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Methods for in vivo expansion of cd8+ t cells and prevention or treatment of gvhd

A technology of cells and therapeutic agents, applied in the field of in vivo expansion of CD8+ T cells to prevent or treat GVHD

Pending Publication Date: 2020-03-24
CITY OF HOPE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The role of IFN-γ in the pathogenesis of acute GVHD remains controversial

Method used

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  • Methods for in vivo expansion of cd8+ t cells and prevention or treatment of gvhd
  • Methods for in vivo expansion of cd8+ t cells and prevention or treatment of gvhd
  • Methods for in vivo expansion of cd8+ t cells and prevention or treatment of gvhd

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0129] Example 1: Donor CD4 + Effects of T cell depletion on GVHD prevention and GVL retention

[0130] This example shows that donor CD4 after HCT + Immediate transient depletion of T cells preserves strong GVL effects while effectively preventing both acute and chronic GVHD in multiple models.

[0131] A previous study showed that sorted CD8 from C57BL / 6 donors + T cells did not induce acute GVHD, but did induce chronic GVHD in lethally irradiated BALB / c recipients, as shown by histopathology of salivary glands, the prototypical target organ of chronic GVHD. Anti-CD4 mAbs against CD4 on days 15 and 30 + Treatment of T cell depletion can prevent the development of chronic GVHD, as shown by the prevention of tissue damage in all GVHD target tissues, especially in the salivary glands (11). Disclosed herein is 1) Donor CD4 in recipient spleen 7 days after passing HCT + Percentage and yield judgment of T, and CD4 + In vivo administration of anti-CD4 mAb on the day of ...

Embodiment 2

[0141] Example 2: Donor CD4 + Effects of T cell depletion on IFN-γ and IL-2

[0142] This example demonstrates that donor CD4 immediately after HCT + Depletion of T cells increased serum IFN-γ but decreased serum IL-2 concentrations.

[0143] In experiments in C57BL / 6 donors and BALB / c recipients, in vivo donor CD4 immediately after HCT was explored + How T cell depletion prevents acute GVHD while preserving GVL effects. High serum levels of IFN-[gamma] and TNF-[alpha] have been associated with acute GVHD (41). Contrary to expectations, donor CD4 + Depletion of T cells increased serum IFN-γ concentrations by approximately 3-fold (p Figure 11 A). Elevated serum levels of IFN-γ are attributed to donor CD8 in lymphoid tissue + Expansion of T cells because of IFN-γ in the spleen of anti-CD4-treated recipients + CD8 + The number of T cells was approximately 3-fold higher than in rat IgG-treated recipients (p+ IFN-γ in T cells + The percentage of cells is similar ( F...

Embodiment 3

[0144] Example 3: Donor CD4 + Depletion of T cells affects donor CD8 in lymphoid tissue + The effect of T cell number

[0145] This example demonstrates that donor CD4 immediately after HCT + Depletion of T cells increases donor CD8 in lymphoid tissues + The number of T cells.

[0146] Next, the in vivo CD4 + T cell depletion on donor CD8 + Effects on T cell expansion and tissue distribution. H-2K in spleen and MLN of anti-CD4 treated recipients at day 5 after HCT b+ donor CD8 + The number of T cells was lower than that of rat IgG-treated recipients (P Figure 11 C). Donor CD8 in the spleen, PLN, and MLN of anti-CD4-treated recipients 7–10 days after HCT + The number of T cells was approximately 3-fold higher than in control IgG-treated recipients (p Figure 11 C). By day 28, donor CD8 + T cells re-expanded in the lymphoid tissue of anti-CD4 treated recipients but not in IgG treated recipients, and IgG treated recipients showed severe lymphopenia ( Figure 1...

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Abstract

The present invention discloses methods of preventing and treating acute GVHD and chronic GVHD after hematopoietic cell transplantation (HCT), as well as methods of in vivo augmenting expansion of donor CD8+ T cells in the lymphoid tissues in vivo after HCT and methods of augmenting recipient tissue expression of programmed death-ligand 1 (PD-L1, or B7H1) after HCT. The methods entail administering one or more doses of an effective amount of a therapeutic agent to a recipient simultaneously, immediately before, or immediately after HCT to temporarily deplete CD4+ T cells or to reduce serum IL-2. Some examples include an anti-CD4 antibody or an anti-CD4-meditope-immunotoxin, an anti-IL-2 antibody, an agent blocking IL-2R, and / or a PD-L1-Ig. One or more additional therapeutic agents such asIFN-y can be administered.

Description

[0001] claim of priority [0002] This application claims the benefit of US Provisional Application No. 62 / 462,853, filed February 23, 2017, which is incorporated herein by reference in its entirety. [0003] Statement of Government Interest [0004] This invention was made with government support under Grant Nos. R01 AI066008, 2R56AI66008-11, R01AI095239, and P30CA033572 awarded by the National Institutes of Health (NIH). The government owns certain rights in inventions. Background technique [0005] Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for hematological malignancies (i.e., leukemia and lymphoma), benefiting from alloreactive T cell-mediated graft-versus leukemia / lymphoma ( GVL) effect. These same T cells also mediate the development of acute graft-versus-host disease (GVHD) and subsequent chronic GVHD (1-9). alloreactive CD4 + and CD8 + Both T cells mediate acute GVHD, and Th1 and Th17 cells play a key role in initiating gastrointe...

Claims

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Application Information

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IPC IPC(8): A61K35/28A61K39/00A61P35/00A61P35/02
CPCA61K39/39A61K35/28A61K38/217C07K16/246C07K16/2812A61K2039/505C07K14/70532C07K2319/30A61P37/06A61K39/39541A61K39/3955A61K2300/00A61K45/06
Inventor 曾德福
Owner CITY OF HOPE
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