Echchannaoui, Hakim

Huang, He

Voss, Ralf-Holger

Xue, Shao-An

English

UCL Discovery

Frontiers in ImmunologyOPEN ACCESSEDITED AND REVIEWED BYGerald Willimsky,Charité University Medicine Berlin,Germany*CORRESPONDENCERalf-Holger Vosshvoss@uni-mainz.deShao-An Xueshao-an.xue@ucl.ac.ukRECEIVED 16 August 2023ACCEPTED 23 August 2023PUBLISHED 07 September 2023CITATIONVoss R-H, Echchannaoui H, Huang H andXue S-A (2023) Editorial: Translation ofgenetically engineered T cellsin cancer immunotherapy.Front. Immunol. 14:1278677.doi: 10.3389/fimmu.2023.1278677COPYRIGHT© 2023 Voss, Echchannaoui, Huang andXue. This is an open-access articledistributed under the terms of the CreativeCommons Attribution License (CC BY). Theuse, distribution or reproduction in otherforums is permitted, provided the originalauthor(s) and the copyright owner(s) arecredited and that the original publication inthis journal is cited, in accordance withaccepted academic practice. No use,distribution or reproduction is permittedwhich does not comply with these terms.TYPE EditorialPUBLISHED 07 September 2023DOI 10.3389/fimmu.2023.1278677Editorial: Translation ofgenetically engineered T cells incancer immunotherapyRalf-Holger Voss1*, Hakim Echchannaoui2,3,4, He Huang5and Shao-An Xue6,7*1Institute of Immunology, Department of Research Center for Immunotherapy, Laboratory U. Sahin,University Medical Center (UMC) of the Johannes Gutenberg University, Mainz, Germany,2Department of Hematology and Medical Oncology, University Medical Center, JohannesGutenberg-University, Mainz, Germany, 3German Cancer Consortium partner site Frankfurt/Mainz,Mainz, Germany, 4University Cancer Center Mainz, Mainz, Germany, 5Institute of Hematology,Zhejiang University, Hangzhou, China, 6Surgery, Medical School, Faculty of Medical Sciences,University College London, London, United Kingdom, 7Genetic Engineering Laboratory, School ofBiological & Environmental Engineering, Xi’An University, Xi’An, ChinaKEYWORDSgenetic/cellular engineering, CAR-T, TCR-T, cancer immunotherapy, tumor specific/associated antigens, genome editing, immunosuppression, CAR toxicityEditorial on the Research TopicTranslation of genetically engineered T cells in cancer immunotherapyGenetically engineered T cells have made tremendous contributions to cancerimmunotherapy. Chimeric antigen receptor (CAR)-modified T cells have demonstratedremarkable efficacy in hematological malignancies (1–5), however, clinical responses have notbeen convincing in solid tumors. T cell receptor (TCR)-engineered T cells showed promisingresults in some solid cancers (6–8), yet many hurdles remain to translate current geneticallyengineered T cells intomore effective therapeutics, to achieve higher and durable clinical responses.In this Research Topic, we compile recent advances in T cell immunotherapy, including theidentification of new promising antigens, the optimisation of genetically modified TCR- and CAR-T cells to improve their persistence and reduce their toxicity.We also discuss strategies to overcomethe suppressive tumor microenvironment (TME) and perspectives in T cell manufacturing.1 Identification and validation of novel antigens forcancer immunotherapyIn recent years, tumor-specific mutated antigens, also called neoantigens (neoAgs) haveemerged as a promising class of immunogenic antigens for immunotherapy (9). Theseantigens are exclusively expressed and presented on tumor cells, and represent an attractivetherapeutic tool for solid tumors, in particular for TCR-engineered T cells (10).In this Research Topic, Immisch et al. identified a neoepitope comprising Rac1P29S aminoacid mutation, which is the third most common hotspot mutation in melanoma. They have notonly isolated and characterised TCRs that can recognise this HLA-A*02:01-binding neoepitope,but also demonstrated TCR-T induced cytotoxicity against Rac1P29S expressing cancer cells invitro and in vivo after adoptive T cell therapy.frontiersin.org01Voss et al. 10.3389/fimmu.2023.1278677Although neoAgs are considered as truly tumor-specific antigens(11), Amerongen et al. pursue the concept of identifying highlyexpressed tumor-associated antigens in ovarian cancer from pooledmRNAseq data bases, and a reverse immunology approach for themost prevalent HLA restriction elements. The candidate antigenscomprising PRAME, CTCFL and CLDN6 exhibited a 20-fold higherexpression in tumors compared to normal cells. High-avidity TCRswere isolated, cloned and characterised in vitro to exclude potential on/off-target-reactivities, and demonstrated potent antitumor activities,making these TCRs especially useful for adoptive therapy in ovariancancers, generally considered as ‘cold tumors’with less T-cell infiltrates.2 Strategies to enhanceexpression, specificity, affinity,and (signaling) functions of theengineered moleculesBarden et al. addressed the issue of cross-activation of a CAR withthe endogenous TCR in CAR-T cells. They found out that the antigen-dependent activation of T-cells by the triggered immunoreceptor (IR)exclusively results in phosphorylation of the CAR/CD3z or TCR/CD3z, respectively, thus excluding reciprocal cross-activation. This isin line with elaborate microscopy analyses elucidating their mutualspatial exclusion upon either IR activation. However, TCRs and CARscan co-operate by means of antigen recognition by the endogenousTCR and costimulation by CD28 incorporated in CD28/z CARs.Collectively, the authors claim that TCR/CD28 CAR-signaling maybe exploited for Boolean logic “AND” gating (12), stressing theimportance of endogenous TCRs for providing a non-TME tonicsignaling for CAR-T persistence in patients.TCR-based bispecific T cell engagers (TCE) are emergingtherapeutics as recently reported by positive phase III clinicalresults of a gp100/HLA-A2-TCR/anti-CD3 bifunctional inmelanoma patients (13). Unlike antibody-based TCE (14), whichhave been widely studied, little is known about how the formats ofTCR-based TCE affect their potencies. In this context, Van Diestet al. recently developed a novel TCE format based on the solubleg9d2TCR-antiCD3 bispecific molecule (GAB) (15), and describedan alternative design based on the multimerisation of GABs toimprove their potency. Here, van Diest et al. could further enhancethe fraction of GAB-dimers by shortening the linker length withinthe anti-CD3 scFv, and showed that GAB-dimers were superior infunction, without apparent on-target/off-tumor reactivity.3 Novel strategies for geneticengineering of T cells, includingCAR-T and TCR-T cellsHiltensperger and Krackhardt have reviewed in depth the TCR-Tand CAR-T field, comprising several aspects, from the design ofdifferent generations of CARs for providing signal 1 to 3 in T-cellactivation, prevention of TCR mispairing by TCR proteinengineering and genome editing, the set up of allogeneic T-cellFrontiers in Immunology 02transfer to boost T-cell fitness and T-cell graft manufacturing,adverse events to reckon with and counteracting tumor escape,persistence of T-cells, to treatment modalities for solid cancers. Thereview also covers gene transfer shuttle systems, persistence of T-cells,gene delivery approaches in vivo, potentially arising adverse eventssuch as on/off-target toxicities, and cellular and molecular strategiesto force back tumor escape mechanisms and resistance of solidtumors in TME, and provides an overview of ongoing clinical trials.Degirmencay et al. have explored how modifications offramework residues in the TCR variable domains affect TCRexpression and function. They used bioinformatic and proteinstructural analyses to identify candidate amino acid residues in theframework of the variable b domain predicted to drive high TCRsurface expression. Replacing these residues in poorly expressedTCRs resulted in improved surface expression and enhanced targetspecific killing by these engineered TCR-T. Their results corroboratedimproved expression and functionality, while at the same timereducing the risk of toxicity associated with TCR mispairing.Autologous T cell engineering is not only costly but also time-consuming, limiting the number of patients who can benefit from thisnew therapy. Yu et al. developed an allogeneic approach by generatingCD19-CAR T cells from cord blood of allogeneic donor, anddemonstrated their anti-tumor activity in vitro and in vivo using adiffuse large B-cell lymphomamodel (DLBCL). The rationale behind thisidea is the higher proportion of naïve T-cells from cord blood that can beredirected into potent effector T cells, thus having a better anti-tumoractivity. This strategy may provide a broader option for immunotherapy,offering readily accessible “off-the-shelf” cellular products.4 Strategies for overcomingthe immunosuppressivetumor microenvironmentIn a previous study, TCR-T cells were engineered to disrupt PD-1upregulation upon antigen encounter by CRISPR/Cas9 genome editingto minimise immunosuppression through PD-L1-positive tumor cells(16). Here, Kim et al. went on one step further and took advantage ofthe tightly regulated PDCD1 locus for replacing PD-1 by a pleiotropiccytokine such as IL-12 to positively affect the persistence of T-cells inTME. By this means, an inhibitory signal of PD-1 would be reversiblyinverted into a stimulatory signal of IL-12 only in the presence of thetumor antigen recognised by the introduced TCR, and hence in a local(TME) and timely (as long as antigen is present) restricted manner soas to avert cytokine-induced toxicities.5 Manufacturing platforms for vectorproduction and cellular engineeringNiu et al. analysed the phenotype of lentivirally (LV) transducedversus PiggyBac transposon (PB)-transfected CAR-T cells in vitro and invivo. They scrutinised biomarker expression rates and phenotype(effector versus central memory subsets), cytokine/chemokinesecretions and cytolyses, including a transcriptomic approach, andfrontiersin.orgVoss et al. 10.3389/fimmu.2023.1278677validation of an in vivo tumor model. In PB- compared to LV-CAR-T,they reported on higher expression of IL-9, a cytokine that enhances anti-tumor responses, and on lower expression of IL-6, the hub cytokinetriggering cytokine release syndrome, suggesting a favourable profile ofthe former manufacturing platform. Importantly, both systems controltumor cells comparably in vivo, in line with recently published work (17).6 Strategies for reducing toxicity andimproving safetyAlthough, CAR-T cell therapy approximates a consolidatedmainstay in the treatment of several hematologic malignancies,Frontiers in Immunology 03adverse side effects may occur. In this Research Topic, Wanget al. reviewed CAR-T treatments in the context of multiplemyeloma and potential toxicities, while Hiltensperger &Krackhardt covered CAR-T and TCR-T approaches ingeneral, highlighting recent innovations capable of enhancingefficacy and reducing toxicity. Zundler et al. also reported acase of a rare complication in a patient treated with CD19 CAR-T for DLBCL, who developed chronic diarrhea withcharacteristics of inflammatory bowel disease-like colitis.Resolution of colitis occurred by using an antibiotic therapythat might have changed the intestinal microbiota, which mostlikely limited the stimulation of these intestinal infiltratingCAR-T cells.FIGURE 1Apple pie chart attributing 11 articles (2 reviews, 8 original research articles, 1 case report) to the 6 topics 1.-6. listed in the Editorial summary in a clockwisemanner. The 11 articles are indicated by their first author names. The 6 apple pie pieces are colour-coded according to their assigned articles covering eitherthe subject TCR (red), CAR (blue), or both (purple). The review articles are shown in the center of the chart indicating to which topics they refer to. TCRs,CARs, MHCs, PD-1, IL-12, and GABs are depicted in a stylised fashion. The outline of the circle represents the T-cell membrane where all immunoreceptors(TCRs, CARs) are embedded. IL-12, GABs and MHCs are either soluble molecules or membrane proteins from target cells, respectively, and hence locatedoutside the circle. Tumor antigens presented by MHC are indicated as coloured spheres, depending on the particular peptide. Antigen specificities of TCRs,CARs and GABs are denoted besides the stylised molecule. Helical DNA, lentivirus, recombinant transposon DNA, and colon are adumbrated as cell or bodyinternal components and hence, located inside the circle. Red double/single arrows represent mutually interacting/inflammatory, a ‘┴’ inhibitory reactions, ablue arrow an activating reaction in transcription/translation, green lines in a TCR denotes point mutations in TCR Vb domain. Abbreviations: TSA tumorspecific antigen, TAA tumor associated antigen, TCR T-cell receptor, CAR chimeric antigen receptor, GAB gamma delta TCR anti-CD3 bispecific molecule,CMV cytomegalovirus, allo alloreactive, IL-12 interleukin 12, KO knock out, KI knock in, CRISPR clustered regularly interspaced short palindromic repeats, PD-1 programmed cell death protein 1, LV lentivirus, PB PiggyBac, IR inverted repeats, GOI gene of interest, Rac1P29S, PRAME, CTCFL, Her2, CEA, CMV, HA1,NY-ESO-1, CD19 represent processed or full length tumor/viral antigens, respectively.frontiersin.orgVoss et al. 10.3389/fimmu.2023.1278677Author contributionsRHV: Writing – review & editing, Conceptualization, Writing –original draft. HE: Writing – review & editing. HH: Writing –review & editing. SAX: Writing – original draft, Writing – review &editing, Conceptualization.FundingSAX is supported by the National Natural Science Foundationof China (NSFC-81972883).AcknowledgmentsWe are in particular very grateful to Mr. Stefan Kindel, scientificillustrator of the University Medical Center Mainz, who preparedFigure 1 of this Editorial summary.Frontiers in Immunology 04Conflict of interestThe authors declare that the research was conducted in theabsence of any commercial or financial relationships that could beconstrued as a potential conflict of interest.The author(s) declared that they were an editorial boardmember of Frontiers, at the time of submission. This had noimpact on the peer review process and the final decision.Publisher’s noteAll claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliatedorganizations, or those of the publisher, the editors and thereviewers. 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Editorial: Translation of genetically engineered T cells in cancer immunotherapy

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Editorial: Translation of genetically engineered T cells in cancer immunotherapy

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