Development of allogeneic HSC-engineered iNKT cells for off-the-shelf cancer immunotherapy

Li, Yan-Ruide; Zhou, Yang; Kim, Yu Jeong; Zhu, Yu; Ma, Feiyang; Yu, Jiaji; Wang, Yu-Chen; Chen, Xianhui; Li, Zhe; Zeng, Samuel; Wang, Xi; Lee, Derek; Ku, Josh; Tsao, Tasha; Hardoy, Christian; Huang, Jie; Cheng, Donghui; Montel‐Hagen, Amélie; Seet, Christopher S.; Larson, Sarah; Sasine, Joshua P.; Wang, Xiaoyan; Pellegrini, Matteo; Ribas, Antoni; Kohn, Donald B.; Witte, Owen N.; Wang, Pin; Yang, Lili

doi:10.1016/j.xcrm.2021.100449

Cited by 54 publications

(109 citation statements)

References 91 publications

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“…Our labs specialize in developing cell therapies, particularly CAR-T and hematopoietic stem cell-engineered invariant natural killer T (CAR-HSC-iNKT) cell therapies, for cancer treatment [ 58 , 59 ]. While we validated IVIPL for application in i.p.…”

Section: Discussionmentioning

confidence: 99%

Minimally Invasive Preclinical Monitoring of the Peritoneal Cavity Tumor Microenvironment

Dunn

et al. 2022

Cancers

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Intraperitoneal (i.p.) experimental models in mice can recapitulate the process of i.p. dissemination in abdominal cancers and may help uncover critical information about future successful clinical treatments. i.p. cellular composition is studied in preclinical models addressing a wide spectrum of other pathophysiological states such as liver cirrhosis, infectious disease, autoimmunity, and aging. The peritoneal cavity is a multifaceted microenvironment that contains various immune cell populations, including T, B, NK, and various myeloid cells, such as macrophages. Analysis of the peritoneal cavity is often obtained by euthanizing mice and performing terminal peritoneal lavage. This procedure inhibits continuous monitoring of the peritoneal cavity in a single mouse and necessitates the usage of more mice to assess the cavity at multiple timepoints, increasing the cost, time, and variability of i.p. studies. Here, we present a simple, novel method termed in vivo intraperitoneal lavage (IVIPL) for the minimally invasive monitoring of cells in the peritoneal cavity of mice. In this proof-of-concept, IVIPL provided real-time insights into the i.p. tumor microenvironment for the development and study of ovarian cancer therapies. Specifically, we studied CAR-T cell therapy in a human high-grade serous ovarian cancer (HGSOC) xenograft mouse model, and we studied the immune composition of the i.p. tumor microenvironment (TME) in a mouse HGSOC syngeneic model.

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Section: Discussionmentioning

confidence: 99%

Minimally Invasive Preclinical Monitoring of the Peritoneal Cavity Tumor Microenvironment

Dunn

et al. 2022

Cancers

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“…The next steps are to incorporate modifications that allow the adoptively transferred cells to persistent autonomously, maintain proliferative potential, outmaneuver the immunosuppressive tumor microenvironment, infiltrate tumor beds, and stimulate endogenous antitumor immunity. Each of these goals has been addressed extensively in preclinical T and NK cell studies [ 163 , 164 , 165 , 166 ], such as through the exogenous expression of IL-15, immune checkpoint inhibitors, chemokine receptors, or immunomodulatory proteins, but are usually targeted individually or in pairs due to the limited genetic pliability of mature immune cells. Stem cell engineering opens the door for increasingly complex designer cell products, and future research will need to reveal if the accumulated changes hinder immune cell antitumor efficacy.…”

Section: Discussionmentioning

confidence: 99%

Development of Stem Cell-Derived Immune Cells for Off-the-Shelf Cancer Immunotherapies

Dunn

Zhou

et al. 2021

Cells

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Cell-based cancer immunotherapy has revolutionized the treatment of hematological malignancies. Specifically, autologous chimeric antigen receptor-engineered T (CAR-T) cell therapies have received approvals for treating leukemias, lymphomas, and multiple myeloma following unprecedented clinical response rates. A critical barrier to the widespread usage of current CAR-T cell products is their autologous nature, which renders these cellular products patient-selective, costly, and challenging to manufacture. Allogeneic cell products can be scalable and readily administrable but face critical concerns of graft-versus-host disease (GvHD), a life-threatening adverse event in which therapeutic cells attack host tissues, and allorejection, in which host immune cells eliminate therapeutic cells, thereby limiting their antitumor efficacy. In this review, we discuss recent advances in developing stem cell-engineered allogeneic cell therapies that aim to overcome the limitations of current autologous and allogeneic cell therapies, with a special focus on stem cell-engineered conventional αβ T cells, unconventional T (iNKT, MAIT, and γδ T) cells, and natural killer (NK) cells.

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“…Nevertheless, allogeneic iNKT cells must be somewhat edited to downregulate their MHC expression to avoid a possible rejection mediated by the allogeneic host immune system. To this purpose, iNKT cells have been differentiated in vitro from human hematopoietic stem cells that express very low levels of HLA-I and almost undetectable HLA-II molecules, which then can be further engineered with CARs to generate stealth anti-tumor effectors for the host immune response ( 106 ). An alternative strategy to generate off-the-shelf allogeneic iNKT cells, currently being assessed in early phase clinical trials for patients with progressing B cell malignancies (ANCHOR NCT03774654), relies in the co-expression of CD19-CAR, IL-15, and shRNAs targeting beta-2 microglobulin and CD74 to downregulate surface HLA class I and class II molecules.…”

Section: Inkt Cell Are Highly Suitable For Adoptive Immunotherapy Of ...mentioning

confidence: 99%

Adoptive Immunotherapy With Engineered iNKT Cells to Target Cancer Cells and the Suppressive Microenvironment

2022

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Invariant Natural Killer T (iNKT) cells are T lymphocytes expressing a conserved semi-invariant TCR specific for lipid antigens (Ags) restricted for the monomorphic MHC class I-related molecule CD1d. iNKT cells infiltrate mouse and human tumors and play an important role in the immune surveillance against solid and hematological malignancies. Because of unique functional features, they are attractive platforms for adoptive cells immunotherapy of cancer compared to conventional T cells. iNKT cells can directly kill CD1d-expressing cancer cells, but also restrict immunosuppressive myelomonocytic populations in the tumor microenvironment (TME) via CD1d-cognate recognition, promoting anti-tumor responses irrespective of the CD1d expression by cancer cells. Moreover, iNKT cells can be adoptively transferred across MHC barriers without risk of alloreaction because CD1d molecules are identical in all individuals, in addition to their ability to suppress graft vs. host disease (GvHD) without impairing the anti-tumor responses. Within this functional framework, iNKT cells are successfully engineered to acquire a second antigen-specificity by expressing recombinant TCRs or Chimeric Antigen Receptor (CAR) specific for tumor-associated antigens, enabling the direct targeting of antigen-expressing cancer cells, while maintaining their CD1d-dependent functions. These new evidences support the exploitation of iNKT cells for donor unrestricted, and possibly off the shelf, adoptive cell therapies enabling the concurrent targeting of cancer cells and suppressive microenvironment.

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Development of allogeneic HSC-engineered iNKT cells for off-the-shelf cancer immunotherapy

Cited by 54 publications

References 91 publications

Minimally Invasive Preclinical Monitoring of the Peritoneal Cavity Tumor Microenvironment

Minimally Invasive Preclinical Monitoring of the Peritoneal Cavity Tumor Microenvironment

Development of Stem Cell-Derived Immune Cells for Off-the-Shelf Cancer Immunotherapies

Adoptive Immunotherapy With Engineered iNKT Cells to Target Cancer Cells and the Suppressive Microenvironment

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