Unedited allogeneic iNKT cells show extended persistence in MHC-mismatched canine recipients

Rotolo, Antonia; Whelan, Eoin C.; Atherton, Matthew J.; Kulikovskaya, Irina; Jarocha, Danuta; Fraietta, Joseph A.; Kim, Michele M.; Diffenderfer, Eric S.; Cengel, Keith A.; Piviani, Martina; Radaelli, Enrico; Duran-Struuck, Raimon; Mason, Nicola J.

doi:10.1016/j.xcrm.2023.101241

Cell Reports Medicine

2023

DOI: 10.1016/j.xcrm.2023.101241

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Unedited allogeneic iNKT cells show extended persistence in MHC-mismatched canine recipients

Antonia Rotolo,

Eoin C. Whelan,

Matthew J. Atherton

et al.

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2024

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Cited by 3 publications

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Human CD4⁺iNKT cell adoptive immunotherapy induces anti‐tumour responses against CD1d‐negative EBV‐driven B lymphoma

Baiu,

Sharma,

Schehr

et al. 2024

Immunology

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Invariant natural killer T (iNKT) cells are a conserved population of innate T lymphocytes that are uniquely suitable as off‐the‐shelf cellular immunotherapies due to their lack of alloreactivity. Two major subpopulations of human iNKT cells have been delineated, a CD4− subset that has a TH1/cytolytic profile, and a CD4+ subset that appears polyfunctional and can produce both regulatory and immunostimulatory cytokines. Whether these two subsets differ in anti‐tumour effects is not known. Using live cell imaging, we found that CD4− iNKT cells limited growth of CD1d+ Epstein–Barr virus (EBV)‐infected B‐lymphoblastoid spheroids in vitro, whereas CD4+ iNKT cells showed little or no direct anti‐tumour activity. However, the effects of the two subsets were reversed when we tested them as adoptive immunotherapies in vivo using a xenograft model of EBV‐driven human B cell lymphoma. We found that EBV‐infected B cells down‐regulated CD1d in vivo, and administering CD4− iNKT cells had no discernable impact on tumour mass. In contrast, xenotransplanted mice bearing lymphomas showed rapid reduction in tumour mass after administering CD4+ iNKT cells. Immunotherapeutic CD4+ iNKT cells trafficked to both spleen and tumour and were associated with subsequently enhanced responses of xenotransplanted human T cells against EBV. CD4+ iNKT cells also had adjuvant‐like effects on monocyte‐derived DCs and promoted antigen‐dependent responses of human T cells in vitro. These results show that allogeneic CD4+ iNKT cellular immunotherapy leads to marked anti‐tumour activity through indirect pathways that do not require tumour cell CD1d expression and that are associated with enhanced activity of antigen‐specific T cells.

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Human CD4⁺iNKT cell adoptive immunotherapy induces anti‐tumour responses against CD1d‐negative EBV‐driven B lymphoma

Baiu,

Sharma,

Schehr

et al. 2024

Immunology

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Applications and Opportunities for Immune Cell CAR Engineering in Comparative Oncology

Rotolo,

Atherton

2024

Clinical Cancer Research

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Chimeric antigen receptor (CAR) T adoptive cell therapy has transformed the treatment of human hematologic malignancies. However, its application for the treatment of solid tumors remains challenging. An exciting avenue for advancing this field lies in the use of pet dogs, in which cancers that recapitulate the biology, immunological features, and clinical course of human malignancies arise spontaneously. Moreover, their large size, outbred genetic background, shared environment with humans, and immunocompetency make dogs ideal for investigating and optimizing CAR therapies before human trials. Here, we will outline how challenges in early clinical trials in canine lymphoma patients, including issues related to autologous CAR-T cell manufacturing, limited CAR-T cell persistence, and tumor antigen escape, mirrored challenges observed in human CAR-T trials. We will then highlight emerging adoptive cell therapy strategies currently under investigation in dogs with hematological and solid cancers, that will provide crucial safety and efficacy data on novel CAR-T regimens that can be used to support clinical trials. By drawing from ongoing studies, we will illustrate how canine patients with spontaneous cancer may serve as compelling screening platforms to establish innovative CAR-therapy approaches and identify predictive biomarkers of response, with a specific emphasis on solid tumors. With increased funding for canine immunotherapy studies, multi-institutional investigations are poised to generate highly impactful clinical data that should translate into more effective human trials, ultimately benefiting both human and canine cancer patients.

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Traversing the bench to bedside journey for iNKT cell therapies

O’Neal,

Mavers,

Jayasinghe

et al. 2024

Front. Immunol.

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Invariant natural killer T (iNKT) cells are immune cells that harness properties of both the innate and adaptive immune system and exert multiple functions critical for the control of various diseases. Prevention of graft-versus-host disease (GVHD) by iNKT cells has been demonstrated in mouse models and in correlative human studies in which high iNKT cell content in the donor graft is associated with reduced GVHD in the setting of allogeneic hematopoietic stem cell transplants. This suggests that approaches to increase the number of iNKT cells in the setting of an allogeneic transplant may reduce GVHD. iNKT cells can also induce cytolysis of tumor cells, and murine experiments demonstrate that activating iNKT cells in vivo or treating mice with ex vivo expanded iNKT cells can reduce tumor burden. More recently, research has focused on testing anti-tumor efficacy of iNKT cells genetically modified to express a chimeric antigen receptor (CAR) protein (CAR-iNKT) cells to enhance iNKT cell tumor killing. Further, several of these approaches are now being tested in clinical trials, with strong safety signals demonstrated, though efficacy remains to be established following these early phase clinical trials. Here we review the progress in the field relating to role of iNKT cells in GVHD prevention and anti- cancer efficacy. Although the iNKT field is progressing at an exciting rate, there is much to learn regarding iNKT cell subset immunophenotype and functional relationships, optimal ex vivo expansion approaches, ideal treatment protocols, need for cytokine support, and rejection risk of iNKT cells in the allogeneic setting.

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Unedited allogeneic iNKT cells show extended persistence in MHC-mismatched canine recipients

Cited by 3 publications

References 87 publications

Human CD4⁺iNKT cell adoptive immunotherapy induces anti‐tumour responses against CD1d‐negative EBV‐driven B lymphoma

Human CD4⁺iNKT cell adoptive immunotherapy induces anti‐tumour responses against CD1d‐negative EBV‐driven B lymphoma

Applications and Opportunities for Immune Cell CAR Engineering in Comparative Oncology

Traversing the bench to bedside journey for iNKT cell therapies

Contact Info

Product

Resources

About

Unedited allogeneic iNKT cells show extended persistence in MHC-mismatched canine recipients

Cited by 3 publications

References 87 publications

Human CD4+iNKT cell adoptive immunotherapy induces anti‐tumour responses against CD1d‐negative EBV‐driven B lymphoma

Human CD4+iNKT cell adoptive immunotherapy induces anti‐tumour responses against CD1d‐negative EBV‐driven B lymphoma

Applications and Opportunities for Immune Cell CAR Engineering in Comparative Oncology

Traversing the bench to bedside journey for iNKT cell therapies

Contact Info

Product

Resources

About

Human CD4⁺iNKT cell adoptive immunotherapy induces anti‐tumour responses against CD1d‐negative EBV‐driven B lymphoma

Human CD4⁺iNKT cell adoptive immunotherapy induces anti‐tumour responses against CD1d‐negative EBV‐driven B lymphoma