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Compositions and methods to modify cells for therapeutic objectives

a technology of cells and molecules, applied in the field of compositions and methods to modify cells for therapeutic objectives, can solve the problems of ineffective anti-managed cells, depletion of immune system resources, and ineffective conventional vaccine approaches against cancer cells and cells affected by certain infectious diseases

Inactive Publication Date: 2016-05-26
FRED HUTCHINSON CANCER RES CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent is about using a special method to modify cells of the immune system to target specific markers on harmful or unwanted cells. This approach allows for selective destruction of harmful cells without damaging healthy tissue. The modified cells can be manufactured on a large scale and stored for a long time, making them suitable for wide distribution and inexpensive treatment. The patent also describes using booster doses or altering the administered composition over time to target different types of cells. This approach provides a potentially effective treatment for various disease states.

Problems solved by technology

The biological processes underlying conventional vaccines, however, can render them ineffective against many unwanted cells based on, among other factors, the time it takes to prime the immune system, the amount or degree to which the natural immune system can be primed against certain unwanted cell types and over time, the depletion of immune system resources.
As examples, conventional vaccine approaches can be ineffective against cancer cells and cells affected by certain infectious diseases.
The immune response using this approach, however, requires months to mature and during this time, cancers can significantly progress and become fatal.
Thus, conventional vaccines do not provide an adequate method to target and destroy unwanted cancer cells.
However, T-cell transfer therapies are also time and labor-intense and must be personalized for each patient in cell production facilities, which are available only at a few highly specialized cancer centers worldwide.
Similar issues are encountered with a number of other unwanted cell types.

Method used

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  • Compositions and methods to modify cells for therapeutic objectives
  • Compositions and methods to modify cells for therapeutic objectives
  • Compositions and methods to modify cells for therapeutic objectives

Examples

Experimental program
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Effect test

example 1

[0287]This example demonstrates that synthetic nanoparticles containing TCR genes can be used to generate functional tumor- or virus-specific T-cells. Lipid nanoparticles (FIG. 2A) were loaded with a minicircle gene (FIG. 3) encoding the chimeric antigen receptor P28z. P28z is a fusion receptor composed of a single-chain antibody (scFv) specific for the extracellular domain of PSMA (J591) combined with CD28 and CD3 cytoplasmic signaling domains (FIG. 4A; SEQ ID NO. 94). In this Example, chimeric antigen receptors (CARs) are fusion receptors including an antigen-binding domain, a transmembrane domain and an intracellular signaling domain resulting in T-cell activation after antigen binding. The P28z CAR directs T-cells toward the prostate-specific membrane antigen (PSMA), which is highly expressed on prostate cancer cells. Therefore, the introduction of the P28z gene into T-cells renders them capable of recognizing and lysing prostate tumor. The P28z gene was cloned under the control...

example 2

[0291]CD3-targeted protocell nanoparticles selectively bind circulating T cells in mice. A goal of the current disclosure is to selectively and quickly edit lymphocyte specificity in vivo to target unwanted cells. To examine how selectively protocells bind circulating host T cells, mice were systemically injected with 1×1011 fluorescently tagged nanoparticles. After 6 hours peripheral blood was collected by retro-orbital puncture and the percentage of fluorescent T cells was quantified by flow cytometry. CD3-targeted protocells labeled the majority of T cells in the blood, with relatively low binding to off-target cells (FIG. 4E, left panel). Confocal imaging of sorted T cells showed that nanoparticles are rapidly internalized from the cell surface into the cytoplasm as a result of receptor-induced endocytosis (FIG. 4E, right panel).

example 3

[0292]Generating an orthotopic bioluminescent mouse model for analyzing treatment of metastatic prostate cancer. Male TRAMP transgenic mice spontaneously develop orthotopic prostate tumors following puberty. However, unlike human prostate adenocarcinoma, TRAMP tumors do not express significant amounts of PSMA, a target in experiments using the P28z CAR. Furthermore, longitudinal studies to measure the prostate cancer volume in TRAMP animals rely on expensive and time-consuming magnetic resonance imaging (MRI) techniques, which preclude analysis of large cohorts of mice. To overcome these issues, a cell line from a primary TRAMP tumor was established and the PSMA gene was introduced through retroviral transduction. To serially monitor tumor burden by bioluminescence imaging, tumor cells were also genetically tagged with Firefly luciferase (FLuc). Following orthotopic transplantation into the dorsal lobe of the prostate gland of C57BL / 6 mice, TRAMP-PSMA-FLuc tumor cells reproducibly d...

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Abstract

The present disclosure provides compositions and methods that rapidly and selectively modify cells of the immune system to achieve therapeutic objectives. The methods can be practiced in vivo and any cell type that expresses a known marker can be targeted for a therapeutic objective. The present disclosure provides compositions and methods that rapidly and selectively modify cells of the immune system to achieve therapeutic objectives. The methods can be practiced in vivo and any cell type that expresses or is associated with a known marker can be targeted for a therapeutic objective by the modified cell.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Patent Application No. 61 / 785,907, filed Mar. 14, 2013, which is incorporated herein by reference in its entirety.FIELD OF THE DISCLOSURE[0002]The present disclosure provides compositions and methods that rapidly and selectively modify cells of the immune system to achieve therapeutic objectives. The methods can be practiced in vivo and any cell type that expresses or is associated with a known marker can be targeted for a therapeutic objective by the modified cell.BACKGROUND OF THE DISCLOSURE[0003]One of the primary goals of clinical health research is to develop compositions and methods that rapidly and selectively direct cells of the immune system to achieve therapeutic objectives. For example, vaccines are used to prime the immune system to target antigens associated with unwanted cells. The biological processes underlying conventional vaccines, however, can render them ineffective ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/40C07K14/725A61K39/395C07K16/28A61K38/17C07K14/705A61K47/48
CPCC07K16/40C07K14/70521C07K14/7051A61K47/48561A61K47/48823C07K2317/622A61K38/1774A61K39/3955C07K2319/74C07K2319/03A61K48/00C07K16/2815A61K9/0019A61K9/1271A61K9/5123A61K38/177C12N15/88C12N2810/859C07K16/3069A61K47/6849A61K47/6913A61K39/464453A61K39/4632A61K39/4631A61K39/4611A61K39/464838A61K2239/58A61K39/464495A61K47/6455A61K47/645
Inventor STEPHAN, MATTHIAS
Owner FRED HUTCHINSON CANCER RES CENT
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