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Car-t therapy for T cell malignancies
Source:fdmd Author:fdmd Follow:279 Time:2021-12-08
Author:fdmd Follow:279 Time:2021-12-08

Chimeric antigen receptor T cell (car-t) therapy has been widely used in the treatment of various types of recurrent / refractory (R / R) B-cell malignant tumors. At present, five car-t products have been approved by the U.S. Food and Drug Administration (FDA). Tisagenelecluel, axicabatagene ciloleucel and liscabatagene maraluel are three kinds of treatment for R / R diffuse large B-cell lymphoma (DLBCL) car-t product, brexucabatagene autoleucel, is used for the treatment of mantle cell lymphoma (MCL). In addition, ideabatagene vicluel is the latest car-t product targeting BCMA, which has been approved by FDA for the treatment of some multiple myeloma (mm).

However, despite all these clinical successes, car-t therapy still has limited response in some types of hematological malignancies and solid tumors. T-cell malignancy is one of the areas where car-t therapy has not yet produced good results. T-cell tumors include T-cell acute lymphoblastic leukemia (T-ALL), T-cell large granular lymphocytic leukemia (LGL), adult T-cell leukemia / lymphoma (ATL or ATLL), T-cell pre lymphocytic leukemia (T-PLL) and peripheral T-cell lymphoma (ptcls).

Compared with B-cell malignancies, First line cancer therapy for patients with T-cell malignancies (including chemotherapy) can only achieve limited clinical response, resulting in poor prognosis of such patients. Considering the clinical success of car-t therapy in B-cell malignancies, it is expected that car-t therapy can also improve the clinical results of patients with T-cell malignancies. However, car-t therapy for T-cell tumors is still quite challenging. The first challenge is the lack of T-cell tumor specificity Car-t target antigen, then cannibalism, T cell regeneration disorder and product pollution of malignant T cells during the production of autologous car-t are the most important challenges of car-t in the treatment of T-cell malignant tumors, which need further research.

Target antigens, cannibalism and Solutions


CD3

CD3 is a pan-t surface antigen that forms a complex with TCR, recognizes with the target antigen and leads to T cell activation. CD3 exists on all mature T cells, which makes the antigen a favorable target for immunotherapy of T cell malignant tumors. However, the use of CD3 as a car-t therapeutic target for T-cell malignancies may lead to adverse reactions due to cannibalism.

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Therefore, people try to produce anti cannibalism car-t cells or use other types of effector cells, such as NK cells, may eliminate the above problems to some extent. Genome editing methods can provide a variety of ways to destroy antigens that cause cannibalism. The modified car-t cells have specific and significant antitumor activity against primary T cells and childhood T-ALL samples.

In addition, other researchers also designed third-generation CD3 targeted cars and expressed them in NK cell line NK-92. Compared with T cells, NK cells lack CD3 expression and have a shorter life cycle. These car nks show antitumor activity against PTCL samples expressing CD3 and various T-cell leukemia cell lines.

CD5

CD5 is a transmembrane glycoprotein, which plays a role in the survival of human lymphocytes and is also a cellular component that negatively regulates TCR signal. Normal expression of CD5 was observed only in thymocytes, peripheral T lymphocytes and B lymphocyte subsets called B-1a cells. Abnormal expression of CD5 was detected in several T-cell malignancies, including T-ALL and PTCL.

In 2015, mamonkin et al designed CD5 redirected car-t and reported that these cells experienced partial and transient cannibalism and had specific antitumor activity. The researchers also expressed the third generation car in NK-92 cell line and proved that in addition to stable expansion in vitro, these car-nk also mediated specific and significant antitumor activity against human T-ALL, PTCL and primary CD5 + cells. In addition, the use of costimulatory domains of 4-1BB or 2B4 can significantly enhance the antitumor activity.

CD7

CD7 is a transmembrane glycoprotein from Ig superfamily, which is usually expressed on NK cells and T lymphocytes. Studies have shown that a high proportion of T-ALL and T-cell lymphoma CD7 are overexpressed.

However, the production of car-t targeting CD7 has been problematic because T cells themselves express CD7, which may lead to cannibalism and destruction of the expansion of car-t products. In 2017, Gomes Silva and his colleagues used crispr-cas9 to destroy CD7 expression in T cells and then convert it into car-t. this method not only did not have any negative impact on the tumor killing function of these car-t, but also improved their amplification efficiency. These car-t have unique antitumor activity against various CD7 expressing cell lines and T-ALL.

In the first human clinical trial of CD7 targeting car-t (nct04004637), the researchers used CD7 specific nanoparticles as the targeting domain of car-t. in addition, they used intelligent technology to prevent CD7 surface expression and subsequent cannibalism by retaining antigens in the endoplasmic reticulum and / or Golgi matrix. The results showed that these car t in 2 patients (66%) showed strong amplification and acceptable persistence, and in less than a month, these patients reported CR with negative minimal residual lesions (MRD), and abnormal T cells were not detected. However, different levels of cytokine release syndrome (CRS) and elevated IL-6 levels were observed in all patients. Other clinical trials (nct04033302 and nct03690011) are also testing the applicability and efficacy of CD7 targeted car-t in various types of T-cell malignancies.

CD1a

CD1a is a cell surface antigen on cortical T-ALL cells, and its specific expression was also observed in developing cortical thymocytes. T cells and CD34 + progenitor hematopoietic cells did not show CD1a expression. This characteristic of CD1a makes it a suitable target antigen, and its targeting can minimize the possibility of targeted non-tumor toxicity.

A research team explored car-t targeting CD1a. The study showed that in addition to cannibalism resistance, these car-t had strong tumor killing ability on T-ALL cell lines expressing CD1a and primary cells of cortical T-ALL samples. In addition, in vivo evaluation in the preclinical model of PDX showed that these effector cells showed persistence and considerable antitumor activity after administration.

CD4

There have been many studies on CD4 targeted car-t. In 2016, pinz et al. Studied the third generation CD8 + CD4 targeting car-t and reported that these cells showed unique antitumor activity against CD4 expressing cell lines and patient derived PTCL cell samples, while retaining their memory stem cell like phenotype.

In addition, in 2017, pinz et al. Generated the third generation CD4 targeted car-nk cells using NK-92 cell line. In an in vivo xenograft model, this CD4 targeted car nks mediates effective antitumor activity against malignant cells and prolongs survival time.

However, some researchers have pointed out that car mediated CD4 targeting in T-cell malignancies may lead to T-cell regeneration disorder and subsequent HIV / AIDS like syndrome. In this regard, Ma et al. Used alemtuzumab (a CD52 monoclonal antibody) as a natural safety switch to eliminate CD4 targeted car-t after administration to prevent T cell regeneration. However, the safety and effectiveness of CD4 targeted car-t in the treatment of T cell malignancies have not been confirmed in clinical trials, some of which have begun (nct03829540).

CD30

CD30, also known as tnfrsf8, is expressed after T cells and B cells receive activation signals stimulated by target antigens. CD30 is also expressed in various T-cell malignancies, including T-ALL and anaplastic large cell lymphoma (ALCL).

At present, CD30 targeted car-t is being studied at different stages of clinical trials. In 2017, A phase I dose escalation clinical trial (nct0136146) reported that 7 patients with R / R HL and 2 patients with ALCL received CD30 targeted second-generation car-t cells. No car-t-related toxicity was reported in the study. In addition, 2 of the 7 patients with HL in this study had CR (one case lasted more than 2.5 years and the other lasted about 2 years), 3 cases of SD. In addition, one of the 2 ALCL patients experienced CR lasting 9 months. In the same year, another clinical trial The report of (nct02259556) involved 18 patients with progressive R / R HL. The report showed that only 2 patients had severe toxicity, and the rest had good tolerance to car-t infusion. In terms of efficacy, 7 patients were in partial remission and 6 patients were in stable condition.

CD37

CD37 is a tetrapeptide leukocyte specific surface antigen expressed on mature normal and transformed B cells. CD37 also plays a regulatory role in T cell proliferation. CTCL and PTCL are T-cell malignancies in which CD37 expression was detected.

In 2018, scarf ò et al. Studied CD37 targeting car-t and reported that these cells mediated target antigen-dependent activation, cytokine secretion and tumoricidal activity against T-cell lymphoma in vitro without any obvious signs of cannibalism. The in vitro evaluation of this study involved cell lines such as hut78 and fedp and cell samples from patients with PTCL, all of which had different levels of CD37 expression. However, the study also pointed out that since not all PTCL cell lines or patient derived samples are CD37 +, it may be necessary to screen the expression of this antigen in future preclinical and clinical studies.

CCR4

CCR4 is a chemokine receptor expressed by normal T cell subsets, including regulatory T cells (Treg), Th2 and Th17 cells. In addition, overexpression of this chemokine receptor was detected in malignant T cells of patients with ATLL, PTCL and CTCL, including mycosis fungoides (MF) and s é zary syndrome (SS).

In 2017, Perera et al. Studied car-t targeted by CCR4, which can mediate effective target antigen dependent antitumor response against patient derived tumor cell lines expressing CCR4. In addition, it also showed antitumor activity in the xenograft model of adult T-cell leukemia. However, the expression of CCR4 on normal T cell subsets may lead to unexpected toxicity, which may require further in-depth evaluation.

Trbc1 and trbc2

Most ptcls are TCR +, and TCR has α Chain sum β Chain, T cell receptor β Constant region 1 (trbc1) and T cell receptor β Constant region 2 (trbc2) gene is responsible for TCR β Chain constant region expression. In the normal T cell population, there is a mixture of trbc1 expressing cells and trbc2 expressing cells. In contrast, the entire malignant T cell population will only express trbc1 or trbc2. Therefore, targeting trbc1 (in the case of trbc1 expressing T-cell malignancies) or targeting trbc2 (in the case of trbc2 expressing T-cell malignancies) can eliminate tumor T cells and partial expression targets β Normal T cells in the chain constant region, but it will not have any antitumor effect on most normal T cells.

Maciocia et al. Studied trbc1 targeted car-t, which mediated a specific antitumor response against malignant trbc1 + but not trbc2 + cells in vitro. An ongoing clinical trial (nct03590574) is testing the safety and efficacy of trbc1 targeted car-t therapy named auto4 in patients with trbc1 + T-cell non-Hodgkin's lymphoma (T-NHL), PTCL, angioimmunoblastic T-cell lymphoma (AITL) and ALCL.



T cell regeneration disorder and its solution


T cell aplastic anemia is the result of car-t targeting normal T cells. T cell aplastic anemia significantly increases the risk of various life-threatening infections. Therefore, the prevention of such adverse events is very necessary for successful car-t treatment in patients with T-cell malignancies.

The occurrence of T cell aplasia can be prevented by various strategies. One strategy is to select the target antigen. During car-t treatment, targeting the missing antigen on normal T cells or the antigen expressed on some T cells may keep at least a certain proportion of normal T cells intact. Another strategy is to use car-t with limited or controllable life or activity. Its limited antitumor effect helps to prevent the occurrence of T cell aplastic anemia. In addition, allogeneic hematopoietic stem cell transplantation (HSCT) after car-t treatment may also be another option to alleviate car-t related T cell regeneration disorders.


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Another suitable strategy to prevent T cell regeneration disorder is to equip cart with safety switch (also known as suicide switch) to control adoptive T cells after administration to patients. So far, different safety switch platforms have been introduced, including metabolic switch, monoclonal antibody dependent switch and inducible caspase (icasp) switches. Currently, several research teams are investigating the applicability of these safety switches in the clinical environment (nct02028455, nct03016377 or nct01815749).

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Car-t can be stably expressed in transduced T cells. These transduced T cells can expand in vivo while maintaining car expression. This open duration of car expression may lead to targeted non-tumor toxicity, such as impairment of T cell regeneration. Car-t generated using electroporation of carmrna into T cells showed limited persistence after administration. Two clinical trials (nct02277522 and nct02624258) investigated the application of non viral mRNA electroporation CD19 targeted car t in patients with R / R HL. According to the report, no signs of reaction and severe toxicity were observed during these trials. Considering that this method may help to reduce the targeted non-tumor toxicity of car-t treatment in patients with T-cell malignancies, it is speculated that continuous car-t administration may be required to obtain stable and reliable results Rely on your antitumor response.


Contamination of malignant T cells and Its Solutions


Since both normal and malignant T cells are isolated during T cell isolation, it is challenging to produce autologous T cells from patients with T cell malignancies. Autologous car-t is more likely to occur in patients with T-cell malignant tumors (especially in patients with T-cell leukemia with a high number of circulating malignant T cells).

In this case, the generation of allogeneic car-t from healthy third-party donors may be considered a suitable solution. However, allogeneic car-t also has their problems. For example, they may mediate life-threatening GVHD, and they may be quickly attacked and destroyed by the host's immune system. Both of these obstacles significantly weakened the antitumor activity of car ts. In this regard, researchers have developed allogeneic car-t to use various strategies to solve the above limitations. Importantly, compared with autologous car ts, allogeneic car ts have shorter in vivo persistence after infusion into patients, which helps to prevent T cell regeneration disorders.

Targeting CS1 and CD22 α and β Knockout allogeneic car-t is currently under clinical research for the treatment of mm (nct04142619) and B-ALL (nct04150497), respectively. The use of these methods helps to generate ready-made allogeneic car-t, which can be safely used in the clinical treatment of patients with T-cell malignant tumors.

Another strategy is to use multivirus specific T (multivst) cells as effector cells for car expression. These cells lack the expression of car target antigen through genetic engineering, so that they have the ability to fight each other. A clinical study (nct01570283) showed that multiple VST cells are safe and can mediate clinical response in immunocompromised recipients of allogeneic transplantation. The use of these T cells may be a suitable method to produce ready-made car-t.

γδ T cells account for 1% to 5% of circulating lymphocytes, which are ubiquitous in the skin, reproductive system and intestine. γδ This characteristic of T cells is very beneficial in adoptive cell therapy because αβ It is difficult for T cells to enter these sites. In addition, γδ T cells express chemokine receptors that interact with chemokines secreted by tumor cells γδ T cells are more likely to migrate to tumor sites, so these characteristics make γδ T cells become a suitable platform for car expression and allogeneic adoptive cell therapy.

In addition, NK cells can be used as reliable effector cells for car expression to reduce or eliminate the possibility of cannibalism. On the other hand, car expressing NK is not as persistent as traditional car-t, which can minimize the possibility of T cell regeneration disorder. Most importantly, NK based effector cells expressing car do not have TCR and do not cause GVHD.

小结


Car-t therapy for T-cell malignancies is one of the most complex and challenging fields in cancer immunotherapy. Compared with car-t therapy for B-cell malignant tumors, this field is full of difficulties due to antigen selection, cannibalism, T cell regeneration disorder and malignant T cell pollution.

However, many methods have been developed to solve these problems, including gene editing, the application of allogeneic car-t and car-nk will give us the opportunity to make a breakthrough in the cell therapy of T-cell malignant tumors. At the same time, more preclinical and clinical data are needed to verify the safety and effectiveness of these methods.



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