Similar Datasets
Project description:While T cell-based immunotherapies have shown promising clinical responses, current cancer treatments are restricted to autologous cellular products due to the risk of graft-versus-host disease (GvHD) by allogeneic cell transfer. Invariant natural killer T (iNKT) cells are ideal cell carriers for developing off-the-shelf allogeneic cellular therapy because they are powerful immune cells targeting a broad range of cancers without causing GvHD. However, current immunotherapies using iNKT cells are impeded by their extremely low number in cancer patients. In this study, we aimed to overcome this limitation by generating a large number of iNKT cells through TCR engineering of human hematopoietic stem cells (HSCs) and differentiation of HSCs to iNKT cells in an in vitro cultured system. Additionally, Chimeric antigen receptor (CAR) engineering and the CRISPR-Cas9 gene editing tool were utilized to enhance the tumor killing efficacy of iNKT cells and eliminate HLA molecules on their surface, making the cellular product suitable for cancer therapy and allogeneic adoptive transfer. Our results demonstrated successful generation of the promising off-the-shelf B cell maturation antigen (BCMA)-CAR engineered iNKT cells for treating multiple myeloma, and the same strategy will be applied to multiple cellular products for treating other cancers.
2021-12-01 | GSE164500 | GEO
Project description:While T cell-based immunotherapies have shown promising clinical responses, current cancer treatments are restricted to autologous cellular products due to the risk of graft-versus-host disease (GvHD) by allogeneic cell transfer. Invariant natural killer T (iNKT) cells are ideal cell carriers for developing off-the-shelf allogeneic cellular therapy because they are powerful immune cells targeting a broad range of cancers without causing GvHD. However, current immunotherapies using iNKT cells are impeded by their extremely low number in cancer patients. In this study, we aimed to overcome this limitation by generating a large number of iNKT cells through TCR engineering of human hematopoietic stem cells (HSCs) and differentiation of HSCs to iNKT cells in an in vitro cultured system. Additionally, Chimeric antigen receptor (CAR) engineering and the CRISPR-Cas9 gene editing tool were utilized to enhance the tumor killing efficacy of iNKT cells and eliminate HLA molecules on their surface, making the cellular product suitable for cancer therapy and allogeneic adoptive transfer. Our results demonstrated successful generation of the promising off-the-shelf B cell maturation antigen (BCMA)-CAR engineered iNKT cells for treating multiple myeloma, and the same strategy will be applied to multiple cellular products for treating other cancers.
2021-12-01 | GSE164425 | GEO
Project description:Generation of Allogeneic Hematopoietic Stem Cell-Engineered Invariant Natural Killer T cells for Off-the-Shelf Immunotherapy
| PRJNA691019 | ENA
Project description:BackgroundNew COVID-19 treatments are desperately needed as case numbers continue to rise and emergent strains threaten vaccine efficacy. Cell therapy has revolutionized cancer treatment and holds much promise in combatting infectious disease, including COVID-19. Invariant natural killer T (iNKT) cells are a rare subset of T cells with potent antiviral and immunoregulatory functions and an excellent safety profile. Current iNKT cell strategies are hindered by the extremely low presence of iNKT cells, and we have developed a platform to overcome this critical limitation.MethodsWe produced allogeneic HSC-engineered iNKT (AlloHSC-iNKT) cells through TCR engineering of human cord blood CD34+ hematopoietic stem cells (HSCs) and differentiation of these HSCs into iNKT cells in an Ex Vivo HSC-Derived iNKT Cell Culture. We then established in vitro SARS-CoV-2 infection assays to assess AlloHSC-iNKT cell antiviral and anti-hyperinflammation functions. Lastly, using in vitro and in vivo preclinical models, we evaluated AlloHSC-iNKT cell safety and immunogenicity for off-the-shelf application.ResultsWe reliably generated AlloHSC-iNKT cells at high-yield and of high-purity; these resulting cells closely resembled endogenous human iNKT cells in phenotypes and functionalities. In cell culture, AlloHSC-iNKT cells directly killed SARS-CoV-2 infected cells and also selectively eliminated SARS-CoV-2 infection-stimulated inflammatory monocytes. In an in vitro mixed lymphocyte reaction (MLR) assay and an NSG mouse xenograft model, AlloHSC-iNKT cells were resistant to T cell-mediated alloreaction and did not cause GvHD.ConclusionsHere, we report a method to robustly produce therapeutic levels of AlloHSC-iNKT cells. Preclinical studies showed that these AlloHSC-iNKT cells closely resembled endogenous human iNKT cells, could reduce SARS-CoV-2 virus infection load and mitigate virus infection-induced hyperinflammation, and meanwhile were free of GvHD-risk and resistant to T cell-mediated allorejection. These results support the development of AlloHSC-iNKT cells as a promising off-the-shelf cell product for treating COVID-19; such a cell product has the potential to target the new emerging SARS-CoV-2 variants as well as the future new emerging viruses.
| S-EPMC8935266 | biostudies-literature
Project description:Generation of Allogeneic Hematopoietic Stem Cell-Engineered Invariant Natural Killer T cells for Off-the-Shelf Immunotherapy [RNA-seq]
| PRJNA690603 | ENA
Project description:Generation of Allogeneic Hematopoietic Stem Cell-Engineered Invariant Natural Killer T cells for Off-the-Shelf Immunotherapy [VDJ-seq]
| PRJNA691020 | ENA
Project description:Invariant natural killer T (iNKT) cells are potent immune cells for targeting cancer; however, their clinical application has been hindered by their low numbers in cancer patients. Here, we developed a proof-of-concept for hematopoietic stem cell-engineered iNKT (HSC-iNKT) cell therapy with the potential to provide therapeutic levels of iNKT cells for a patient's lifetime. Using a human HSC engrafted mouse model and a human iNKT TCR gene engineering approach, we demonstrated the efficient and long-term generation of HSC-iNKT cells in vivo. These HSC-iNKT cells closely resembled endogenous human iNKT cells, could deploy multiple mechanisms to attack tumor cells, and effectively suppressed tumor growth in vivo in multiple human tumor xenograft mouse models. Preclinical safety studies showed no toxicity or tumorigenicity of the HSC-iNKT cell therapy. Collectively, these results demonstrated the feasibility, safety, and cancer therapy potential of the proposed HSC-iNKT cell therapy and laid a foundation for future clinical development.
| S-EPMC7018522 | biostudies-literature
Project description:Invariant natural killer T (iNKT) cells serve as a bridge between innate and adaptive immunity and have been shown to play an important role in immune regulation, defense against pathogens, and cancer immunity. Recent data also suggest that this compartment of the immune system plays a significant role in reducing graft-versus-host disease (GVHD) in the setting of allogeneic hematopoietic stem cell transplantation. Murine studies have shown that boosting iNKT numbers through certain conditioning regimens or adoptive transfer leads to suppression of acute or chronic GVHD. Preclinical work reveals that iNKT cells exert their suppressive function by expanding regulatory T cells in vivo, though the exact mechanism by which this occurs has yet to be fully elucidated. Human studies have demonstrated that a higher number of iNKT cells in the graft or in the peripheral blood of the recipient post-transplantation are associated with a reduction in GVHD risk, importantly without a loss of graft-versus-tumor effect. In two separate analyses of many immune cell subsets in allogeneic grafts, iNKT cell dose was the only parameter associated with a significant improvement in GVHD or in GVHD-free progression-free survival. Failure to reconstitute iNKT cells following allogeneic transplantation has also been associated with an increased risk of relapse. These data demonstrate that iNKT cells hold promise for future clinical application in the prevention of GVHD in allogeneic stem cell transplantation and warrant further study of the immunoregulatory functions of iNKT cells in this setting.
| S-EPMC5534641 | biostudies-other
Project description:Natural killer (NK) cells are part of the innate immune system and are an alluring option for immunotherapy due to their ability to kill infected cells or cancer cells without prior sensitization. Throughout the past 20 years, different groups have been able to reproduce NK cell development in vitro, and NK cell ontogeny studies have provided the basis for the establishment of protocols to produce NK cells in vitro for immunotherapy. Here, we briefly discuss NK cell development and NK cell immunotherapy approaches. We review the factors needed for NK cell differentiation in vitro, which stem cell sources have been used, published protocols, challenges and future directions for Good Manufacturing Practice protocols.
| S-EPMC4012863 | biostudies-literature
Project description:The most common cause of death in patients with acute myeloid leukemia (AML) who receive allogeneic hematopoietic stem cell transplantation (allo-HSCT) is AML relapse. Therefore, additive therapies post allo-HSCT have significant potential to prevent relapse. Natural killer (NK)-cell-based immunotherapies can be incorporated into the therapeutic armamentarium for the eradication of AML cells post allo-HSCT. In recent studies, NK cell-based immunotherapies, the use of adoptive NK cells, NK cells in combination with cytokines, immune checkpoint inhibitors, bispecific and trispecific killer cell engagers, and chimeric antigen receptor-engineered NK cells have all shown antitumor activity in AML patients. In this review, we will discuss the current strategies with these NK cell-based immunotherapies as possible therapies to cure AML patients post allo-HSCT. Additionally, we will discuss various means of immune escape in order to further understand the mechanism of NK cell-based immunotherapies against AML.
| S-EPMC6539946 | biostudies-literature