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Gene-Edited-αβ T Cells: History
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Contributor: Zhicheng Du , Sumin Zhu ,
Xi Zhang
, Zhiyuan Gong ,
Shu Wang

Multiple Myeloma (MM), characterized by the progressive accumulation of clonal plasma cells in bone marrow, remains a severe medical problem globally. Almost all MM patients who have received standard treatments will eventually relapse. Autologous anti-BCMA (anti-B cell maturation antigen) chimeric antigen receptor (CAR)-T cells are one of the Food and Drug Administration (FDA)-approved immunotherapy cell-based products for treating adults with relapsed or refractory (r/r) multiple myeloma. However, this type of CAR-T cell product has several limitations, including high costs, long manufacturing times, and possible manufacturing failure, which significantly hinder its wider application for more patients. In general, anti-BCMA CAR gene-edited αβ T cells and CAR-Natural Killer (NK) cells are at the forefront, with multiple clinical trials ongoing, while CAR-γδ T cells and CAR-invariant Natural Killer T (iNKT) cells are still in pre-clinical studies. Inactivation of the endogenous TCR (T cell’s receptor) by genome engineering methods is one of the most promising strategies for generating αβ T cells for allogeneic use. 

  • non-conventional
  • off-the-shelf
  • immune cells

1. Introduction

Multiple Myeloma (MM) is the second most common hematological malignancy and is characterized by the progressive accumulation of clonal plasma cells in bone marrow [1][2]. In 2016, there were 138,509 cases of MM globally, a rise of 126% compared to figures from 1990 [3]. In contrast, the average mortality rate has decreased significantly, from 4.0/100,000 in 1994 to 3.2/100,000 in 2017, likely due to the advancement of the therapeutical armamentarium and increased survival [4]. In the US, 34,470 people are expected to be diagnosed with MM, and 12,640 deaths are expected to be confirmed for the previous year 2022 [5]. In China, these numbers were estimated to be 22,450 and 17,360 in 2022, respectively [6]. Nevertheless, MM is not a very common malignancy and only accounts for approximately 1% of all types of cancers, which indicates that the absolute number of affected patients of MM might not be a priority from the perspective of public health [7]. Indeed, the current main challenges of managing MM globally focus on three other aspects. Firstly, similar to many other cancers, the cost of treating MM remains a medical burden for most patients. According to a recent study conducted in the US, for older adults (mean = 75.8 years old) who have been diagnosed with MM, the incremental lifetime MM cost is $184,495, with the majority going to inpatient and outpatient expenditures and prescribed drugs [8]. Secondly, although therapies for MM have developed rapidly in recent years, not all patients are treated properly or can access those treatments. The possible reasons for this are complicated, including low socioeconomic development and delays in the inclusion of new therapies in national formularies by the government [3][9]. The last issue for treating MM is the problem of relapse and refractory (r/r). The current standard treatment for MM is “triplet regimens-based” [10]. In China, according to the latest version of the Chinese Society of Hematology’s guideline for the diagnosis and management of multiple myeloma, the combination of one proteasome inhibitor (PI, such as Bortezomib and Carfilzomib), one immunomodulatory drug (IMiD, such as Lenalidomide and thalidomide), and dexamethasone is recommended for newly diagnosed MM patients [11]. In the US, the treatment strategy is comparably more specific. Referring to the guideline from the National Comprehensive Cancer Network (NCCN), a combined therapy with Bortezomib, Lenalidomide, and dexamethasone was set as the preferred regimen for both autologous stem cell transplantation (ASCT)-eligible and -non-eligible MM patients [12]. However, almost all patients, including those who achieve complete remission (CR) after the initial treatments, will eventually relapse [10][13]. Compared to newly diagnosed MM, r/r MM is usually less responsive and easy to progress either during or shortly after treatment [14]. For patients in early relapses, different combinations of triplet regimens or monoclonal antibodies (mAbs) could be applied [11][12]. For example, Daratumumab, a type of mAbs targeting CD38, received approval from the US Food and Drug Administration (FDA) for treating MM in 2015 [15]. For patients with late relapse, chimeric antigen receptor (CAR)-T therapies are usually recommended [11][12]. Until September 2022, there were already two anti-B cell maturation antigen (BCMA) CAR-T cell therapies that had been approved by the US FDA to treat adults with r/r multiple myeloma after four or more prior lines of therapy [16].
BCMA, also known as tumour necrosis factor receptor (TNFR) superfamily member 17, is a transmembrane glycoprotein mainly involved in the maturation, survival, and differentiation of B cells into plasma cells with the coordination of two other TNFR superfamily members [17]. It is known to be one of the most promising antigens for developing CAR-T therapy for MM treatment, given its universal overexpression in malignant plasma cells and restricted expression in B-cell lineage cells [18][19].
CAR is an artificial receptor designed to direct immune cells (e.g., T cells and Natural Killer (NK) cells) to cancer cells, stimulating the immune response to kill those target cells [20]. A CAR molecule typically comprises four parts: an antigen recognition domain, a hinge region, a transmembrane domain, and an intracellular signaling domain [21]. The antigen recognition domain is generally designed to recognize and bind to the tumour-associated or specific surface antigens on cancer cells [22]. It is usually adapted from mAb’s heavy and light chains, named single chain variable fragments (scFvs). However, in some cases, it can also be directly derived from native immune cell receptors such as the NKG2D [22][23]. The hinge region and transmembrane domain (H/T) are comparably more conserved and are usually obtained from a portion of widely expressed receptors on T cells, such as CD8 and CD28. In general, H/T provides the CAR with spatial flexibility and anchors the construct on the cell surface [24]. The intracellular signaling domain triggers intracellular cascade signaling and leads to subsequent anti-tumour effects of immune cells [24]. The first-generation CAR only contains one CD3-ζ domain derived from the cytoplasmic tail of the T cell’s receptor (TCR) in the intracellular signaling domain. For the second-generation CAR, a co-stimulatory molecule is incorporated to further sustain the immune cells’ responses and proliferation in vivo, including the most well-known CD28 and 4-1BB’s endodomains [25][26]. Although many other modifications have been initiated to further enhance CAR’s functions, such as introducing more than one co-stimulatory molecule or other cytokine inducers, the second-generation CAR construct with only one co-stimulatory domain is still considered today’s breakthrough in CAR immunotherapy for cancer. This is mostly because more modifications do not confer consistent improvements for CAR-equipped immune cells and instead may lead to cell exhaustion and terminal differentiation [27].
The current two FDA-approved anti-BCMA CAR-T cells are both second-generation autologous CAR-T cells. ABECMA (idecabtagene vicleucel) is the 1st cell-based therapy for treating MM. An open-label, single-arm, multicenter phase II clinical trial-KarMMa showed 72% of the overall response rate (ORR) and 11 months of median duration of response (DoR) for r/r MM patients who had received this treatment [28]. Soon after, CARVYKTI (ciltacabtagene autoleucel) also received approval based on the results of an encouraging phase I/II clinical study (CARTITUDE-1), with the ORR at 97.9% and a median DoR of 21.8 months, respectively [29]. Autologous CAR-T cell therapies usually possess a comparably good safety profile, with very limited graft versus host diseases (GvHD) and hyperreactive self-immune responses observed [28][29][30]. However, there are also a few limitations. Firstly, the cost of these cell products is high; this is mainly attributed to their sophisticated and bespoke manufacturing process [31]. The prices for one single infusion of the two anti-BCMA CAR-T cells products mentioned above are USD 441,743 and 489,654.5, which are not affordable for most families worldwide [32]. Secondly, the manufacturing of autologous CAR-T cells is also time-consuming. According to statistics from the FDA, an estimation of 4 to 5 weeks is typically required for the two anti-BCMA CAR-T cells to be produced [28][29]. This is a rather lengthy process, especially for r/r MM patients. As shown by the data from clinical trials, 4 out of 135 patients for ABECMA and 11 out of 113 patients for CARVYKTI failed to receive treatment due to death, adverse events, or disease progression [28][29]. The last major issue is the possible manufacturing failure of CAR-T cells. Autologous T cells must be produced from patients who have already experienced several rounds of other types of standard treatments. Hematological adverse drug reactions, especially leukopenia, are the most commonly reported problems for patients taking PI and IMiD drugs, which can significantly affect the quality of the collected cells [33][34]. Referring to the clinical studies’ results, 1.5% (2/135) and 18% (17/97) manufacturing failures were reported for ABECMA and CARVYKTI, respectively [28][29]. Besides the quality problems regarding donor blood, other factors such as the contamination of pathogens or myeloma cells could also give rise to manufacturing risks and eventually lead to manufacturing failure [35].
To address the above-listed limitations, recently, scientists have been attempting to convert autologous anti-BCMA CAR-T therapy into allogeneic CAR-based immune cell therapy. As shown in Figure 1, allogeneic CAR-based immune cell therapy is independent of patients’ own cells. By starting with the collection of healthy donor blood, specific immune cells are then isolated, genetically modified, and expanded in vitro. Ideally, these cells undergo necessary quality control (QC) testing and are stored for future use. One of the key advantages of allogeneic cell therapy is its potential to be applied “off-the-shelf”. In this scenario, patients are not required to wait for the personalized cells to be manufactured and need not be concerned about whether their cells will qualify for the treatment. Additionally, by creating an inventory of healthy donor-derived CAR-based immune cells, the cost per patient can be significantly reduced [36]. However, achieving this goal is not easy. The widely applied T cells for CAR-based immune cell manufacturing nowadays are known as αβ T cells, which refer to T cells bearing the TCR α/β that represent the majority (~95%) of the peripheral blood-circulating T cell population [37]. Unfortunately, this type of cell source is not suitable for allogenic use due to potential alloreactivity caused by the recognition by TCR of peptide-allogeneic MHC complexes [38].
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Figure 1. Allogeneic and autologous adoptive transfer of CAR-based immune cells.

2. Gene-Edited-αβ T Cells

Inactivation of the endogenous TCR by genome engineering methods is one of the most promising strategies for generating αβ T cells for allogeneic use. For example, ALLO-715 is a type of genetically modified anti-BCMA CAR-T cell that uses TALEN technology to disrupt the T-cell receptor alpha constant gene (TRAC) to reduce the risk of graft-versus-host disease (GvHD) (Figure 2) [39]. Additionally, the CD52 gene of ALLO-715 is knocked-out to allow for the use of an anti-CD52 monoclonal antibody (mAb) for selective and transient lymphodepletion (LD) for the patient prior to CAR-T treatment [39]. ALLO-715 is currently being evaluated in a Phase I clinical trial (NCT04093596) for adult patients with r/r multiple myeloma who have failed with three prior lines of therapy; patients receive ALLO-715 at one of four dose levels (40, 160, 320, and 480 × 106 CAR+ T cells) post-LD [39]. As of 14 October 2021, the interim report showed that in 43 treated subjects, no GVHD events had been observed, 53% had developed Grade 1 and 2 Cytokine Release Syndrome (CRS), and 14% had experienced low-grade neurotoxicity [40]. The overall response rate among the 320 × 106 dose cohort was 71% [40]. ALLO-605 is another allogeneic anti-BCMA CAR-T cell from the same company, Allogene Therapeutics, and was granted by the FDA with Fast Track designation in June 2021 and orphan-drug designation in April 2022 [41]. Compared to ALLO-715, ALLO-605 is equipped with an additional Constitutively Active Chimeric Cytokine Receptor (CACCR) to further regulate T cell exhaustion and improve T cell function and potency [42]. Currently, this product is also under a Phase 1 clinical trial evaluation with similar patient inclusion criteria as that for ALLO-715 [41][43]. The other gene edited-αβ T cell products targeting BCMA for MM treatment, CTX120, are produced using the CRISPR/Cas9 system to eliminate TCR and MHC class I, coupled with specific insertion of the CAR at the TRAC locus [44]. These genetically modified T cells demonstrated desired in vivo persistence and anti-tumour effects in MM mouse models, which is currently being investigated in a Phase I clinical trial for r/r MM patients who have been treated with at least two prior lines of therapy [44][45].
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Figure 2. The general cell manufacturing process of gene edited-αβ T cells.
Nevertheless, engineered endonucleases for genetic editing such as the CRISPR/Cas9 system may bring potential off-target risks. Researchers have attempted to optimize the nuclease design [46]. Recently, Madison et al. reported the application of the high-fidelity RNA-guided endonuclease Cas-CLOVER for T cell receptor beta constant (TRBC) and β2 microglobulin (B2M) gene editing and the piggyBac transposon for CAR delivery. They successfully produced allogeneic anti-BCMA CAR-T cells composed of high percentages of stem cell memory T cells (over 60% with some donors) and exhibited potent anti-tumour cytotoxicity against MM.1S cells in xenograft mouse MM models [47]. Specifically, Cas-CLOVER consists of a fusion of catalytically dead SpCas9 with the nuclease domain from a Clostridium Clo051 type IIs restriction endonuclease. Cas-CLOVER is activated upon the dimerization of the Clo051 nuclease domain by RNA-guided recognition of two adjacent 20-nucleotide target sequences. Compared to the paired nickase approach with a Cas9-D10A mutant, Cas-CLOVER does not induce double-strand break (DSB) or nick and has lower off-target nuclease activity with off-target indel rates among donors ranging between 0.012% and 0.089% [47]. However, further head-to-head fidelity comparisons between various gene editing tools and extensive safety evaluations for “off-the-shelf” clinical applications must be performed. Another strategy to avoid the potential risk of genomic modification is to knock down TCR expression at the mRNA level. Ceylad Oncology has generated such allogeneic anti-BCMA CAR-T cell products (CYAD-211) by applying short hairpin RNA [48]. In the ongoing Phase I exploratory trial IMMUNICY-1 for treating r/r MM patients with at least two prior MM treatment regimens that include exposure to IMiD and PIs either alone or in combination, CYAD-211 has achieved 2/8 partial responses and 5/8 stable diseases in low dosage levels with no GvHD observed, suggesting the potential of applying this technology in allogeneic settings [48].

This entry is adapted from the peer-reviewed paper 10.3390/cancers15030567

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