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Continuous Cell Programming Devices

a cell and continuous technology, applied in the field of continuous cell programming devices, can solve the problems of slow research on using dendritic cells for therapeutic benefits, and achieve the effects of reducing tumor progression, reducing tumor progression, and improving immune responses to cancer antigens

Inactive Publication Date: 2016-08-04
PRESIDENT & FELLOWS OF HARVARD COLLEGE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0006]The methods are used to treat a wide variety of diseases and to develop vaccines against a wide variety of antigens. In a preferred embodiment, the present invention is used to develop a cancer vaccine. Another preferred embodiment of the present invention comprises an infection-mimicking microenvironment with means to activate the host immune system and subsequently induce an immune response. The use of a synthetic cytosine-guanosine oligonucleotide (CpG-ODN) sequence with exogenous granulocyte macrophage colony stimulating factor (GM-CSF) provides a method for precisely controlling dendritic cell migration and modulating antigen-specific immune responses. In fact, the new approach of using of this synthetic cytosine-gyanosine oligonucleotide (CpG-ODN) sequence demonstrates significant improvements and provides a new avenue for development of immune therapy.
[0039]The inability of traditional and ex vivo DC-based vaccination strategies to coordinate and sustain an immune response mediated by the heterogeneous DC network in cancer patients has led to limited clinical effectiveness of these approaches. The devices and methods described herein have distinct advantages, because preferential recruitment and expansion of pDCs dramatically improves immune responses to cancer antigens and reduces tumor progression compared to previous vaccine approaches.

Problems solved by technology

Research focused on using dendritic cells for a therapeutic benefit has been slow because dendritic cells are rare and difficult to isolate.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

PLG Devices Loaded with GM-CSF

[0168]PLG matrices loaded with 3 μg of GM-CSF were implanted into the subcutaneous pockets of C57BL / 6J mice. The macroporous PLG matrix presents GM-CSF, danger signals, and cancer antigens in a defined spatiotemporal manner in vivo, and serves as a residence for recruited DCs as they are programmed. These matrices released approximately 60% of their bioactive GM-CSF load within the first 5 days, followed by slow and sustained release of bioactive GM-CSF over the next 10 days (FIG. 11A) to effectively recruit resident DCs.

[0169]The matrices were made as follows. A 85:15, 120 kD copolymer of D,L-lactide and glycolide (PLG) (Alkermes, Cambridge, Mass.) was utilized in a gas-foaming process to form macroporous PLG matrices (Harris, L L S., Kim, B. S., and Mooney, D. J. Open pore biodegradable matrices formed with gas foaming. J. Biomed. Mater. Res. 42,396-402 (1998)). GM-CSF was encapsulated (54% efficiency) into PLG scaffolds using a high pressure CO2 foam...

example 2

Condensation of Synthetic CpG-ODN Molecules Increases Cellular Uptake

[0182]Synthetic CpG-ODN molecules were condensed with PEI, which resulted in positively charged, small PEI-CpG-ODN condensates that facilitates cellular internalization via promoting association with the cell membrane and enhancing transmembrane transport (FIG. 2). ODN Condensation at charge ratios of 7 and 15, between the amine groups of PEI and the phosphate groups of ODNs, resulted in optimal particle sizes and positive charge (FIGS. 2B and C), but a charge ratio of 7 was utilized in experiments due to PEI toxicity at high doses.

[0183]PEI condensation of CpG-ODN dramatically enhanced nucleotide uptake into DCs in vitro (FIG. 3A-C). Quantification of CpG-ODN uptake into DCs revealed orders of magnitude differences (up to ˜100-fold) between ODN condensates and naked ODN, which were maintained for extended time periods (>80 hrs) in vitro (FIG. 3C). The complexes subsequently decondense (FIG. 3D) allowing for CpG-OD...

example 3

CpG-ODN Induced DC Activation and DC Mobilization

[0184]Because effective CpG stimulation of DCs requires intercellular localization, the effects of PEI-condensation were evaluated on DC activation. DCs stimulated with PEI-CpG-ODN in vitro exhibited enhanced levels of CD86, MHCII and CCR7 expression, in comparison to those stimulated with naked CpG-ODN, which correlated strongly with DC uptake of condensates (FIGS. 4A and B). DCs exhibited an activated morphology, upon cellular uptake of PEI-CpG-ODN including the development of fine needle-like dendrites and large membrane expansion, which allows mature DCs to “wrap-up” T-cells promoting strong cell-cell interactions. The activation states of PEI-CpG-ODN stimulated DCs mirrored or surpassed that of positive controls stimulated with TNF-α and LPS (FIG. 3C) and PEI-CpG-ODN condensates promoted a 3-fold increase in DC migration toward CCL19 in vitro, over unstimulated DCs (FIG. 4D).

[0185]PEI-CpG-ODN condensates also released DCs from GM...

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Abstract

The present invention comprises compositions, methods, and devices for creating an infection-mimicking environment within a polymer scaffold to stimulate antigen-specific dendritic cell activation. Devices of the present invention are used to provide protective immunity to subjects against infection and cancer.

Description

RELATED APPLICATIONS[0001]This application is a continuation of U.S. Ser. No. 12 / 867,426, which is a national stage application, filed under 35 U.S.C. §371, of International Application No. PCT / US2009 / 000914, filed Feb. 13, 2009, claiming the benefit of priority of U.S. Provisional Application No. 61 / 143,630 filed Jan. 9, 2009 and U.S. Provisional Application No. 61 / 065,672 filed Feb. 13, 2008, the contents of which are incorporated by reference in their entireties.GOVERNMENT SUPPORT[0002]This invention was made with Government support under R37 DE013033 awarded by the National Institutes of Health. The Government has certain rights in the invention.INCORPORATION-BY-REFERENCE OF SEQUENCE LISTING[0003]The contents of the text file named “29297_044_Sequence_Listing.txt”, which was created on Apr. 21, 2016 and is 19.5 KB in size, is hereby incorporated by reference in its entirety.BACKGROUND OF THE INVENTION[0004]Dendritic cells are the most potent activators of the immune system among...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/39A61K45/06A61K39/00
CPCA61K39/39A61K2039/55561A61K2039/55588A61K39/0011A61K2039/6093A61K45/06A61K2039/54A61K2039/55522A61K2039/55516A61K31/4745A61K31/708A61K31/7088A61K38/193A61P35/00A61P37/02A61P37/04
Inventor MOONEY, DAVID J.ALI, OMAR ABDEL-RAHMANDRANOFF, GLENN
Owner PRESIDENT & FELLOWS OF HARVARD COLLEGE
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