-established in vitro validation methods, TCR-T immunotherapy targeting personalized neoantigens may become a popular option in the next few years. Cancer treatment methods.
In addition, emerging TAA classes, such as carcinoembryonic antigens, may also constitute viable targets for future TCR-T development.
Maximize therapeutic TCR expression
The correct pairing of transgenic α and β chains is one of the major challenges hindering the development of TCR-T cells.
Since each transduced T cell includes two endogenous and two transformed TCR chains, heterodimers with unknown specificity can lead to potential autoimmune consequences.
Another related issue is that inappropriate α/β chain TCR pairing will compete for the CD3 complex , thereby reducing the surface expression and signaling of therapeutic TCRs.
There are several ways to properly pair the transduced TCR chains, including:
(1) the constant regions of partially murine TCRs ;
(2) the addition of cysteine residues to facilitate the introduction of disulfide bonds into the TCR chains;
( 3) Alter the secondary structure of the endogenous TCR constant region ;
(4) Add a signaling domain to the intracellular portion of the transduced TCR ;
(5) Introduce the TCR-α/β chain into surrogate effector cells or construct a single-chain TCR .
Methods to enhance therapeutic TCR expression include: (1) codon optimization of the TCR-α and TCR-β chain transgenes, and (2) changing the TCR-α/TCR-β vector configuration to optimize expression.
Reduce adverse events
Often, targeting non-tumor toxicity is a major key hurdle for TAAs, a risk that has prompted researchers to look more closely at common neoantigens.
Currently, multiple oncogene hotspot mutations are being investigated as potential TCR targets, such as phosphoinositide-3-kinase (PI3K) , KRAS and TP53 .
In addition, genetic engineering of TCR-T cells with suicide genes is an important safety measure employed.
Clearly, the development of individually identified, highly specific, and immunogenic tumor antigen targets is critical for reducing adverse events associated with TCR-T cell therapy.
Graft-versus-host disease with allogeneic T cells
The use of allogeneic T cells is a very promising option to overcome manufacturing problems, patient-related immune cell deficiencies, and treatment delays.
In order to use allogeneic T cells, it is necessary to control graft-versus-host disease caused by transduced alloreactive lymphocytes and the rejection of engineered lymphocytes by the host immune system.
Deletion of endogenous TCR genes, HLA-I sites, or CD52 molecules is one of the strategies to avoid TCR-T transplantation failure, which can be achieved by various methods, such as gene editing or the use of siRNA. In addition, pluripotent stem cell technology is also considered as a potential solution.
In recent years, engineered T cells have shown excellent efficacy in the treatment of hematological tumors .
TCR regulation is critical for the reactivation of T cells, immune responses and their clinical effects on foreign antigens .
TCR-T cells have incomparable advantages over CAR-T and show great potential in preclinical and clinical research.
However, several key challenges remain to improve the antitumor efficacy of TCR-T immunotherapy, including how to safely increase the affinity of therapeutic TCRs, how to identify shared tumor-specific antigens and TCRs in patient populations, and how to modulate TCR Express and achieve optimal functionality .
The solution of these problems will help to give full play to the potential of TCR-T cell therapy and bring hope to cancer patients to relieve their pain.
1.Engineered TCR-T CellI mmunotherapy in Anticancer Precision Medicine: Pros and Cons. Front Immunol. 2021;12: 658753.
2. Evolution of CD8+ T Cell Receptor(TCR) Engineered Therapies for the Treatment of Cancer. Cells. 2021 Sep;10(9): 2379.
What is TCR-T cell therapy different from CAR-T Immunotherapy?
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