Neoantigen-specific stimulation of tumor-infiltrating lymphocytes enables effective TCR isolation and expansion while preserving stem-like memory phenotypes
Background Tumor-infiltrating lymphocytes (TILs) targeting neoantigens can effectively treat a selected set of metastatic solid cancers. However, harnessing TILs for cancer treatments remains challenging because neoantigen-reactive T cells are often rare and exhausted, and ex vivo expansion can furt...
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BMJ Publishing Group
2024-05-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/5/e008645.full |
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| author | Yong Li Steven A Rosenberg Paul F Robbins Zhiya Yu Maria Parkhurst Billel Gasmi Nikolaos Zacharakis Todd D Prickett Jared J Gartner Sri Krishna Stephanie L Goff Satyajit Ray Frank J Lowery Sivasish Sindiri Alakesh Bera Noam Levin Sanghyun P Kim Charles A Marquardt Nolan R Vale Lior Levy Tiffany Benzine Robert V Masi Rafiqul Islam |
| author_facet | Yong Li Steven A Rosenberg Paul F Robbins Zhiya Yu Maria Parkhurst Billel Gasmi Nikolaos Zacharakis Todd D Prickett Jared J Gartner Sri Krishna Stephanie L Goff Satyajit Ray Frank J Lowery Sivasish Sindiri Alakesh Bera Noam Levin Sanghyun P Kim Charles A Marquardt Nolan R Vale Lior Levy Tiffany Benzine Robert V Masi Rafiqul Islam |
| author_sort | Yong Li |
| collection | DOAJ |
| description | Background Tumor-infiltrating lymphocytes (TILs) targeting neoantigens can effectively treat a selected set of metastatic solid cancers. However, harnessing TILs for cancer treatments remains challenging because neoantigen-reactive T cells are often rare and exhausted, and ex vivo expansion can further reduce their frequencies. This complicates the identification of neoantigen-reactive T-cell receptors (TCRs) and the development of TIL products with high reactivity for patient treatment.Methods We tested whether TILs could be in vitro stimulated against neoantigens to achieve selective expansion of neoantigen-reactive TILs. Given their prevalence, mutant p53 or RAS were studied as models of human neoantigens. An in vitro stimulation method, termed “NeoExpand”, was developed to provide neoantigen-specific stimulation to TILs. 25 consecutive patient TILs from tumors harboring p53 or RAS mutations were subjected to NeoExpand.Results We show that neoantigenic stimulation achieved selective expansion of neoantigen-reactive TILs and broadened the neoantigen-reactive CD4+ and CD8+ TIL clonal repertoire. This allowed the effective isolation of novel neoantigen-reactive TCRs. Out of the 25 consecutive TIL samples, neoantigenic stimulation enabled the identification of 16 unique reactivities and 42 TCRs, while conventional TIL expansion identified 9 reactivities and 14 TCRs. Single-cell transcriptome analysis revealed that neoantigenic stimulation increased neoantigen-reactive TILs with stem-like memory phenotypes expressing IL-7R, CD62L, and KLF2. Furthermore, neoantigenic stimulation improved the in vivo antitumor efficacy of TILs relative to the conventional OKT3-induced rapid TIL expansion in p53-mutated or KRAS-mutated xenograft mouse models.Conclusions Taken together, neoantigenic stimulation of TILs selectively expands neoantigen-reactive TILs by frequencies and by their clonal repertoire. NeoExpand led to improved phenotypes and functions of neoantigen-reactive TILs. Our data warrant its clinical evaluation.Trial registration number NCT00068003, NCT01174121, and NCT03412877. |
| format | Article |
| id | doaj-art-f685ba7746d3429ab6dd6d6e8a83fc10 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-05-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-f685ba7746d3429ab6dd6d6e8a83fc102025-02-03T05:00:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-05-0112510.1136/jitc-2023-008645Neoantigen-specific stimulation of tumor-infiltrating lymphocytes enables effective TCR isolation and expansion while preserving stem-like memory phenotypesYong Li0Steven A Rosenberg1Paul F Robbins2Zhiya Yu3Maria Parkhurst4Billel Gasmi5Nikolaos Zacharakis6Todd D Prickett7Jared J Gartner8Sri Krishna9Stephanie L Goff10Satyajit Ray11Frank J Lowery12Sivasish Sindiri13Alakesh Bera14Noam Levin15Sanghyun P Kim16Charles A Marquardt17Nolan R Vale18Lior Levy19Tiffany Benzine20Robert V Masi21Rafiqul Islam221 Singapore Eye Research Institute, Singapore National Eye Centre, Singapore1National Cancer Institute, NIH, Bethesda, MD, USA2National Cancer Institute, National Institutes of Health, Surgery Branch, Bethesda, MD, USA1National Cancer Institute, NIH, Bethesda, MD, USA1National Cancer Institute, Bethesda, MD, USASurgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA1National Cancer Institute, National Institutes of Health, Bethesda, MD, USASurgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USASurgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA1National Cancer Institute, NIH, Bethesda, MD, USA1National Cancer Institute, NIH, Bethesda, MD, USA1National Cancer Institute, National Institutes of Health, Bethesda, MD, USA1National Cancer Institute, NIH, Bethesda, MD, USASurgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USASurgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USASurgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA1National Cancer Institute, NIH, Bethesda, MD, USASurgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USASurgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USASurgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USASurgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USASurgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USASurgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USABackground Tumor-infiltrating lymphocytes (TILs) targeting neoantigens can effectively treat a selected set of metastatic solid cancers. However, harnessing TILs for cancer treatments remains challenging because neoantigen-reactive T cells are often rare and exhausted, and ex vivo expansion can further reduce their frequencies. This complicates the identification of neoantigen-reactive T-cell receptors (TCRs) and the development of TIL products with high reactivity for patient treatment.Methods We tested whether TILs could be in vitro stimulated against neoantigens to achieve selective expansion of neoantigen-reactive TILs. Given their prevalence, mutant p53 or RAS were studied as models of human neoantigens. An in vitro stimulation method, termed “NeoExpand”, was developed to provide neoantigen-specific stimulation to TILs. 25 consecutive patient TILs from tumors harboring p53 or RAS mutations were subjected to NeoExpand.Results We show that neoantigenic stimulation achieved selective expansion of neoantigen-reactive TILs and broadened the neoantigen-reactive CD4+ and CD8+ TIL clonal repertoire. This allowed the effective isolation of novel neoantigen-reactive TCRs. Out of the 25 consecutive TIL samples, neoantigenic stimulation enabled the identification of 16 unique reactivities and 42 TCRs, while conventional TIL expansion identified 9 reactivities and 14 TCRs. Single-cell transcriptome analysis revealed that neoantigenic stimulation increased neoantigen-reactive TILs with stem-like memory phenotypes expressing IL-7R, CD62L, and KLF2. Furthermore, neoantigenic stimulation improved the in vivo antitumor efficacy of TILs relative to the conventional OKT3-induced rapid TIL expansion in p53-mutated or KRAS-mutated xenograft mouse models.Conclusions Taken together, neoantigenic stimulation of TILs selectively expands neoantigen-reactive TILs by frequencies and by their clonal repertoire. NeoExpand led to improved phenotypes and functions of neoantigen-reactive TILs. Our data warrant its clinical evaluation.Trial registration number NCT00068003, NCT01174121, and NCT03412877.https://jitc.bmj.com/content/12/5/e008645.full |
| spellingShingle | Yong Li Steven A Rosenberg Paul F Robbins Zhiya Yu Maria Parkhurst Billel Gasmi Nikolaos Zacharakis Todd D Prickett Jared J Gartner Sri Krishna Stephanie L Goff Satyajit Ray Frank J Lowery Sivasish Sindiri Alakesh Bera Noam Levin Sanghyun P Kim Charles A Marquardt Nolan R Vale Lior Levy Tiffany Benzine Robert V Masi Rafiqul Islam Neoantigen-specific stimulation of tumor-infiltrating lymphocytes enables effective TCR isolation and expansion while preserving stem-like memory phenotypes Journal for ImmunoTherapy of Cancer |
| title | Neoantigen-specific stimulation of tumor-infiltrating lymphocytes enables effective TCR isolation and expansion while preserving stem-like memory phenotypes |
| title_full | Neoantigen-specific stimulation of tumor-infiltrating lymphocytes enables effective TCR isolation and expansion while preserving stem-like memory phenotypes |
| title_fullStr | Neoantigen-specific stimulation of tumor-infiltrating lymphocytes enables effective TCR isolation and expansion while preserving stem-like memory phenotypes |
| title_full_unstemmed | Neoantigen-specific stimulation of tumor-infiltrating lymphocytes enables effective TCR isolation and expansion while preserving stem-like memory phenotypes |
| title_short | Neoantigen-specific stimulation of tumor-infiltrating lymphocytes enables effective TCR isolation and expansion while preserving stem-like memory phenotypes |
| title_sort | neoantigen specific stimulation of tumor infiltrating lymphocytes enables effective tcr isolation and expansion while preserving stem like memory phenotypes |
| url | https://jitc.bmj.com/content/12/5/e008645.full |
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