Chimeric Antigen Receptor: History
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Contributor:
Piamsiri Sawaisorn
,
Korakot Atjanasuppat
,
Usanarat Anurathapan
,
Somchai Chutipongtanate
,
Suradej Hongeng

Chimeric antigen receptors (CARs) are among the curative immunotherapeutic approaches that exploit the antigen specificity and cytotoxicity function of potent immune cells against cancers. Neuroblastomas, the most common extracranial pediatric solid tumors with diverse characteristics, could be a promising candidate for using CAR therapies. Several methods harness CAR-modified cells in neuroblastoma to increase therapeutic efficiency, although the assessment has been less successful. Regarding the improvement of CARs, various trials have been launched to overcome insufficient capacity. However, the reasons behind the inadequate response against neuroblastoma of CAR-modified cells are still not well understood. It is essential to update the present state of comprehension of CARs to improve the efficiency of CAR therapies.

  • CAR T cells,immunotherapy,pediatric neuroblastom

1. Introduction

Neuroblastoma, an extracranial solid tumor that initiates from the sympathetic nervous system’s neuroendocrine tissue, is one of the most common causes of death in pediatric cancers [1][2]. It is often diagnosed during the perinatal period, which accounts for 8% in patients under 15 years. This childhood neoplasm appears each year in more than 600 cases in the United States and 200 in Japan [3][4][5]. According to clinical presentation, neuroblastoma is an extremely variant characteristic tumor. It ranges from an adrenal mass tumor that regresses without treatment to a metastatic tumor that causes critical illness [6]. At present, while intensive therapies can be beneficial for patients with localized disease, these therapies have frequently not been useful against patients with high-risk disease (approximately 40% of cases associated with the extent of metastases and genetic factors) nor patients with relapse [7][8]. Hence, novel therapies based on immunotherapy were subsequently developed to improve survival for high-risk patients.

One such approach is treatment with anti-GD2 monoclonal antibody, which has already been assessed in a Phase III clinical trial. The use of this antibody-based therapy was compiled into a therapeutic protocol for high-risk neuroblastoma patients and revealed promising results [9][10]. This effectiveness has led to other immunotherapeutic approaches, even though their integration into conventional multimodality therapies requires further investigation.

After discovering that GD2, a disialoganglioside highly expressed in most neuroblastomas, is also targeted by T cells, cellular immunotherapies including genetic engineering of T lymphocytes to express anti-GD2 chimeric antigen receptors (CARs) have emerged and are now being studied. With the combination of antigen specificity and cytolytic capacity, anti-GD2 CAR T cells have demonstrated safety and antitumor efficacy in relapsed neuroblastoma patients [11][12]. Various preclinical studies have improved the antitumor effects, proliferation, and cytokine release of CAR T cells, and some approaches have reached clinical trials. Currently, the anti-GD2 CAR T cell approach might represent a potential therapeutic for pediatric neuroblastoma.

2. CARs in Neuroblastoma

The knowledge of tumor immunology has been used in translating this comprehension into productive cancer therapies. A number of immunotherapy approaches represent a new borderline in treating cancers. One such strategy to overcome tolerance in cancer is to genetically engineer immune cells to express CAR. This concept of artificial antigen-specific receptors first originated in 1989–1993 [13][14]. By fusing an antibody-derived binding domain to T cell signaling domains, the CAR construct gains the tumor antigen specificity and the capacity to induce multiple signals in the response of immune cells. Over three decades, tremendous progress has been made and CARs were refined into the first, second, third, and currently fourth generations of their structure. Based on the potential of CAR T cells directed against the CD19 protein for treatment of hematologic malignancies shown in clinical trials, cancer immunotherapy was named the “Breakthrough of the Year” in 2013 by Science [15]. In addition, the use of anti-CD19 CAR T cells for relapsed/refractory acute lymphoblastic leukemia and in children and young adults was approved by the US Food and Drug Administration (FDA) in 2017 and two licensed products of CAR T cells including tisagenlecleucel and axicabtagene ciloleucel have been launched [16][17]. This success, therefore, has brought new insights for clinical translation in treating solid cancers.

CARs have been developed to fulfill the applicability of adoptive cellular immunotherapy for neuroblastoma in a major histocompatibility complex (MHC)-unrestricted manner in effector T cells. Effector immune cells, commonly T lymphocytes, have been genetically engineered to express an extracellular antigen-binding domain that is mostly a single-chain variable fragment (scFv) joined with a transmembrane domain and an intracellular signaling domain. The first-generation CARs were designed to have a single CD3-ζ intracellular signaling domain. The second- and third-generation CAR products were improved by adding one or two costimulatory endodomains to the CD3-ζ motif to achieve the optimal activation and survival of CAR cells. Current intracellular endodomains based on the costimulatory receptors include CD27, CD28, 41BB, ICOS, and OX40 [18][19]. Each of the CAR design components reflects the variations of therapeutics achievement, and novel CAR engineering has been developed for decades to broaden CAR therapeutics in solid tumors like neuroblastoma [20].

2.1. Summary of CAR Experience

Several CAR approaches in neuroblastoma have been developed according to discovered putative cancer antigens. There are some novel target antigens for CAR T cell therapy in neuroblastoma that have been investigated in the preclinical phase (Figure 1).

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Figure 1. Target antigens conducted on the safety and efficacy of CAR therapy for neuroblastoma. Six surface antigens of neuroblastoma, including L1-CAM, GPC2, NCAM, GD2, ALK, and B7H3, are under development and investigation. L1-CAM and GD2 are the only two target antigens currently in completed clinical trials for neuroblastoma (labeled with star).

Anaplastic lymphoma kinase (ALK), an oncogene expressed in neuroblastoma cells, is associated with familial neuroblastoma cases [21][22]. Anti-ALK CAR has demonstrated its effectiveness against this neuroblastoma subtype in vitro and in vivo [23][24]. This line of research also suggested that antigen density must be considered to achieve CAR T cell potential. Another tyrosine kinase receptor that may be rendered an ideal target for CAR therapies is glypican 2 (GPC2). The high expression of GPC2 on the neuroblastoma cell surface brought promising clearance of disseminated neuroblastoma in the mouse model by anti-GPC2 CAR T cells [25]. B7H3 (CD276), a checkpoint molecule expressed in neuroblastomas, is another candidate for CAR therapies of neuroblastoma [26][27]. This attractive target brought useful immunotherapeutic strategies, including monoclonal antibodies and CARs targeting B7H3. Recently, the efficacy of anti-B7H3 CAR has been demonstrated in vivo [28][29]. Many target antigens that are specific to neuroblastoma cells have also been more characterized. Such antigens, including neural cell adhesion molecule (NCAM or CD56), New York esophageal squamous cell carcinoma 1 (NY-ESO1), and preferentially expressed antigen in melanoma (PRAME), were investigated both in vitro and in vivo for safety and efficacy, which gained attention for further development as CAR features [30][31][32][33].

To date, only CAR T cells targeting L1-CAM (CD171) and GD2 have reached the early phase of clinical trials. L1-CAM, an adhesion molecule in the immunoglobulin superfamily, is another suitable target in neuroblastoma [34]. Because of the specificity of CE7, the monoclonal antibody that can bind to the L1-CAM epitope, the anti-L1-CAM CAR with the scFv from CE7 was generated. The first-generation anti-L1-CAM CARs’ efficacy and safety were investigated in patients with relapsed/refractory neuroblastoma in a Phase 1 clinical trial [12]. To augment the persistence of anti-L1-CAM CAR, second-generation CAR was generated using a 41BB costimulation domain, followed by third-generation CAR, including CD28 costimulation addition, which is currently being investigated in phase 1 clinical trials [35][36]. Until now, the most critical target antigen in neuroblastoma has been GD2, a disialoganglioside highly expressed on neuroblastoma tissue [37]. Owing to the presence of this antigen during chemotherapy and the success of anti-GD2 monoclonal antibody therapy, this antigen has been the most studied targeted for CAR T cell therapy in neuroblastoma [38]. Many approaches of first-generation anti-GD2 CAR have been reported, including anti-GD2 CAR containing a single-chain variable fragment (scFv) derived from 14g2a monoclonal antibody or Epstein–Barr virus-specific cytotoxic T cell transduced CARs (so-called GD2 CAR-CTL), with the knowledge that the prolonged persistence in vivo was associated with the costimulation domain of CAR [39][40][41][42]. Anti-GD2 CAR constructs are now considered on costimulatory endodomains. The second and third generations of CAR were then generated for in vitro and in vivo assessments of CAR T cell survival [43][44]. The third-generation anti-GD2 CAR, containing an inducible caspase 9 (iC9) safety switch, has been tested in clinical trials for its safety (clinicaltrials.gov identifier NCT01953900 and NCT01822652). Various clinical trials based on CAR therapy are underway to augment the reliable therapeutic outcomes. However, improving the efficacy and persistence of CAR is still a significant issue.

2.2. Obstacles to Using CARs in Neuroblastoma

2.2.1. CAR T Cell Persistence and Exhaustion

Restrictive CAR T cell persistence has occurred as a major problem in neuroblastoma. Evidence from the first generation of CAR studies in vivo and clinical trials suggested that the limited persistence of CAR T cells from low activation and proliferation of cells also affected the antitumor efficacy [45][43][46][47]. One clinical study demonstrated that the infused, first-generation, anti-L1-CAM CAR cells were detectable in the peripheral blood up to 1–7 days after adoptive transfer in most patients with bulk disease but significantly longer (42 days) in a patient with limited disease burden [12]. T cell exhaustion might be a significant cause of shortening persistence. This is confirmed by discovering the exhausted CAR T cell phenotype in GD2 CAR T cells with low-level tonic signaling [48]. The persistence of infused CAR T cells might be prolonged if the exhaustion was reduced. Thus, several methods have been proposed to increase the persistence of CAR T cells. One such way is the utilization of second- and third-generation CARs, which improve costimulation after antigen binding (e.g., 4-1BB costimulatory domain) to protect shortened persistence. This development is under investigation for feasibility [49][50][48].

2.2.2. Target Selection and On-Target, Off-Tumor Effect

Ideally, the target antigen for CAR T cells should have a high expression in cancer cells, a low expression in normal cells, and not be associated with oncogenesis [51]. It is known that there are challenges in the path of choosing an optimal CAR T cell target antigen in neuroblastoma, since many target antigens are related to normal peripheral nerves or neural tissue expression. Toxicities caused by particular interactions between the CAR and its target antigen expressed by normal cells termed on-target, off-tumor effects have been reported in previous CAR studies in solid tumors [52][53][54][55]. One clinical trial in metastatic colon cancer reported pulmonary infiltration by CAR T cells that caused a systemic cytokine storm in patients who received HER2-targeted CAR T cell therapy, demonstrating strong evidence of on-target, off-tumor toxicities [54]. On the other hand, there was no such effect in a pediatric sarcoma study using anti-HER2 CAR T cells and anti-GD2 CAR T cells in neuroblastoma studies [42][56][57]. This evidence suggested that the variation of antigen density on the different types of cancer is an additional factor to consider during target selection to avoid on-target, off-tumor effects.

2.2.3. Tumor Microenvironment

Unlike the remarkable success of CAR T cells in the treatment of hematological malignancies, the efficacy of CAR T cells in neuroblastoma can be obstructed by the immunosuppressive tumor microenvironment (TME), which is a manifest barrier to achieve full effective CAR T cell therapy for solid tumors [58]. Significant factors derived from TME in neuroblastomas include immunosuppressive cells like tumor-associated macrophages (TAMs), Type 2 regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs), which contributed to poor results of CAR therapy [59]. Another factor is the inhibitory ligands present in the TME, such as PD-L1, the ligand for an inhibitory receptor expressed on activated T cells, named PD-1 [60][61]. Remarkably, this habitual expression of the inhibitory ligand in neuroblastoma can cause the loss of CAR T cells [62]. In addition to inhibitory signals, the availability of soluble factors in the TME, including galactin 1 and 3, TGF-β, and IL-10, can trigger T cell inhibitory pathways or inhibit T cell function [61][63][64][65][66], while secretory HMGB1 may be responsible for Treg differentiation in the neuroblastoma TME [67]. Furthermore, there are physical barriers that prevent the tumor access of T cells, such as protease fibroblast activation protein (FAP) expressed by tumor-associated stromal fibroblasts, the extracellular matrix (ECM), and immunosuppressive tumor vasculature-like vascular endothelial growth factor (VEGF) [68][69].

2.2.4. CAR Trafficking

Trafficking of CAR cells into solid tumor sites to exert antitumor activity needs to be improved, especially in neuroblastoma. Several chemokines that can mediate immune cell trafficking are generally excreted by tumor or stromal cells like CC-chemokine ligand 17 (CCL17), CCL22, and CCL2 to enhance the localization of immune cells [70]. Moreover, suitable trafficking of immune cells, like T cells, can occur when there is an upregulation of a chemokine receptor that is matched to chemokine-related trafficking on T cells. However, in a previous study using CAR T cells derived from neuroblastoma patients, low expression of CCR2, a chemokine receptor, was detected [71][72][73]. Thus, various approaches to generate CAR T cells with an ability to traffic to neuroblastoma sites are underway.

This entry is adapted from the peer-reviewed paper 10.3390/vaccines8040753

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