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Immunotherapy in Pediatric Brain Tumors: Comparison
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Please note this is a comparison between Version 2 by Bruce Ren and Version 1 by Wan-Tai Wu.

Immunotherapy, including chimeric antigen receptor (CAR) T-cell therapy, immune checkpoint inhibitors, cancer vaccines, and dendritic cell therapy, has been incorporated as a fifth modality of modern cancer care, along with surgery, radiation, chemotherapy, and target therapy. Among them, CAR T-cell therapy emerges as one of the most promising treatments. In 2017, the first two CAR T-cell drugs, tisagenlecleucel and axicabtagene ciloleucel for B-cell acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL), respectively, were approved by the Food and Drug Administration (FDA). In addition to the successful applications to hematologi-cal malignancies, CAR T-cell therapy has been investigated to potentially treat solid tumors, in-cluding pediatric brain tumor, which serves as the leading cause of cancer-associated death for children and adolescents.

  • chimeric antigen receptor (CAR) T cells
  • gene modified-based cellular platform
  • immunothera-py
  • pediatric brain tumor

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1. Introduction of Pediatric Brain Tumors

Primary malignant central nervous system (CNS) tumors, including medulloblastomas, ependymomas, astrocytomas, and germ cell tumors, serve as the second most common pediatric malignancies, just after hematological cancers [1]. Nevertheless, they last as a main reason of pediatric cancer-related death [2]. Among them, more than 90% are located in the brain, with an incidence of 1.12–5.14 cases per 100,000 children [3]. While the etiology of childhood brain tumors remains unclear, it has been proposed that genetic factors, environmental factors, family history, parental age at birth and cancer predisposition syndromes might be related [4].

Currently, surgical resection, chemotherapy, and radiotherapy are the major therapeutic strategies for pediatric brain tumors [5]. Even though chemotherapy and radiotherapy are more effective in pediatric patients with brain tumors than their adult counterparts [6], significant neurologic deficits and neurocognitive morbidities which impede future ability to live independently are concern [7]. Under these circumstances, immunotherapy, which only selectively destroys malignant cells expressing target antigen while leaving healthy tissues undamaged, may be a valuable therapeutic option. Chimeric antigen receptor (CAR) T-cell therapy, in particular, targeting tumor-specific antigens via genetically modified T cells, might be more useful for pediatric brain tumors, as they are well-known for the lack of high somatic tumor mutational burden [8,9].

Currently, surgical resection, chemotherapy, and radiotherapy are the major therapeutic strategies for pediatric brain tumors [5]. Even though chemotherapy and radiotherapy are more effective in pediatric patients with brain tumors than their adult counterparts [6], significant neurologic deficits and neurocognitive morbidities which impede future ability to live independently are concern [7]. Under these circumstances, immunotherapy, which only selectively destroys malignant cells expressing target antigen while leaving healthy tissues undamaged, may be a valuable therapeutic option. Chimeric antigen receptor (CAR) T-cell therapy, in particular, targeting tumor-specific antigens via genetically modified T cells, might be more useful for pediatric brain tumors, as they are well-known for the lack of high somatic tumor mutational burden [8][9].

2. Chimeric Antigen Receptor (CAR) T-Cell Therapy

CARs are artificially synthesized proteins which incorporate three major components: an extracellular tumor-specific antibody, an intracellular signaling motif, and a transmembrane domain serving as a bridge [10,11]. The outermost part is responsible for antigen targeting, as it possesses a single-chain fragment (scFv) purified from antibody that is specific for tumor antigens [12]. This part of CARs is responsible for being bound to tumor cells and triggering consequent T-cell activation and proliferation, and inaugurates cytokine release and cytolytic degranulation [13]. As for intracellular domain, it determines the strength, quality, and persistence of a T-cell response to tumor antigens [14], and it is frequently manipulated to enhance the potency of CAR T-cell therapy. To date, there are five generations of CARs being developed. The endodomain of the first generation of CARs comprises the CD3-ζ chain alone, with limited T-cell expansion and insufficient cytokine release [15]. Under this consideration, the second generation of CARs incorporated costimulatory domain, either CD28 [16,17] or 4-1BB [18], intracellularly, to ameliorate T-cell proliferation and persistence [19]. The third generation combined CD28 and 4-1BB [20,21], to further increase T-cell expression and persistence. Meanwhile there are two main immune systems, namely innate immune and adaptive immune in human body. Innate immune system, which serves as the first line of immune response and is antigen-independent, is thought to be helpful in adaptive T-cell therapy. Thus, another modulation combining innate immune response with CAR T cells was proposed. The recent fourth generation added cytokines, such as interleukin-12 (IL-12), to the endodomain of the second generation; they which could activate T cells, as well as natural killer cells, simultaneously, when encountering tumor cells [22]. A natural killer cell is capable of appealing cytokine cassette and inducing cytotoxicity against tumor cells [23]. This combination allows antigen-negative cancer cells to be eliminated concurrently. This mergence was termed T cell redirected for universal cytokine-mediated killing (TRUCKs) [19]. In this situation, tumor microenvironments are amended, and the lifespan of CAR T cells is prolonged. The clinical trials of this concept combining innate and adaptive immunity are still in cradle [24]. By synchronous installation of IL-2 receptor and binding site for the transcription factor STAT3 to the endodomain, vigorous JAK–STAT3/5 cytokine, cascade can be instigated in local tumor environment and thus minimizes systemic inflammation [25] (Figure 1). The contemporary protocol of CAR T-cell therapy adopted autologous T cells (Figure 2).

2. Chimeric Antigen Receptor (CAR) T-Cell Therapy

CARs are artificially synthesized proteins which incorporate three major components: an extracellular tumor-specific antibody, an intracellular signaling motif, and a transmembrane domain serving as a bridge [10][11]. The outermost part is responsible for antigen targeting, as it possesses a single-chain fragment (scFv) purified from antibody that is specific for tumor antigens [12]. This part of CARs is responsible for being bound to tumor cells and triggering consequent T-cell activation and proliferation, and inaugurates cytokine release and cytolytic degranulation [13]. As for intracellular domain, it determines the strength, quality, and persistence of a T-cell response to tumor antigens [14], and it is frequently manipulated to enhance the potency of CAR T-cell therapy. To date, there are five generations of CARs being developed. The endodomain of the first generation of CARs comprises the CD3-ζ chain alone, with limited T-cell expansion and insufficient cytokine release [15]. Under this consideration, the second generation of CARs incorporated costimulatory domain, either CD28 [16][17] or 4-1BB [18], intracellularly, to ameliorate T-cell proliferation and persistence [19]. The third generation combined CD28 and 4-1BB [20][21], to further increase T-cell expression and persistence. Meanwhile there are two main immune systems, namely innate immune and adaptive immune in human body. Innate immune system, which serves as the first line of immune response and is antigen-independent, is thought to be helpful in adaptive T-cell therapy. Thus, another modulation combining innate immune response with CAR T cells was proposed. The recent fourth generation added cytokines, such as interleukin-12 (IL-12), to the endodomain of the second generation; they which could activate T cells, as well as natural killer cells, simultaneously, when encountering tumor cells [22]. A natural killer cell is capable of appealing cytokine cassette and inducing cytotoxicity against tumor cells [23]. This combination allows antigen-negative cancer cells to be eliminated concurrently. This mergence was termed T cell redirected for universal cytokine-mediated killing (TRUCKs) [19]. In this situation, tumor microenvironments are amended, and the lifespan of CAR T cells is prolonged. The clinical trials of this concept combining innate and adaptive immunity are still in cradle [24]. By synchronous installation of IL-2 receptor and binding site for the transcription factor STAT3 to the endodomain, vigorous JAK–STAT3/5 cytokine, cascade can be instigated in local tumor environment and thus minimizes systemic inflammation [25] (Figure 1). The contemporary protocol of CAR T-cell therapy adopted autologous T cells (Figure 2).
Ijms 22 02404 g001 550

Figure 1. Five generations of chimeric antigen receptor (CAR) T-cell therapy. The blue cloudy shape in the middle symbolizes tumor cells with tumor antigens. The tumor is circled by five generations of CAR T cells. The five generations of CAR T-cell therapy are sequentially placed in clockwise direction. Gray Y type represents antigen-binding domains. The green shadow symbolizes intracellular space. The transmembrane domain serves as a bridge between the ectodomain and the endodomain. The first generation only contains CD3ζ as an intracellular domain, which is the sky-blue box in the figure. CD28 or 4-1BB is then added, to generate the second generation. The third generation consists of both CD28 and 4-1BB motifs. Genes encoding cytokines including IL-12 or IL18 are tethered to the intracellular domain, to develop the fourth generation. The fifth generation comprises the IL-2 receptor and binding site for the transcription factor STAT3, in order to induce cytokine storm.

Five generations of chimeric antigen receptor (CAR) T-cell therapy. The blue cloudy shape in the middle symbolizes tumor cells with tumor antigens. The tumor is circled by five generations of CAR T cells. The five generations of CAR T-cell therapy are sequentially placed in clockwise direction. Gray Y type represents antigen-binding domains. The green shadow symbolizes intracellular space. The transmembrane domain serves as a bridge between the ectodomain and the endodomain. The first generation only contains CD3ζ as an intracellular domain, which is the sky-blue box in the figure. CD28 or 4-1BB is then added, to generate the second generation. The third generation consists of both CD28 and 4-1BB motifs. Genes encoding cytokines including IL-12 or IL18 are tethered to the intracellular domain, to develop the fourth generation. The fifth generation comprises the IL-2 receptor and binding site for the transcription factor STAT3, in order to induce cytokine storm.

Ijms 22 02404 g002 550

Figure 2. Protocol of CAR T-cell therapy: (1) T cells are gathered from patient. (2) CAR structure is engineered into the collected T cells. (3) The modified CAR T cells are augmented to sufficient amounts. (4) CAR T cells are infused back into the patient via either catheter into intratumor cavity or intraventricular, or through peripheral infusion.

Protocol of CAR T-cell therapy: (1) T cells are gathered from patient. (2) CAR structure is engineered into the collected T cells. (3) The modified CAR T cells are augmented to sufficient amounts. (4) CAR T cells are infused back into the patient via either catheter into intratumor cavity or intraventricular, or through peripheral infusion.

3. Application of CAR T-Cell Therapy, from Hematological Malignancies to Pediatric Brain Tumors

In 2012, the first child received CD19-targeted CAR-T therapy for her relapsed B-cell acute lymphoblastic leukemia exhibited complete remission and no refractory or relapse for more than five years [26]. This finding opened up a new era of CAR-T therapy for malignancies. Afterwards, several studies demonstrated promising response, ranging from 60% to 93% complete remission rate, with minimal residual disease (MRD)-negative of CAR-T therapy for pediatric hematological malignancies [27–30]. The first CAR-T therapy, tisagenlecleucel, was approved by the FDA in August 2017 for refractory or relapsed acute lymphoblastic leukemia in patients younger than 25 years old [31–33]. In October of the same year, axicabtagene ciloleucel was approved for refractory or relapsed diffuse large B-cell lymphoma as well [34]. These striking successes may be due to specific homogeneous tumor target antigens in B-cell lineages [35]. With the encouraging results in hematological malignancies, CAR-T therapy was used to treat a variety of solid tumors. However, the response to solid tumors was not as effective as that of hematological malignancies [36]. The possible reasons include heterogeneous and low specific target antigen expression on tumor surface, insufficient CAR T cells traveling to and infiltrating into the tumor, limited T-cell expansion, and poor persistence because of the immunosuppressive tumor microenvironment [35,37]. Brain tumors are notorious for their immunosuppression environment, possibly due to the unique composition of the extracellular matrix; distinctive tissue-resident cell types, such as astrocytes, which are known to blunt cytotoxicity; and a natural inflammation shelter/blood–brain barrier (BBB) [38]. Furthermore, possible on-target off-tumor toxicity of CAR-T therapy may reduce the cytotoxic effect on tumor cells and may increase potential treatment-related toxicities on normal tissues [39]. Nevertheless, several clinical and preclinical studies have shown favorable efficacy in solid tumors, especially anti-carcinoembryonic antigen (CEA) therapy, including CD3ζ, CD28–CD3ζ, and locally administered CAR T cells [40].

Zhang et al. demonstrated that 7 of 10 patients with metastatic colorectal cancer refractory to standard treatments became stable disease (SD) from progressive disease (PD) after undergoing treatment with CAR T cells [41]. Thistlethwaite and her colleagues also reported that 7 of 14 relapsed and refractory metastatic gastrointestinal patients achieved stable disease and persisted for six weeks after CAR T-cells infusion. One of the patients even stayed alive for 56 months [42]. In other kinds of malignancies, such as high-risk osteosarcoma, Chulanetra et al. proved that CAR T cells have synergistic effect with doxorubicin on eliminating tumor cells of osteosarcoma [43]. Some patients developed transient side effects such as acute respiratory toxicity, but no severe irreversible toxicity was observed in patients underwent treatment [44]. The outcomes of these abovementioned trials support the efficacy and safety of the CAR-T therapy. Therefore, more and more clinical trials aim to achieve the promising results of application in pediatric solid tumors, especially brain tumors [45–48]. Though medical technology has improved largely in the past few decades, treatments for brain tumors are still disappointing [49,50]. Highly specific and personalized treatments such as CAR T-cell therapy offer an opportunity to fight against pediatric brain tumors [51].

CAR T cells against tumor-specific antigens, including epidermal growth factor receptor variant III (EGFRvIII), human epidermal growth factor receptor 2 (HER2), and interleukin 13 receptor alpha 2 subunit (IL13Rα2) of glioblastoma (GBM), were under clinical studies to collect data about their safety and feasibility in recent years. The routes of administration, such as intravenous and intratumor infusion, were also evaluated in these researches. Meanwhile, many preclinical trials are also being conducted to find out more possibilities of CAR T-cell therapy in pediatric brain tumors. Further details are discussed below.

3. Application of CAR T-Cell Therapy, from Hematological Malignancies to Pediatric Brain Tumors

In 2012, the first child received CD19-targeted CAR-T therapy for her relapsed B-cell acute lymphoblastic leukemia exhibited complete remission and no refractory or relapse for more than five years [26]. This finding opened up a new era of CAR-T therapy for malignancies. Afterwards, several studies demonstrated promising response, ranging from 60% to 93% complete remission rate, with minimal residual disease (MRD)-negative of CAR-T therapy for pediatric hematological malignancies [27][28][29][30]. The first CAR-T therapy, tisagenlecleucel, was approved by the FDA in August 2017 for refractory or relapsed acute lymphoblastic leukemia in patients younger than 25 years old [31][32][33]. In October of the same year, axicabtagene ciloleucel was approved for refractory or relapsed diffuse large B-cell lymphoma as well [34]. These striking successes may be due to specific homogeneous tumor target antigens in B-cell lineages [35]. With the encouraging results in hematological malignancies, CAR-T therapy was used to treat a variety of solid tumors. However, the response to solid tumors was not as effective as that of hematological malignancies [36]. The possible reasons include heterogeneous and low specific target antigen expression on tumor surface, insufficient CAR T cells traveling to and infiltrating into the tumor, limited T-cell expansion, and poor persistence because of the immunosuppressive tumor microenvironment [35][37]. Brain tumors are notorious for their immunosuppression environment, possibly due to the unique composition of the extracellular matrix; distinctive tissue-resident cell types, such as astrocytes, which are known to blunt cytotoxicity; and a natural inflammation shelter/blood–brain barrier (BBB) [38]. Furthermore, possible on-target off-tumor toxicity of CAR-T therapy may reduce the cytotoxic effect on tumor cells and may increase potential treatment-related toxicities on normal tissues [39]. Nevertheless, several clinical and preclinical studies have shown favorable efficacy in solid tumors, especially anti-carcinoembryonic antigen (CEA) therapy, including CD3ζ, CD28–CD3ζ, and locally administered CAR T cells [40].

Zhang et al. demonstrated that 7 of 10 patients with metastatic colorectal cancer refractory to standard treatments became stable disease (SD) from progressive disease (PD) after undergoing treatment with CAR T cells [41]. Thistlethwaite and her colleagues also reported that 7 of 14 relapsed and refractory metastatic gastrointestinal patients achieved stable disease and persisted for six weeks after CAR T-cells infusion. One of the patients even stayed alive for 56 months [42]. In other kinds of malignancies, such as high-risk osteosarcoma, Chulanetra et al. proved that CAR T cells have synergistic effect with doxorubicin on eliminating tumor cells of osteosarcoma [43]. Some patients developed transient side effects such as acute respiratory toxicity, but no severe irreversible toxicity was observed in patients underwent treatment [44]. The outcomes of these abovementioned trials support the efficacy and safety of the CAR-T therapy. Therefore, more and more clinical trials aim to achieve the promising results of application in pediatric solid tumors, especially brain tumors [45][46][47][48]. Though medical technology has improved largely in the past few decades, treatments for brain tumors are still disappointing [49][50]. Highly specific and personalized treatments such as CAR T-cell therapy offer an opportunity to fight against pediatric brain tumors [51].

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