أعرض في EDS

Combination of Three Unique Anti-Tumor Modalities Engineered into iPSC-Derived T Cells Demonstrate a Synergistic Effect in Overcoming Tumor Heterogeneity and Cancer Escape

التفاصيل البيبلوغرافية
العنوان: Combination of Three Unique Anti-Tumor Modalities Engineered into iPSC-Derived T Cells Demonstrate a Synergistic Effect in Overcoming Tumor Heterogeneity and Cancer Escape
المؤلفون: Bi-Huei Yang, Sjoukje J. C. van der Stegen, Soheila Shirinbak, Mochtar Pribadi, Jason ORourke, Chia-Wei Chang, Alec Witty, Martin P. Hosking, Amit R. Mehta, Earl Avramis, Eigen Peralta, Yu-Sheng Eason Lin, Benjamin M. Whitlock, Roseanna Petrovic, Thomas H. Lee, Wen-I Yeh, Alma Gutierrez, Hui-yi Chu, Bahram Valamehr
المصدر: Blood. 138:2793-2793
بيانات النشر: American Society of Hematology, 2021.
سنة النشر: 2021
مصطلحات موضوعية: Antitumor activity, Modalities, business.industry, Immunology, Cancer research, Medicine, Cancer, Cell Biology, Hematology, business, medicine.disease, Biochemistry, Tumor heterogeneity
الوصف: Chimeric antigen receptor (CAR) is known to trigger an effective immune response through surface antigen recognition enhanced by T-cell activation signal one (ex. CD3) and signal two (ex. CD28); however, targeting neoantigens and intracellular antigens remains a challenge. On the other hand, the T-cell receptor (TCR) can target neo/intracellular antigens presented by MHC molecules, but often the response is not as potent. The CD16 Fc receptor, which is naturally expressed on NK cells, mediates antibody-dependent cellular cytotoxicity (ADCC), but its application in T cells is yet not fully appreciated. Utilizing our proprietary induced pluripotent stem cell (iPSC) platform to engineer multiple modalities into a clonal iPSC line, which can serve as the starting cell source for mass production of off-the-shelf, iPSC-derived CAR-T cells (CAR-iT cells), we aimed to study the combination of these three targeting modalities, CAR, TCR, and CD16 (tri-modal), to determine whether challenges associated with the treatment of heterogeneous tumors may be overcome. To evaluate the benefit of the three distinct targeting modalities, we tested the functional activity of individual and various combinations of i) anti-CD19 CAR, anti-MICA/B CAR, and anti-BCMA CAR, ii) high-affinity, non-cleavable CD16 (hnCD16), and iii) MR1 and NYESO1 TCR modalities in iT cells. All tested combinations successfully expressed the designated edits and differentiated into iT cells (T-lymphocytes > 95%). Initially, we tested CD19 CAR and MR1 TCR in a 9-day serial killing assay of Nalm6 leukemia cells (CD19 high, MR1 +), where we observed CD19 CAR-iT cells induce prompt CAR-mediated tumor growth inhibition (TGI), saw similar effective killing by MR1 TCR-iT cells but with a 24-hr delay, and observed the most effective response of tumor cell elimination when both where combined in the same iT cell population (relative tumor counts; Day 1, no stim: 2.6, CAR: 0.28, TCR: 1.02, CAR+TCR: 0.02; Day 2, no stim: 5.36, CAR: 0.25, TCR: 0.05, CAR+TCR: 0.02). All conditions (CAR, TCR, and CAR+TCR) reached and maintained complete TGI by Day 9 of the assay (relative tumor count, Day 9, no stim: 50.97, all other stim conditions: 90%), indicating a synergistic effect and compatibility between CAR and TCR. Assessing anti-MICA/B CAR and hnCD16, we confirmed the hnCD16-mediated response in iT cells in the presence of anti-MICA/B CAR when crosslinking hnCD16 via biotinylated anti-CD16 antibody with streptavidin (phosphorylated CD3zeta peaked at 10 min upon ADCC triggering), indicating the compatibility between a CAR-iT cell and the hnCD16 motif. Lastly, combining iT cells expressing anti-BCMA CAR + MR1 TCR + hnCD16 with daratumumab (anti-CD38 mAb) in a 9-day serial killing assay demonstrated the best TGI among the groups with a near-elimination of transgenic Nalm6 cells (area under curve, no stim: 30.29, TCR: 1.564, CAR: 0.7087, hnCD16+mAb: 1.452, trimodal+mAb: 0.5824). To assess the function of the tri-modal iT cells in vivo, we used a disseminated xenograft model of B-cell leukemia where a heterogenous mixture of transgenic Nalm6 leukemia cells was used to mimic tumor heterogeneity. Assessment of the bone marrow revealed the unique capacity of each target modality to eliminate its target designated Nalm6 leukemia group, with tri-modal iT cells effectively clearing all populations (Figure 1). In summary, using the unique approach to engineer iPSCs at the clonal level to create a distinct population of engineered iT cells, we successfully demonstrated the compatibility between CAR, TCR, and hnCD16 to mitigate tumor heterogeneity. This approach is an ideal strategy to create off-the-shelf cellular immunotherapy for a promising therapeutic approach to combat heterogeneous and difficult to treat solid tumors, including those that are resistant due to antigen escape. Figure 1 Figure 1. Disclosures Yang: Fate Therapeutics, Inc.: Current Employment. Lin: Fate Therapeutics, Inc.: Current Employment. Shirinbak: Fate Therapeutics, Inc.: Current Employment. Pribadi: Fate Therapeutics, Inc.: Current Employment. Chu: Fate Therapeutics, Inc.: Current Employment. Gutierrez: Fate Therapeutics, Inc.: Current Employment. Mehta: Fate Therapeutics, Inc.: Current Employment. Avramis: Fate Therapeutics, Inc.: Current Employment. Whitlock: Fate Therapeutics, Inc.: Current Employment. ORourke: Fate Therapeutics, Inc.: Current Employment. van der Stegen: Fate Therapeutics, Inc.: Current Employment. Lee: Fate Therapeutics, Inc.: Current Employment. Witty: Fate Therapeutics, Inc.: Current Employment. Peralta: Fate Therapeutics, Inc.: Current Employment. Hosking: Fate Therapeutics: Current Employment. Chang: Fate Therapeutics, Inc.: Current Employment. Valamehr: Fate Therapeutics, Inc.: Current Employment.
تدمد: 1528-0020
0006-4971
DOI: 10.1182/blood-2021-153268
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_________::6247b3a5df20a5dfa135ea0c4e547c0e
https://doi.org/10.1182/blood-2021-153268
Rights: OPEN
رقم الانضمام: edsair.doi...........6247b3a5df20a5dfa135ea0c4e547c0e
قاعدة البيانات: OpenAIRE
ResultId 1
Header edsair
OpenAIRE
edsair.doi...........6247b3a5df20a5dfa135ea0c4e547c0e
834
3

unknown
833.678283691406
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&scope=site&db=edsair&AN=edsair.doi...........6247b3a5df20a5dfa135ea0c4e547c0e&custid=s6537998&authtype=sso
FullText Array ( [Availability] => 0 )
Array ( [0] => Array ( [Url] => https://explore.openaire.eu/search/publication?articleId=doi_________::6247b3a5df20a5dfa135ea0c4e547c0e# [Name] => EDS - OpenAIRE [Category] => fullText [Text] => View record in OpenAIRE [MouseOverText] => View record in OpenAIRE ) )
Items Array ( [Name] => Title [Label] => Title [Group] => Ti [Data] => Combination of Three Unique Anti-Tumor Modalities Engineered into iPSC-Derived T Cells Demonstrate a Synergistic Effect in Overcoming Tumor Heterogeneity and Cancer Escape )
Array ( [Name] => Author [Label] => Authors [Group] => Au [Data] => <searchLink fieldCode="AR" term="%22Bi-Huei+Yang%22">Bi-Huei Yang</searchLink><br /><searchLink fieldCode="AR" term="%22Sjoukje+J%2E+C%2E+van+der+Stegen%22">Sjoukje J. C. van der Stegen</searchLink><br /><searchLink fieldCode="AR" term="%22Soheila+Shirinbak%22">Soheila Shirinbak</searchLink><br /><searchLink fieldCode="AR" term="%22Mochtar+Pribadi%22">Mochtar Pribadi</searchLink><br /><searchLink fieldCode="AR" term="%22Jason+ORourke%22">Jason ORourke</searchLink><br /><searchLink fieldCode="AR" term="%22Chia-Wei+Chang%22">Chia-Wei Chang</searchLink><br /><searchLink fieldCode="AR" term="%22Alec+Witty%22">Alec Witty</searchLink><br /><searchLink fieldCode="AR" term="%22Martin+P%2E+Hosking%22">Martin P. Hosking</searchLink><br /><searchLink fieldCode="AR" term="%22Amit+R%2E+Mehta%22">Amit R. Mehta</searchLink><br /><searchLink fieldCode="AR" term="%22Earl+Avramis%22">Earl Avramis</searchLink><br /><searchLink fieldCode="AR" term="%22Eigen+Peralta%22">Eigen Peralta</searchLink><br /><searchLink fieldCode="AR" term="%22Yu-Sheng+Eason+Lin%22">Yu-Sheng Eason Lin</searchLink><br /><searchLink fieldCode="AR" term="%22Benjamin+M%2E+Whitlock%22">Benjamin M. Whitlock</searchLink><br /><searchLink fieldCode="AR" term="%22Roseanna+Petrovic%22">Roseanna Petrovic</searchLink><br /><searchLink fieldCode="AR" term="%22Thomas+H%2E+Lee%22">Thomas H. Lee</searchLink><br /><searchLink fieldCode="AR" term="%22Wen-I+Yeh%22">Wen-I Yeh</searchLink><br /><searchLink fieldCode="AR" term="%22Alma+Gutierrez%22">Alma Gutierrez</searchLink><br /><searchLink fieldCode="AR" term="%22Hui-yi+Chu%22">Hui-yi Chu</searchLink><br /><searchLink fieldCode="AR" term="%22Bahram+Valamehr%22">Bahram Valamehr</searchLink> )
Array ( [Name] => TitleSource [Label] => Source [Group] => Src [Data] => <i>Blood</i>. 138:2793-2793 )
Array ( [Name] => Publisher [Label] => Publisher Information [Group] => PubInfo [Data] => American Society of Hematology, 2021. )
Array ( [Name] => DatePubCY [Label] => Publication Year [Group] => Date [Data] => 2021 )
Array ( [Name] => Subject [Label] => Subject Terms [Group] => Su [Data] => <searchLink fieldCode="DE" term="%22Antitumor+activity%22">Antitumor activity</searchLink><br /><searchLink fieldCode="DE" term="%22Modalities%22">Modalities</searchLink><br /><searchLink fieldCode="DE" term="%22business%2Eindustry%22">business.industry</searchLink><br /><searchLink fieldCode="DE" term="%22Immunology%22">Immunology</searchLink><br /><searchLink fieldCode="DE" term="%22Cancer+research%22">Cancer research</searchLink><br /><searchLink fieldCode="DE" term="%22Medicine%22">Medicine</searchLink><br /><searchLink fieldCode="DE" term="%22Cancer%22">Cancer</searchLink><br /><searchLink fieldCode="DE" term="%22Cell+Biology%22">Cell Biology</searchLink><br /><searchLink fieldCode="DE" term="%22Hematology%22">Hematology</searchLink><br /><searchLink fieldCode="DE" term="%22business%22">business</searchLink><br /><searchLink fieldCode="DE" term="%22medicine%2Edisease%22">medicine.disease</searchLink><br /><searchLink fieldCode="DE" term="%22Biochemistry%22">Biochemistry</searchLink><br /><searchLink fieldCode="DE" term="%22Tumor+heterogeneity%22">Tumor heterogeneity</searchLink> )
Array ( [Name] => Abstract [Label] => Description [Group] => Ab [Data] => Chimeric antigen receptor (CAR) is known to trigger an effective immune response through surface antigen recognition enhanced by T-cell activation signal one (ex. CD3) and signal two (ex. CD28); however, targeting neoantigens and intracellular antigens remains a challenge. On the other hand, the T-cell receptor (TCR) can target neo/intracellular antigens presented by MHC molecules, but often the response is not as potent. The CD16 Fc receptor, which is naturally expressed on NK cells, mediates antibody-dependent cellular cytotoxicity (ADCC), but its application in T cells is yet not fully appreciated. Utilizing our proprietary induced pluripotent stem cell (iPSC) platform to engineer multiple modalities into a clonal iPSC line, which can serve as the starting cell source for mass production of off-the-shelf, iPSC-derived CAR-T cells (CAR-iT cells), we aimed to study the combination of these three targeting modalities, CAR, TCR, and CD16 (tri-modal), to determine whether challenges associated with the treatment of heterogeneous tumors may be overcome. To evaluate the benefit of the three distinct targeting modalities, we tested the functional activity of individual and various combinations of i) anti-CD19 CAR, anti-MICA/B CAR, and anti-BCMA CAR, ii) high-affinity, non-cleavable CD16 (hnCD16), and iii) MR1 and NYESO1 TCR modalities in iT cells. All tested combinations successfully expressed the designated edits and differentiated into iT cells (T-lymphocytes > 95%). Initially, we tested CD19 CAR and MR1 TCR in a 9-day serial killing assay of Nalm6 leukemia cells (CD19 high, MR1 +), where we observed CD19 CAR-iT cells induce prompt CAR-mediated tumor growth inhibition (TGI), saw similar effective killing by MR1 TCR-iT cells but with a 24-hr delay, and observed the most effective response of tumor cell elimination when both where combined in the same iT cell population (relative tumor counts; Day 1, no stim: 2.6, CAR: 0.28, TCR: 1.02, CAR+TCR: 0.02; Day 2, no stim: 5.36, CAR: 0.25, TCR: 0.05, CAR+TCR: 0.02). All conditions (CAR, TCR, and CAR+TCR) reached and maintained complete TGI by Day 9 of the assay (relative tumor count, Day 9, no stim: 50.97, all other stim conditions: 90%), indicating a synergistic effect and compatibility between CAR and TCR. Assessing anti-MICA/B CAR and hnCD16, we confirmed the hnCD16-mediated response in iT cells in the presence of anti-MICA/B CAR when crosslinking hnCD16 via biotinylated anti-CD16 antibody with streptavidin (phosphorylated CD3zeta peaked at 10 min upon ADCC triggering), indicating the compatibility between a CAR-iT cell and the hnCD16 motif. Lastly, combining iT cells expressing anti-BCMA CAR + MR1 TCR + hnCD16 with daratumumab (anti-CD38 mAb) in a 9-day serial killing assay demonstrated the best TGI among the groups with a near-elimination of transgenic Nalm6 cells (area under curve, no stim: 30.29, TCR: 1.564, CAR: 0.7087, hnCD16+mAb: 1.452, trimodal+mAb: 0.5824). To assess the function of the tri-modal iT cells in vivo, we used a disseminated xenograft model of B-cell leukemia where a heterogenous mixture of transgenic Nalm6 leukemia cells was used to mimic tumor heterogeneity. Assessment of the bone marrow revealed the unique capacity of each target modality to eliminate its target designated Nalm6 leukemia group, with tri-modal iT cells effectively clearing all populations (Figure 1). In summary, using the unique approach to engineer iPSCs at the clonal level to create a distinct population of engineered iT cells, we successfully demonstrated the compatibility between CAR, TCR, and hnCD16 to mitigate tumor heterogeneity. This approach is an ideal strategy to create off-the-shelf cellular immunotherapy for a promising therapeutic approach to combat heterogeneous and difficult to treat solid tumors, including those that are resistant due to antigen escape. Figure 1 Figure 1. Disclosures Yang: Fate Therapeutics, Inc.: Current Employment. Lin: Fate Therapeutics, Inc.: Current Employment. Shirinbak: Fate Therapeutics, Inc.: Current Employment. Pribadi: Fate Therapeutics, Inc.: Current Employment. Chu: Fate Therapeutics, Inc.: Current Employment. Gutierrez: Fate Therapeutics, Inc.: Current Employment. Mehta: Fate Therapeutics, Inc.: Current Employment. Avramis: Fate Therapeutics, Inc.: Current Employment. Whitlock: Fate Therapeutics, Inc.: Current Employment. ORourke: Fate Therapeutics, Inc.: Current Employment. van der Stegen: Fate Therapeutics, Inc.: Current Employment. Lee: Fate Therapeutics, Inc.: Current Employment. Witty: Fate Therapeutics, Inc.: Current Employment. Peralta: Fate Therapeutics, Inc.: Current Employment. Hosking: Fate Therapeutics: Current Employment. Chang: Fate Therapeutics, Inc.: Current Employment. Valamehr: Fate Therapeutics, Inc.: Current Employment. )
Array ( [Name] => ISSN [Label] => ISSN [Group] => ISSN [Data] => 1528-0020<br />0006-4971 )
Array ( [Name] => DOI [Label] => DOI [Group] => ID [Data] => 10.1182/blood-2021-153268 )
Array ( [Name] => URL [Label] => Access URL [Group] => URL [Data] => <link linkTarget="URL" linkTerm="https://explore.openaire.eu/search/publication?articleId=doi_________::6247b3a5df20a5dfa135ea0c4e547c0e" linkWindow="_blank">https://explore.openaire.eu/search/publication?articleId=doi_________::6247b3a5df20a5dfa135ea0c4e547c0e</link><br /><link linkTarget="URL" linkTerm="https://doi.org/10.1182/blood-2021-153268" linkWindow="_blank">https://doi.org/10.1182/blood-2021-153268</link> )
Array ( [Name] => Copyright [Label] => Rights [Group] => Cpyrght [Data] => OPEN )
Array ( [Name] => AN [Label] => Accession Number [Group] => ID [Data] => edsair.doi...........6247b3a5df20a5dfa135ea0c4e547c0e )
RecordInfo Array ( [BibEntity] => Array ( [Identifiers] => Array ( [0] => Array ( [Type] => doi [Value] => 10.1182/blood-2021-153268 ) ) [Languages] => Array ( [0] => Array ( [Text] => Undetermined ) ) [PhysicalDescription] => Array ( [Pagination] => Array ( [PageCount] => 1 [StartPage] => 2793 ) ) [Subjects] => Array ( [0] => Array ( [SubjectFull] => Antitumor activity [Type] => general ) [1] => Array ( [SubjectFull] => Modalities [Type] => general ) [2] => Array ( [SubjectFull] => business.industry [Type] => general ) [3] => Array ( [SubjectFull] => Immunology [Type] => general ) [4] => Array ( [SubjectFull] => Cancer research [Type] => general ) [5] => Array ( [SubjectFull] => Medicine [Type] => general ) [6] => Array ( [SubjectFull] => Cancer [Type] => general ) [7] => Array ( [SubjectFull] => Cell Biology [Type] => general ) [8] => Array ( [SubjectFull] => Hematology [Type] => general ) [9] => Array ( [SubjectFull] => business [Type] => general ) [10] => Array ( [SubjectFull] => medicine.disease [Type] => general ) [11] => Array ( [SubjectFull] => Biochemistry [Type] => general ) [12] => Array ( [SubjectFull] => Tumor heterogeneity [Type] => general ) ) [Titles] => Array ( [0] => Array ( [TitleFull] => Combination of Three Unique Anti-Tumor Modalities Engineered into iPSC-Derived T Cells Demonstrate a Synergistic Effect in Overcoming Tumor Heterogeneity and Cancer Escape [Type] => main ) ) ) [BibRelationships] => Array ( [HasContributorRelationships] => Array ( [0] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Bi-Huei Yang ) ) ) [1] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Sjoukje J. C. van der Stegen ) ) ) [2] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Soheila Shirinbak ) ) ) [3] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Mochtar Pribadi ) ) ) [4] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Jason ORourke ) ) ) [5] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Chia-Wei Chang ) ) ) [6] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Alec Witty ) ) ) [7] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Martin P. Hosking ) ) ) [8] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Amit R. Mehta ) ) ) [9] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Earl Avramis ) ) ) [10] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Eigen Peralta ) ) ) [11] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Yu-Sheng Eason Lin ) ) ) [12] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Benjamin M. Whitlock ) ) ) [13] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Roseanna Petrovic ) ) ) [14] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Thomas H. Lee ) ) ) [15] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Wen-I Yeh ) ) ) [16] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Alma Gutierrez ) ) ) [17] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Hui-yi Chu ) ) ) [18] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Bahram Valamehr ) ) ) ) [IsPartOfRelationships] => Array ( [0] => Array ( [BibEntity] => Array ( [Dates] => Array ( [0] => Array ( [D] => 05 [M] => 11 [Type] => published [Y] => 2021 ) ) [Identifiers] => Array ( [0] => Array ( [Type] => issn-print [Value] => 15280020 ) [1] => Array ( [Type] => issn-print [Value] => 00064971 ) [2] => Array ( [Type] => issn-locals [Value] => edsair ) [3] => Array ( [Type] => issn-locals [Value] => edsairFT ) ) [Numbering] => Array ( [0] => Array ( [Type] => volume [Value] => 138 ) ) [Titles] => Array ( [0] => Array ( [TitleFull] => Blood [Type] => main ) ) ) ) ) ) )
IllustrationInfo