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Adoptive t-cell therapy for cmv infection and cmv-associated diseases

A cell and cell proliferation technology, applied in animal cells, vertebrate cells, preparation methods of peptides, etc., can solve problems such as increasing the risk of transplant rejection

Pending Publication Date: 2021-04-23
COUNCIL OF THE QUEENSLAND INST OF MEDICAL RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Reducing immunosuppression may be used to improve viral control but increases risk of transplant rejection

Method used

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  • Adoptive t-cell therapy for cmv infection and cmv-associated diseases
  • Adoptive t-cell therapy for cmv infection and cmv-associated diseases
  • Adoptive t-cell therapy for cmv infection and cmv-associated diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0126] Example 1: Patient Characteristics

[0127] To assess the safety of autologous T cell therapy in solid organ transplant (SOT) recipients with CMV-related complications, patients were selected and considered eligible once they met one of the following four criteria:

[0128] (A) CMV reactivation or disease (as defined by histology) following successful initial therapy, e.g., ganciclovir-resistant CMV reactivation;

[0129] (B) Persistent CMV disease, i.e. unresponsive to 2 weeks of salvage foscarnet or other second-line antiviral agents, e.g., recurrent CMV relapse due to refractory to second-line drug therapy;

[0130] (C) Persistence of CMV replication (over 6 weeks by PCR) despite appropriate antiviral therapy; or

[0131] (D) Any CMV reactivation or disease when antiviral therapy is contraindicated based on intolerance or end-organ limitation (eg, renal insufficiency, bone marrow insufficiency), such as end-organ CMV disease or intolerance to antiviral therapy by...

Embodiment 2

[0156] Example 2: Preparation for T cell therapy

[0157]To generate CMV-specific T-cell therapy, peripheral blood mononuclear cells (PBMCs) obtained from each patient were separately stimulated with a clinical-grade CMV peptide pool in the presence of IL-21 (day 0, 40 ng / mL) Predefined HLA class I and II restricted peptide epitopes including pp65, pp50, IE-1, gH and gB (Table 1). Stimulated samples were then plated in Grex-10 flasks (WilsonWolf Corporation, Saint Paul, MN) at 2-5 x 10 6 cells / cm 2 cultured at the starting cell density. These cultures were supplemented with IL-2 (120 IU / mL) on day 2 and every three days thereafter. On day 14, expanded T cells were harvested and frozen in 1 mL single-dose aliquots in Alpexex 4 (CSLBehring, Broadmeadows, Australia) containing 10% dimethyl sulfoxide (WAK-Chemie Medical GmbH, Steinbach, Germany) in the sample. T cells were tested for microbial contamination prior to infusion and characterized for phenotype and function usin...

Embodiment 3

[0167] Example 3: Clinical Outcomes After Adoptive Immunotherapy

[0168] None of the patients who received adoptive CMV-specific T-cell therapy exhibited treatment-related grade 3, 4, or 5 adverse events (Table 4). All adverse events considered at least possibly attributable to T-cell infusion were grade 1 and 2, including fatigue and malaise. Importantly, no adverse events related to changes in graft status were detected. Clinical follow-up of patients designated for T-cell therapy intervention showed that 11 of 13 patients showed objective symptom improvement. These improvements include reducing or resolving CMV reactivation and / or disease, as well as improving response to antiviral drug therapy. Among the 11 patients who demonstrated clinical response, the median peak viral load prior to adoptive T-cell therapy was 3.2 × 10 4 CMV copies / mL blood (range 1.4 × 10 3 –3.44×10 5 copy). Median viral load decreased to 1.2 × 10 after adoptive immunotherapy 3 CMV copies / mL...

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Abstract

Provided herein are immunogenic polypeptides, compositions, and methods related to the development of CMV-specific prophylactic and / or therapeutic immunotherapy based on T cell epitopes (e.g., CMV epitopes) that are recognized by cytotoxic T cells (CTLs) and can be employed in the prevention and / or treatment of CMV infection, reactivation, and / or disease (e.g., CMV-associated end organ disease), especially in solid organ transplant recipients.

Description

[0001] Related applications [0002] This application claims the benefit of priority to US Provisional Patent Application Serial No. 62 / 673,260, filed May 18, 2018, the entire contents of which are incorporated herein by reference. Background technique [0003] Herpesviruses represent a large and nearly ubiquitous family of eukaryotic viruses associated with various animal and human diseases. The Herpesviridae share several structures in common, for example, a double-stranded, linear DNA genome, and a virion comprising an icosahedral capsid that itself is encapsulated in the viral coat and lipid bilayer (viruses film). In addition, herpesviruses contain characteristic and highly conserved glycoproteins that are carried on the lipid bilayer envelope of herpesvirus virions. At least some of these glycoproteins play a role in initial viral adhesion to the cell surface and subsequent penetration into the cell. [0004] Members of the herpesvirus family represent important human...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K7/08C07K14/045A61K38/08A61K38/10A61K35/17A61K39/245G01N33/53
CPCA61K39/245A61K38/08A61K38/10A61P31/22A61K41/00C07K1/08C40B40/10A61K2039/605A61K39/295C07K7/06C07K7/08A61K2239/31A61K39/464838A61K2239/38A61K39/4611C12N5/0636A61K39/12A61P31/20C12N2710/16134C12N2710/16122A61K38/00C07K14/045C07K14/005C07K14/70539C12N2501/2302A61K35/17A61K2039/5158C12N2501/998
Inventor R·康纳C·史密斯
Owner COUNCIL OF THE QUEENSLAND INST OF MEDICAL RES
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