Methods of Generating T-Cells from Stem Cells and Immunotherapeutic Methods Using the T-Cells
Patent Number: WO2017075389A8
Executive Summary:
General Description:
Adoptive cell therapy using T cells engineered to express antigen-specific T cell receptors (TCR-T) or chimeric antigen receptors (CAR-T) offer targeted and potentially curative treatments for malignancy. Current approaches rely on the genetic modification and expansion of mature circulating T-cells. Such processes are limited to autologous T cells due to the risk of graft-versus-host (GvHD) disease from allogeneic T cells through endogenous TCR expression as well as rejection through MHC incompatibility. Furthermore, prolonged ex-vivo expansion of T cells may reduce in vivo efficacy and harvesting sufficient T cells from lymphopenic patients is challenging. Direct in vitro differentiation of engineered T cells from human pluripotent stem cells (HSPCs) may overcome these problems by providing an unlimited source of cells that can be genetically edited, permitting the suppression of endogenous TCR expression through allelic exclusion, and the de novo generation of naïve antigen-specific T cells. The invention includes development of an in vitro Artificial Thymic Organoid (ATO) system that induces highly efficient and reproducible production of mature naïve T cells from human hematopoietic stem cells and progenitor cells (HSPC).
Scientific Progress:
The invention has been tested in vitro and has potential for scalability for clinical use. Needs to scale up with equal efficacy.
Future Directions:
Strengths:
Weaknesses:
Patent Status:
Legal status: Pending
Publication PMID: 28369043
Publication:
Seet CS, He C, Bethune MT, Li S, Chick B, Gschweng EH, Zhu Y, Kim K, Kohn DB, Baltimore D, Crooks GM, Montel-Hagen A. Generation of mature T cells from human hematopoietic stem and progenitor cells in artificial thymic organoids. Nat Methods. 2017 May;14(5):521-530.
Inventor Bio: Gay Crooks
http://www.crooks-lab.com/about-the-pi
Executive Summary:
- Invention Type: Therapeutic
- Patent Status: Pending
- Patent Link: https://patents.google.com/patent/WO2017075389A8
- Research Institute: University of California, Los Angeles
- Disease Focus: Brain tumors
- Basis of Invention: Current engineered T cell therapies (including TCR-engineered and CAR-T approaches) rely on genetically modifying autologous peripheral blood T cells. The use of patient-specific autologous engineered T cell therapies is extremely labor and cost-intensive, of uncertain scalability, and in some cases may exclude patient populations who lack enough T cells. Given these many concerns, methods to generate safe “universal” or “off-the shelf” engineered non-alloreactive T cells therapies are a great unmet commercial need in the field of adoptive cellular therapy
- How it works: The inventors have developed human stem cells (including hematopoietic stem cells and pluripotent stem cells) that lack the expression of the genes RAG1 and/or RAG2, which, in combination with an introduced antigen specific receptor sequence and in vitro differentiation to effector T cells, can be used to generate non-alloreactive, antigen specific T cells for adoptive cell therapy for cancer and other diseases
- Lead Challenge Inventor: Gay Crooks
- Inventors: Gay Crooks, Christopher Seet, Amelie Montel Hagen
- Development Stage: Preclinical
- Novelty:
- Patients can use T cells, derived from donors
- Novel three-dimensional cell culture system to produce non-alloreactive T cells from less differentiated cells such as embryonic stem cells, pluripotent stem cells, hematopoietic stem or progenitor cells
- Clinical Applications:
- Exclude graft vs Host disease issue during adoptive T cell therapy
General Description:
Adoptive cell therapy using T cells engineered to express antigen-specific T cell receptors (TCR-T) or chimeric antigen receptors (CAR-T) offer targeted and potentially curative treatments for malignancy. Current approaches rely on the genetic modification and expansion of mature circulating T-cells. Such processes are limited to autologous T cells due to the risk of graft-versus-host (GvHD) disease from allogeneic T cells through endogenous TCR expression as well as rejection through MHC incompatibility. Furthermore, prolonged ex-vivo expansion of T cells may reduce in vivo efficacy and harvesting sufficient T cells from lymphopenic patients is challenging. Direct in vitro differentiation of engineered T cells from human pluripotent stem cells (HSPCs) may overcome these problems by providing an unlimited source of cells that can be genetically edited, permitting the suppression of endogenous TCR expression through allelic exclusion, and the de novo generation of naïve antigen-specific T cells. The invention includes development of an in vitro Artificial Thymic Organoid (ATO) system that induces highly efficient and reproducible production of mature naïve T cells from human hematopoietic stem cells and progenitor cells (HSPC).
Scientific Progress:
The invention has been tested in vitro and has potential for scalability for clinical use. Needs to scale up with equal efficacy.
Future Directions:
- Testing in syngeneic animal models
- Clinical validation
Strengths:
- Less labor and cost-intensive
- Works for patient populations lacking T cells
- No need for patient-derived T cells for gene editing
Weaknesses:
- Not yet tested in humans or rodent models
- Scalability with retained efficacy
- Regulatory challenges to establish safety and efficacy
Patent Status:
Legal status: Pending
- Priority date: 2015-10-30
- Filing date: 2016-10-28
- Publication date: 2018-05-24
Publication PMID: 28369043
Publication:
Seet CS, He C, Bethune MT, Li S, Chick B, Gschweng EH, Zhu Y, Kim K, Kohn DB, Baltimore D, Crooks GM, Montel-Hagen A. Generation of mature T cells from human hematopoietic stem and progenitor cells in artificial thymic organoids. Nat Methods. 2017 May;14(5):521-530.
Inventor Bio: Gay Crooks
http://www.crooks-lab.com/about-the-pi
