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Cancer immunotherapy

A technology of cancer cells and agonists, applied in the field of cancer immunotherapy, compositions for treating cancer patients, and kits

Inactive Publication Date: 2014-07-30
THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, local GM-CSF secreted by GVAX can mobilize myeloid precursors to become macrophages and dendritic cells, but this cytokine may not induce their activation

Method used

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Experimental program
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Effect test

Embodiment 1

[0057] Materials and methods

[0058] Mice and reagents: 6-8 week old female C57BL / 6, Balb / c, and C3H / HeOUJ mice (Jackson Laboratories) were maintained according to the Johns Hopkins Hospital (JHH) Animal Care and Use Committee. C57BL / 6MyD88 - / - TRIF - / - and B6(Cg)Rag2tml(Rag2 - / - ) mice were obtained from Dr. Franck Housseau and Dr. Fan Pan (JHH), respectively. B16 and B16GVAX cells were cultured in RPMI1640 medium containing 10%ΔFCS, penicillin (100U / ml) and streptomycin (100U / ml). Cytofix / Cytoperm kits and antibodies were purchased from BD Bioscience. CD11c+ cells were isolated by anti-mouse CD11c microBeads (MACS, Miltenyi Biotec). CD4 depleting GK1.5 antibody (CD4 depleting GK1.5 antibody) and CD8 depleting 2.43 (CD8 depleting 2.43) (Bio X Cell) were injected intraperitoneally once every 2 days (5 times in total). A hybridoma expressing a blocking anti-PD-1 antibody (clone G4) was obtained from Dr. Charles Drake (JHH).

[0059] Glucopyranosyl lipid A (GLA) at 1 mg / ...

Embodiment 2

[0067] Multiple TLR Agonist Enhanced GVAX (TEGVAX) Increases Both Conventional and Plasmacytoid Dendritic Cells Activated in Draining Lymph Nodes Compared to GVAX

[0068] To further increase the antitumor response produced by GVAX, we combined GLA and R848 with GVAX and tested whether this TEGVAX formulation would increase the number of activated dendritic cells in the DLN of non-tumor-bearing mice. Compared with GVAX, TEGVAX was able to enhance the activated phenotype of dendritic cells in the DLN from the vaccination site ( figure 1 ). Both plasmacytoid DCs (pDCs) and conventional DCs (cDCs) were analyzed, and both populations in the TEGVAX-treated group showed enhanced expression of CD80 and CD86 activation markers ( figure 1 A-C). On day 3 after adjuvant injection, gated DCs showed increased peak activation markers, and this persisted until day 7 ( figure 1 D). Finally, to assess whether these activated DCs provide a suitable cytokine environment for anti-tumor respon...

Embodiment 3

[0070] TEGVAX treatment of established tumors significantly reduces tumor growth rate in vivo

[0071] We initially tested our TEGVAX in a therapeutic model with established B16 tumors. When inoculated B16 tumors were palpable (usually on days 7-10), we treated tumor-bearing mice subcutaneously in the contralateral limb with TEGVAX, GVAX, GLA / R848 (IDC-1005), and vehicle control . Such as figure 2 As shown in A, mice receiving TEGVAX showed significantly lower tumor growth rates after only one treatment. Both GVAX alone and TLR agonists alone had some modest benefit, but combination therapy produced the best in vivo antitumor response. When we compared formulations of TEGVAX with GVAX with GLA alone or with R848 alone, we found that the combination of GLA / R848 formulations into GVAX had the best antitumor response (Supplementary figure 2 A).

[0072] To further enhance the anti-tumor response, we experimented with multiple TEGVAX treatments and found that none of the mu...

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Abstract

We formulated multiple TLR agonists into GVAX (lethally irradiated tumor cell vaccines engineered to secrete GM-CSF). Specifically, GLA and R848, TLR4 and TLR7 / 8 agonists found to be safe in patients, were formulated with GVAX (TEGVAX - for TLR agonists enhanced GVAX), and this formulation was effective in producing anti-tumor responses in 3 different preclinical models, including palpable B16. These anti-tumor responses were correlated with increased CD4 and CD8 T-cells that can secrete IFN circulating in the tumor microenvironment as well as significantly higher level of p15E specific CTL mediated cell killing in mice treated with TEGVAX in comparison to controls. When combined with anti-PD-1 antibody, TEGVAX was able to induce regression of established B16 tumors.

Description

[0001] This invention was made with support from the National Institutes of Health. Accordingly, the US Government reserves certain rights under the terms of Grant No. NIH K23-DE018464-02. [0002] invention technical field [0003] The present invention relates to the field of cancer therapy. In particular, the invention relates to cancer immunotherapy. Background of the invention [0004] Because of its extensive history of safety and availability in multiple tumor types, lethally irradiated tumor cell vaccine (GVAX) engineered to secrete GM-CSF is a promising candidate for use in conjunction with immune checkpoint blockers. (blockade) antibody vaccine platform for potential combination therapy. However, local GM-CSF secreted by GVAX can mobilize myeloid precursors to become macrophages and dendritic cells, but this cytokine may not induce their activation. Thus, the major limitation of GVAX is the activation of antigen presenting cells (APCs) necessary for optimal tumor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61K38/19A61K38/18A61P35/00
CPCA61K39/395A61K45/06A61K35/13C07K16/2818A61P35/00A61P35/02A61K2039/876A61K39/0011A61K2039/5152A61K2300/00A61K39/39A61K2039/55516
Inventor Y·J·金D·M·帕多略J·傅
Owner THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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