Cord blood-derived iNK T cells as a platform for allogeneic CAR T cell therapy
CD1d-restricted invariant Natural Killer (iNK) T cells are a suitable candidate for allogeneic Chimeric Antigen Receptor (CAR) T cell therapy as they do not cause graft-versus-host disease (GvHD) due to the monomorphic nature of CD1d proteins. However, the phenotypic and functional heterogeneity of...
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Frontiers Media S.A.
2025-05-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1621260/full |
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| author | Maison Grefe Abel Trujillo-Ocampo Jelita Clinton Hong He Ling Yu Dan Li Qing Ma Elizabeth J. Shpall Jeffrey J. Molldrem Jin S. Im Jin S. Im |
| author_facet | Maison Grefe Abel Trujillo-Ocampo Jelita Clinton Hong He Ling Yu Dan Li Qing Ma Elizabeth J. Shpall Jeffrey J. Molldrem Jin S. Im Jin S. Im |
| author_sort | Maison Grefe |
| collection | DOAJ |
| description | CD1d-restricted invariant Natural Killer (iNK) T cells are a suitable candidate for allogeneic Chimeric Antigen Receptor (CAR) T cell therapy as they do not cause graft-versus-host disease (GvHD) due to the monomorphic nature of CD1d proteins. However, the phenotypic and functional heterogeneity of iNK T cells from adult donors (AD) may lead to the inconstant CAR-iNK T cell products. Cord blood-derived (CB) iNK T cells, in contrast, exhibit inter-donor homogeneity in phenotype including uniform CD4 expression and are enriched in memory iNK T cell populations. Thus, we evaluated the preclinical therapeutic potential of iNK T cells derived from cord blood (CB) as an off the shelf CAR T cell therapy platform, given the dominant presence of CD4+ iNK T cells. First, CB-derived iNK T cells were extremely enriched with CD4+ iNK T cells that express various NK receptors and display iNK-TCR mediated cytotoxicity but in a lesser degree than AD-derived CD4- iNK T cells. When engineered with an 8F4CAR targeting the acute myeloid leukemia-associated antigen PR1 presented in HLA-A2*01, CB-8F4CAR-iNK T cells showed a greater expansion capacity with higher CD62L expression than AD-8F4CAR-iNK T cells but with similar 8F4CAR expression and iNK T purity. CB-8F4CAR-iNK T cells displayed in vitro cytotoxicity against PR1/HLA-A2+ primary Acute Myeloid Leukemia (AML) and cell lines better than AD-8F4CAR iNK T cells and maintained potent cytotoxicity in repeated antigenic challenges. Moreover, CB-8F4CAR-iNK T cells showed anti-leukemia activity in vivo in a dose dependent manner. Lastly, CB-8F4CAR-iNK T cells were polarized to produce Th2-biased cytokines but in a lesser amount after 8F4CAR-mediated leukemia cytolysis compared to iNK-TCR mediated activation. In conclusion, consistent CD4+ phenotype, superior expansion capacity, and enhanced CD62L expression of CB-CAR-iNK T cells suggest that they may provide an alternative off-the-shelf source for effective CAR-iNK T cell therapy, while reducing the risk of severe cytokine release syndrome through their immunomodulatory properties. Thus, our results support the potential use of CB-iNK T cells as an allogeneic CAR-T cell therapy platform as they maintain a potent cytotoxicity with potentially better safety profile given a Th2-biased cytokine production upon activation. |
| format | Article |
| id | doaj-art-0db22e8251bd4706b496a2676d97176a |
| institution | OA Journals |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-0db22e8251bd4706b496a2676d97176a2025-08-20T02:16:49ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-05-011610.3389/fimmu.2025.16212601621260Cord blood-derived iNK T cells as a platform for allogeneic CAR T cell therapyMaison Grefe0Abel Trujillo-Ocampo1Jelita Clinton2Hong He3Ling Yu4Dan Li5Qing Ma6Elizabeth J. Shpall7Jeffrey J. Molldrem8Jin S. Im9Jin S. Im10Department of Hematopoietic Biology & Malignancies, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Hematopoietic Biology & Malignancies, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Hematopoietic Biology & Malignancies, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Hematopoietic Biology & Malignancies, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Hematopoietic Biology & Malignancies, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Hematopoietic Biology & Malignancies, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Hematopoietic Biology & Malignancies, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Stem Cell Transplantation & Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Hematopoietic Biology & Malignancies, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Hematopoietic Biology & Malignancies, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Stem Cell Transplantation & Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesCD1d-restricted invariant Natural Killer (iNK) T cells are a suitable candidate for allogeneic Chimeric Antigen Receptor (CAR) T cell therapy as they do not cause graft-versus-host disease (GvHD) due to the monomorphic nature of CD1d proteins. However, the phenotypic and functional heterogeneity of iNK T cells from adult donors (AD) may lead to the inconstant CAR-iNK T cell products. Cord blood-derived (CB) iNK T cells, in contrast, exhibit inter-donor homogeneity in phenotype including uniform CD4 expression and are enriched in memory iNK T cell populations. Thus, we evaluated the preclinical therapeutic potential of iNK T cells derived from cord blood (CB) as an off the shelf CAR T cell therapy platform, given the dominant presence of CD4+ iNK T cells. First, CB-derived iNK T cells were extremely enriched with CD4+ iNK T cells that express various NK receptors and display iNK-TCR mediated cytotoxicity but in a lesser degree than AD-derived CD4- iNK T cells. When engineered with an 8F4CAR targeting the acute myeloid leukemia-associated antigen PR1 presented in HLA-A2*01, CB-8F4CAR-iNK T cells showed a greater expansion capacity with higher CD62L expression than AD-8F4CAR-iNK T cells but with similar 8F4CAR expression and iNK T purity. CB-8F4CAR-iNK T cells displayed in vitro cytotoxicity against PR1/HLA-A2+ primary Acute Myeloid Leukemia (AML) and cell lines better than AD-8F4CAR iNK T cells and maintained potent cytotoxicity in repeated antigenic challenges. Moreover, CB-8F4CAR-iNK T cells showed anti-leukemia activity in vivo in a dose dependent manner. Lastly, CB-8F4CAR-iNK T cells were polarized to produce Th2-biased cytokines but in a lesser amount after 8F4CAR-mediated leukemia cytolysis compared to iNK-TCR mediated activation. In conclusion, consistent CD4+ phenotype, superior expansion capacity, and enhanced CD62L expression of CB-CAR-iNK T cells suggest that they may provide an alternative off-the-shelf source for effective CAR-iNK T cell therapy, while reducing the risk of severe cytokine release syndrome through their immunomodulatory properties. Thus, our results support the potential use of CB-iNK T cells as an allogeneic CAR-T cell therapy platform as they maintain a potent cytotoxicity with potentially better safety profile given a Th2-biased cytokine production upon activation.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1621260/fullinvariant natural killer t cellscord bloodchimeric antigen receptoracute myeloid leukemiaCAR T cell therapy |
| spellingShingle | Maison Grefe Abel Trujillo-Ocampo Jelita Clinton Hong He Ling Yu Dan Li Qing Ma Elizabeth J. Shpall Jeffrey J. Molldrem Jin S. Im Jin S. Im Cord blood-derived iNK T cells as a platform for allogeneic CAR T cell therapy Frontiers in Immunology invariant natural killer t cells cord blood chimeric antigen receptor acute myeloid leukemia CAR T cell therapy |
| title | Cord blood-derived iNK T cells as a platform for allogeneic CAR T cell therapy |
| title_full | Cord blood-derived iNK T cells as a platform for allogeneic CAR T cell therapy |
| title_fullStr | Cord blood-derived iNK T cells as a platform for allogeneic CAR T cell therapy |
| title_full_unstemmed | Cord blood-derived iNK T cells as a platform for allogeneic CAR T cell therapy |
| title_short | Cord blood-derived iNK T cells as a platform for allogeneic CAR T cell therapy |
| title_sort | cord blood derived ink t cells as a platform for allogeneic car t cell therapy |
| topic | invariant natural killer t cells cord blood chimeric antigen receptor acute myeloid leukemia CAR T cell therapy |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1621260/full |
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