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CAR-T in Cancer Treatment: Develop in Self-Optimization, Win-Win in Cooperation

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CAR-T in Cancer Treatment: Develop in Self-Optimization, Win-Win in Cooperation cancers Review CAR-T in Cancer Treatment: Develop in Self-Optimization, Win-Win in Cooperation Feifei Guo and Jiuwei Cui * Cancer Center, The First Hospital of Jilin University, 71 Xinmin Street, Changchun 130021, China; [email protected] * Correspondence: [email protected]; Tel.: +86-431-88782178 Simple Summary: Chimeric antigen receptor (CAR)-T cell therapy has exhibited good application prospects in the treatment of hematologic malignancies. However, there are still many unsolved problems, such as the limited antitumor effect of CAR-T on solid tumors and the potential risk of CAR-T therapy in clinical applications. In order to meet these challenges, more and more solutions are proposed. Therefore, in this review, we have discussed the recent breakthroughs in CAR-T therapy for cancer treatment, with an emphasis on the potentially effective CAR-T modifications and combined strategies. Abstract: Despite remarkable achievements in the treatment of hematologic malignancies, chimeric antigen receptor (CAR)-T cell therapy still faces many obstacles. The limited antitumor activity and persistence of infused CAR-T cells, especially in solid tumors, are the main limiting factors for CAR-T therapy. Moreover, clinical security and accessibility are important unmet needs for the application of CAR-T therapy. In view of these challenges, many potentially effective solutions have been proposed and confirmed. Both the independent and combined strategies of CAR-T therapy have exhibited Citation: Guo, F.; Cui, J. CAR-T in good application prospects. Thus, in this review, we have discussed the cutting-edge breakthroughs Cancer Treatment: Develop in in CAR-T therapy for cancer treatment, with the aim of providing a reference for addressing the Self-Optimization, Win-Win in current challenges. Cooperation. Cancers 2021, 13, 1955. https://doi.org/10.3390/ Keywords: chimeric antigen receptor T cell therapy; cancer immunotherapy; CAR structure; com- cancers13081955 bined therapy Academic Editor: Jan Joseph Melenhorst Received: 7 March 2021 1. Introduction Accepted: 15 April 2021 In 2017, chimeric antigen receptor (CAR)-T cell products, represented by Kymriah Published: 19 April 2021 (CTL019) [1] and Yescarta (KTE-C19) [2], were approved for marketing by the Food and Drug Administration (FDA), which highlights the therapeutic potential of CAR-T in hema- Publisher’s Note: MDPI stays neutral tologic malignancies. However, despite being a promising antitumor candidate, CAR-T still with regard to jurisdictional claims in faces many problems as it continues to encounter sequent obstacles in the treatment of solid published maps and institutional affil- tumors. It is difficult for CAR-T cells to properly migrate and infiltrate into solid tumor sites iations. due to the chemokine mismatches between CAR-T and tumor cells [3] and the presence of abnormal vascular [4] and stromal [5] components in the tumor microenvironment (TME). Subsequently, CAR-T cells entering tumor tissues compete with diverse immunosuppres- sive cells (e.g., regulatory T cells and myeloid-derived suppressor cells) [6,7], immune Copyright: © 2021 by the authors. checkpoints (e.g., programmed death-ligand 1 [PD-L1]) [8], and metabolic checkpoints (e.g., Licensee MDPI, Basel, Switzerland. hypoxia and glycolysis) [9,10] in the TME. Even after successfully entering tumor tissues, This article is an open access article these CAR-T cells have to cope with problems such as tumor antigen heterogeneity and distributed under the terms and antigen escape [11,12]. Moreover, activity reduction and persistence limitation of infused conditions of the Creative Commons CAR-T products may be the leading cause of tumor recurrence in hematologic and solid Attribution (CC BY) license (https:// tumors [13]. The inevitable immune-mediated toxicity, manifested as cytokine release creativecommons.org/licenses/by/ syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), is 4.0/). Cancers 2021, 13, 1955. https://doi.org/10.3390/cancers13081955 https://www.mdpi.com/journal/cancers Cancers 2021, 13, 1955 2 of 16 Cancers 2021, 13, x 2 of 17 also a critical problemsyndrome for (ICANS), the clinical is also application a critical problem of CAR-T for [14the]. clinical Although application mild patients of CAR-T [14]. may present onlyAlthough self-limited mild patients symptoms may suchpresent as only fever self and-limited hypotension, symptoms life-threatening such as fever and hypo- organ damage andtension, death life-threatening can also occur, organ similar damage to that and reporteddeath can inalso the occur, P-PSMA-101 similar to studythat reported or with the UCARTCS1in the P-PSMA-101 product [study15].Although or with the CAR-TUCARTC productsS1 product of [15]. good Alth manufacturingough CAR-T products practice (GMP) gradeof good are manufacturing currently available, practice the(GMP) CAR-T grade manufacturing are currently available, process stillthe CAR-T needs manu- to be improvedfacturing to increase process clinical still access needs [to16 be]. Methodsimproved ofto obtainingincrease clinical T cell access isolation, [16]. acti-Methods of vation, expansion,obtaining and genetic T cell isolation, modification activation, more expansion, effectively and and genetic economically modification are more worth effectively exploring [17,18and]. The economically success of are CAR-T worth therapy exploring in cancer[17,18]. treatment The success traps of CAR-T it into therapy obstacles. in cancer Recently, moretreatment effective solutionstraps it into have obstacles. been Recently, developed more and effective reported. solutions Therefore, have been in this developed and reported. Therefore, in this review, we have discussed and summarized the recent review, we have discussed and summarized the recent remarkable improvements and remarkable improvements and breakthroughs in CAR-T therapy to address the existing breakthroughs inchallenges CAR-T therapy(Figure 1). to address the existing challenges (Figure1). Figure 1.Figure Challenges 1. Challenges and optimizations and optimizations of CAR-T persistence of CAR-T and antitumor persistence proper andties. antitumor CAR—Chimeric properties. antigen CAR— recep- tor; NKT—Natural killer T; γδT—gamma delta T; CSC—Cancer stem cells; CD—Cluster of differentiation; NKG2DL— Chimeric antigen receptor; NKT—Natural killer T; γδT—gamma delta T; CSC—Cancer stem Natural killer group 2 member D ligand; EGFR—Epidermal growth factor receptor; HER2—Human epidermal growth factor receptorcells; CD—Cluster 2; amR—Antibody of differentiation; mimic receptor; NKG2DL—Natural scFv—Single-chain variable killer group fragment; 2 member 4-1BB (TNFRSF9)—Tumor D ligand; EGFR— ne- crosis factorEpidermal receptor growthsuperfamily factor 9; ICOS—Combining receptor; HER2—Human inducible costimulatory; epidermal growthICOSL—Combining factor receptor inducible 2; amR— costimu- latory ligand;Antibody ITAM—Immunoreceptor mimic receptor; scFv—Single-chain tyrosine-based activation variable motif. fragment; 4-1BB (TNFRSF9)—Tumor necrosis factor receptor superfamily 9; ICOS—Combining inducible costimulatory; ICOSL—Combining 2. Enhanced Persistence and Antitumor Properties of CAR-T Therapy inducible costimulatory ligand; ITAM—Immunoreceptor tyrosine-based activation motif. 2.1. Optimization of CAR-T Structures 2. Enhanced Persistence2.1.1. Optimization and Antitumor of the Extracellular Properties Domain of CAR-T Therapy 2.1. Optimization of CAR-TThe single-chain Structures variable fragment (scFv), designed to identify tumor antigens, is the 2.1.1. Optimizationmajor of component the Extracellular of the CAR-T Domain extracellular segment. Antigen heterogeneity is an im- The single-chainportant variable factor hindering fragment CAR-T (scFv), efficacy designed in cancer to identify treatment. tumor The antigens,varying antigen is the expres- major componentsion of densities the CAR-T and extracellularthe simultaneous segment. existence Antigen of different heterogeneity antigens have is an been impor- reported to be critical for tumor escape or recurrence [11]. Therefore, promoting CAR-T-specific anti- tant factor hindering CAR-T efficacy in cancer treatment. The varying antigen expression gen recognition may be helpful for augmenting CAR-T efficacy in cancer treatment. densities and the simultaneous existence of different antigens have been reported to be critical for tumorOptimization escape or recurrenceof the Extracellular [11]. Therefore, Domain promoting CAR-T-specific antigen recognition may be helpful for augmenting CAR-T efficacy in cancer treatment. A fraction of cells with stem-like properties in solid tumors called cancer stem cells (CSCs) are widely known for their association with tumor-heterogeneity evolution and Optimization of the Extracellular Domain resistance to conventional anti-tumor therapies [19]. Given this, a growing number of A fractionCSC-associated of cells with stem-like antigens propertieshave been inselect solided tumorsto enhance called CAR-T cancer function. stem cells Cluster of (CSCs) are widely known for their association with tumor-heterogeneity evolution and resistance to conventional anti-tumor therapies [19]. Given this, a growing number of CSC-associated antigens have been selected to enhance CAR-T function. Cluster of dif- ferentiation (CD)133 is a common marker of CSCs in multiple aggressive solid tumors, and Vora et al. constructed a CAR-T-targeting CD133 (CART133) and confirmed its supe- Cancers 2021, 13, 1955 3 of 16 rior
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