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Future prospect of car T cells in the treatment of solid tumors
Source:fdmd Author:fdmd Follow:306 Time:2021-12-08
Author:fdmd Follow:306 Time:2021-12-08

We have discussed the importance of T cell composition for lymphoma / solid tumor patients and the use of car T cell products. Importantly, it is possible to indirectly regulate T cell composition by using optimized extension protocols. Schmueck henneresse et al. It is reported that IL2 (including yescarta) is widely used in clinical car-t proliferation ® And kymriah ®) In contrast, the combination of il7 and IL15 increased the production of car T cells derived from TSCM and TCM [95]. In addition, a recent study by vodnala et al. Reveal that til dysfunction caused by caloric restriction and increased K + concentration in tumors leads to reduced T cell activation and differentiation [30]. The authors used this tumor mediated mechanism to demonstrate that T cells pretreated in vitro at high K + concentration subsequently maintained a less differentiated phenotype in vivo. The persistence of these T cells in the tumor is also better than that of unregulated cells, thus prolonging the survival time and better tumor regression in the mouse model of melanoma. Other strategies to limit cell differentiation include pharmacological blocking of inositol phosphate 3-kinase (PI3K) or shortening the duration of amplification in vitro [121].



Car T cell product design


The idea of double antigen targeting, especially in solid tumors, has long been regarded as a very promising and effective treatment.

Hurd et al. Solved the problem of the optimal number of simultaneously targeted antigens, and studied human epidermal growth factor receptor 2 (HER2) and il13r α 2 and EphA2 antigen expression in tumor samples obtained from glioblastoma patients [122]. The authors confirmed that HER2 and il13r were targeted in series α 2 antigen and autologous car T cells reduced the escape of tumor antigen and had a significant positive effect on tumor elimination in vitro and in vivo, while the addition of the third antigen did not have any significant effect. Beneficial effects. In addition, they confirmed that anti-HER2 and anti-il13r were expressed simultaneously compared with mixed cells expressing car alone α 2 the bispecific car T cells of car provide more lasting activity. The authors further reported a tandem car outer domain, tancar, with HER2 binding domain and il13r α 2 combinatorial structural features of binding domains [123]. Compared with the above mixed and bispecific car T cells, these tancar cells resulted in higher cytokine release and tumor cell lysis intensity and prolonged mouse survival. Interestingly, the expression of T cell depletion marker (PD-1), lymphocyte activating gene 3 (Lag3) and T cell receptor (TCR) inhibitory molecule 3 (tim3) on tancar cells and bispecific car - may lead to ts with higher clinical potential.

The primary problem is the optimal design of car itself and the enhancement of immune synapse between car and tumor specific target antigen. For example, scFv affinity, hinge and spacer length may affect car T cell activity [124], as further discussed below.

In addition, the concept of T cells with synthetic notch (synnotch) receptors introduced by Roybal et al. It is proved that T cells are transformed into "soldiers" with a fully customized response to the target antigen [125]. This includes cytokine release, T cell differentiation, or local delivery of unnatural therapeutic payloads, such as antibodies.


Promising combination methods


Generally, tumors have a unique combination of driving mechanisms, including TGF caused by a series of immune checkpoints β Dependent T cell depletion and local microenvironment (e.g. tumor phase M2 macrophages). In this case, a promising solution is to use car T cells with anti-tumor specific effects or their combination with other therapies. Some modifications can enhance the anti-tumor weapons of car T cells, such as the expression of dominant inactivated receptors that block inhibitory signal transduction in T cells, such as TGF β [126] or PD-1 [127].

Car T cells based on prostate specific membrane antigen (PSMA) and dominant negative TGF in patients with R / R metastatic prostate cancer β Receptor II (TGF β Phase I clinical trial of RII co expression is in progress (nct03089203).

Other advanced car-t strategies include the release of costimulatory molecules [128] and cytokines [129]. A more flexible option is to combine car T cells with a range of Ci, antibodies or kinase inhibitors. Unfortunately, so far, TME modified drugs are only represented by a few clinically available CIS, such as anti-PD-1 / pd-l1nivolumab, pembrolizumab, cemiplimab, atezolizumab) and anti-CTLA4 (ipilimumab).

A series of novel cis, such as anti-lag3 (imp321 / immunotep) ®), Research is being conducted in phase I or phase II clinical trials [22]. The other is based on anti-PD-1 and anti TGF β The combination therapy is being tested for the treatment of advanced lung cancer / hepatocellular carcinoma (NCT02423343) and metastatic pancreatic cancer (NCT02734160) [130]. Plerixafor is an anti TAM drug which causes almost all the malignant cells in the pancreatic cancer mouse model to disappear. [33] is currently being evaluated in patients with pancreatic cancer, ovarian cancer and colorectal adenocarcinoma (NCT02179970, NCT03277209). Finally, the above synnotch T cells can be administered in combination with conventional T cells to regulate the tumor microenvironment [125].

We should emphasize that the clinical validation of new car-t therapies is crucial because the intercellular interaction between tumors and a fully functional human immune system is not always reproduced in immunocompromised animal models.

In fact, attempts to inhibit the VEGF pathway were made in a preclinical environment by using a combination of anti VEGF bevacizumab and anti gD2 car T cell therapy, which resulted in prolonged survival of SCID / beige mice (orthogonal xenograft model of human neuroblastoma) [131].

However, the combination of bevacizumab and standard treatment lomustine, although no immunotherapy, did not demonstrate improved survival in patients with R / R glioblastoma [79]. Similarly, bevacizumab combined with chemotherapy has not achieved positive results in lymphoma patients [75]. Other preclinical successful therapies, such as truck expressing IL12 [132], showed unexpected toxicity and lack of therapeutic effect after clinical transformation (nct01236573, nct01457131), which eventually led to the termination of clinical trials.


Universal car T cells


The limited clinical availability of car-t therapy is due to high cost, time-consuming manufacturing and production failure, which together make the concept of universal car-t (ucar-t) particularly attractive. In 2017, Qasim et al reported that two infants with recurrent all were treated with anti-CD19 UCAR ts and genetically engineered through transcription activator like effector nuclease (talen) to destroy TCR α Expression of chain (prevention of graft-versus-host disease, GVHD) and CD52 (prevention of rejection) [133]. Children were still in CR 12 and 18 months after treatment. Similarly designed anti-cd123 ucar-t is currently being studied in patients with refractory AML in phase I clinical trials [134].

Celyad Inc. used a different approach to develop two car T cell products with natural killer receptors (NKR) (allogeneic cyad-101 and autologous cyad-01), which target a series of ligands expressed in various cancers. The important feature of cyad-101 is the expression of inhibitory peptide T cell receptor (TCR) inhibitory molecule (TIM), which can reduce TCR signal transduction, So as to reduce the possibility of GVHD. These products are now being studied in phase I clinical trials.

In the alloshrink trial (colorectal cancer, cyad-101), 2 of 12 patients achieved partial remission (PR) and 5 achieved SD [135]. In the think test (AML, cyad-01), 6 of 13 patients obtained ANTI LEUKEMIA activity [136]. Neither car T cell product reported significant toxicity.

Allogeneic car T cell therapy may face major obstacles on the road to successful clinical application. The main challenge is to achieve prolonged car T cell persistence without continuous consumption of patient immune cells described by Qasim et al. [133]。 The method of destroying human leukocyte antigen (HLA) expression in car T cells is basically limited by NK and NKT cells that may eliminate HLA negative cells. Additional modifications to HLA-H, HLA-E, or HLA-G expression are needed to protect therapeutic cells from host NK.

Taylor et al. Proposed a similar concept, that is, a "universal" stem cell bank for artificial solid organ transplantation. He confirmed in bioinformatics that 150 homozygous HLA volunteers covered 93% of the UK population and fully matched donor tissues [137]. Theoretically, selective consumption of HLA-A and HLA-B while retaining HLA-C on car T cells may limit the basic pool of allogeneic "off the shelf" cell products to dozens or even fewer. Nevertheless, small histocompatibility antigens (mihags) [138] are derived from an almost infinite diversity of single nucleotide polymorphisms (SNPs) in donors and patients [139]. These antigens can lead to GVHD (in hematopoietic stem cell transplantation) or transplantation rejection (in solid organ recipients) and may also limit the persistence of allogeneic car T cells.






The main feature of car T cells is its HLA independent mechanism of action, but car can not provide a panacea because of the limited number of tumor specificity and tumor associated antigens. Paradoxically, the limitation of TCR based therapy lies in HLA dependence, Although balanced by an almost unlimited number of potential target antigens (Fig. 1). Mutations usually occur in intracellular proteins, and then a large number of related antigenic peptides are presented by HLA [58] , so that these tumor cells can not be directly targeted by car T cells. To support this, it is reported that the high immunogenicity of p53 mutant tumors can be explained by HLA mediated presentation of mutant p53 derived new antigens [140]. Oncogenic p53 mutations are prevalent in different types of human cancers, resulting in poor prognosis, and the potential clinical utility of TCR mediated p53 targeting is emphasized.

Laumont et al analyzed the abundance of new antigens derived from the noncoding region of the human genome / alternative reading frame (RF) and predicted that their number was much higher than that of antigens derived from the canonical RF of the known protein coding region [141]. The protein coding region accounts for only about 2% of the human genome, while the transcriptome covers about 75%, including "non protein coding" transcripts that are still translated [142143]. Considering that 99% of gene mutations are located in those so-called noncoding regions, the number of potential new antigens is expected to be high even in tumors with low TMB.


转载分享:CAR T 细胞治疗实体瘤的未来展望(图1)


Harris et al. Designed two single chain TCRs for T cell 1 (mart1) / HLA-A2 or Wilms tumor protein (WT1) / HLA-A2 and their recognized melanoma antigens, and directly compared TCR and car based treatment methods in vitro to recognize the car of these antigen / HLA complexes [114].

Despite higher surface expression, car (CD3 ζ  Or CD3 ζ/ CD28) is still 10 to 100 times less sensitive than TCR to its matched peptide / HLA-A2 complex. These findings raise the potential of using car T cells to target antigens that are highly expressed in tumors and low expressed in healthy tissues.

However, case reports of fatal toxicity caused by the effect of car T cells on healthy tissues with low antigen expression suggest that cars must be designed with extreme caution to avoid disproportionate sensitivity problems [144]. Parameters to be considered include the nature of the recognition domain (TCR derived or antibody derived) and its regulation of antigenic affinity [124], and the length of the non signal spacer [8,9]. Considering the relative surface density of tumor antigens, car-t seems to have a higher activation threshold (about 200 antigens per tumor cell) than T cells (1-4 antigen HLA complexes per tumor cell) [124]。 Intelligent solutions to potential toxicity problems involve suicide genes that can be controllably activated in vivo and lead to the safe elimination of car-t cells in patients [145]. It is speculated that car T cells can be administered in combination with traditional T cells and NKR T cells, and double / triple target HLA positive and HLA negative cells to completely eliminate tumors.






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