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Modified t cells and methods of making and using the same

A cell and lymphocyte technology, applied in the field of modified T cells and their preparation and use

Pending Publication Date: 2018-03-27
PRESIDENT & FELLOWS OF HARVARD COLLEGE 17 Q
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The present invention is directed to other solutions that address this need and have other desirable features

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  • Modified t cells and methods of making and using the same
  • Modified t cells and methods of making and using the same
  • Modified t cells and methods of making and using the same

Examples

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[0310] 教导以上含磷键的制备的代表性美国专利包括但不限于美国专利号3,687,808;4,469,863;4,476,301;5,023,243;5,177,195;5,188,897;5,264,423;5,276,019;5,278,302;5,286,717;5,321,131;5,399,676;5,405,939;5,453,496;5,455,233;5,466,677 ;5,476,925;5,519,126;5,536,821;5,541,316;5,550,111;5,563,253;5,571,799;5,587,361;5,625,050;6,028,188;6,124,445;6,160,109;6,169,170;6,172,209;6,239,265;6,277,603;6,326,199;6,346,614;6,444,423;6,531,590;6,534,639;6,608,035;6,683,167;6,858,715;6,867,294 6,878,805; 7,015,315; 7,041,816; 7,273,933; 7,321,029; and US Patent RE39464, each of which is incorporated herein by reference in its entirety.

[0311] Modified internucleoside linkages in which the phosphorus atom is not included have short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatoms and alkyl or cycloalkyl internucleoside linkages, or one or more short chain Internucleoside linkages formed by heteroatom or heterocyclic internucleoside linkages. These include those with morpholino linkages (formed in part fro...

Embodiment 1

[0346] Example 1: Identification of CRISPR guide ribonucleic acid (gRNA) that efficiently removes endogenous TCR from primary human T cells to prevent autoreactivity of CART cells.

[0347] Prevention of autoreactivity has the highest priority to improve existing T cell-based therapies. The present invention aims to develop gRNAs with high on-target and no / low off-target activity that allow efficient and safe deletion of the endogenous T-cell receptor (TCR) in primary human T cells. The inventors designed multiple gRNAs targeting the TCR α and β chain loci (TRA and TRB) located on chromosomes 14 and 7, respectively ( Figure 10 ). Each gRNA first uses SURVEYOR TM Assays (data not shown) were tested for the ability to direct site-specific mutations in HEK293T cells. Then by flow cytometry (FACS) and SURVEYOR TM The gRNA candidate with the highest on-target efficiency was analyzed to assess functional TCR depletion in Jurkat T cells (FIG. 11A and FIG. 11B). Directions are d...

Embodiment 2

[0348] Example 2: Allogeneic T cells for CAR-T therapy.

[0349] T cell-based therapies are currently limited to the infusion of autologous cells obtained from the same patient. Extending the origin of T cells to allogeneic sources by generating universally applicable cell products will not only greatly reduce costs, but also open the door to a wider range of patients for this novel and promising class of therapies.

[0350] Complete loss of MHC class I surface expression can be achieved using CRISPR gRNA targeting the gene encoding accessory strand β2 microglobulin (B2M). The present inventors have recently identified gRNAs targeting B2M with extremely high on-target efficiency, which may have been adapted for use in gene therapy (Mandal et al., "Efficient Ablation of Genes in Human Hematopoietic Stem and Effector Cells using CRISPR / Cas9" Cell Stem Cell, 15:5, 643-652 (2014); Meissner et al., "Genome editing for human gene therapy," Methods inenzymology, 546, 273-295 (2014);...

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Abstract

Disclosed herein are modified primary human T cells and populations thereof comprising a genome in which the CTLA4, PD1, TCRA, TCRB, and / or B2M genes have been edited to generate an off-the-shelf universal CAR T cell from allogeneic healthy donors that can be administered to any patient while reducing or eliminating the risk of immune rejection or graft versus host disease, and which are not proneto T cell inhibition, and methods for allogeneic administration of such cells to reduce the likelihood that the cells will trigger a host immune response when the cells are administered to a subjectin need of such cells.

Description

[0001] related application [0002] This application claims the benefit of US Provisional Application No. 62 / 139,479, filed March 27, 2015, the entire teachings of which are incorporated herein by reference. [0003] governmental support [0004] This invention was made with government support under grant R01DK097768 from the National Institutes of Health. The US Government has rights in this invention. Background of the invention [0005] T cell therapy using chimeric antigen receptors (CARs) represents a major breakthrough in cancer immunotherapy (eg, adoptive immunotherapy) and serves as a new form of treatment especially for viral and fungal infections. Several obstacles currently prevent the safe translation of CART therapies, such as the risk of autoreactivity of endogenous T-cell receptors (TCRs), T-cell suppression by cancerous or infected cells, and dependence on autologous T-cell grafts. Summary of the invention [0006] There is a need for modified T cells and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K35/17C12N15/85
CPCC12N5/0636C12N15/85C12N15/1138C07K14/70521C07K14/7051C07K14/70539C12N2510/00C12N2310/20C12N2800/107A61K39/4644A61K2239/26A61K39/4611A61K39/4631C12N5/0638A61K2035/124A61P31/04A61P35/00A61P37/06C12N15/102A61K35/17A61K2039/5156A61K2039/5158
Inventor 托斯滕·B·迈斯纳卡本戈·Y·穆隆巴莱奥纳尔多·M·R·费雷拉沙达·A·考恩
Owner PRESIDENT & FELLOWS OF HARVARD COLLEGE 17 Q
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