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Treatment of cancer by infusion of oncolytic herpes simplex virus to the blood

Inactive Publication Date: 2018-09-06
VIRTTU BIOLOGICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0041]Sagiv-Barfi et al reported that ibrutinib, an inhibitor of ITK, an essential enzyme in Th2 T cells can shift the balance between Th1 and Th2 T cells towards Th1 and thereby enhance anti-tumor responses. They describe the combination of anti-PD-L1 antibody and ibrutinib to suppress tumor growth in

Problems solved by technology

The dosing regime involves numerous injections in different locations, which is generally disadvantageous for the patient.
It has also failed to statistically establish an overall survival benefit in any group of patients and shows limited evidence of a systemic effect, particularly in late stage and visceral disease.
Administration to human patients is exclusively by injection with notable patient reactions and the pre-clinical data indicates an unsuitability for systemic administration.
In many animal models, oncolytic viruses (including oncolytic herpes simplex viruses) work spectacularly well but repeating the results in human trials has proven challenging.
Brain tumors, deep-seated visceral tumors and multiple active metastases pose considerable barriers to successful intratumoral administration and attempts to treat such tumors are often accompanied by significant safety and technical issues, cost and resource requirements.
As reported in the Imlygic® data, the proposed use of intra-tumo

Method used

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  • Treatment of cancer by infusion of oncolytic herpes simplex virus to the blood
  • Treatment of cancer by infusion of oncolytic herpes simplex virus to the blood
  • Treatment of cancer by infusion of oncolytic herpes simplex virus to the blood

Examples

Experimental program
Comparison scheme
Effect test

example 1

—Cytokine Responses Following Intrapleural Administration of Oncolytic HSV SEPREHVIR® in Patients with Malignant Pleural Mesothelioma

[0584]We are currently conducting a phase I / 11a trial at Cancer Clinical Trials Centre, Weston Park Hospital, Sheffield and Queen Elizabeth University Hospital, Glasgow, United Kingdom to determine the safety and potential for efficacy of SEPREHVIR® given intrapleurally to patients with malignant pleural mesothelioma (MPM). Patients receive 1×107 iu SEPREHVIR® through their pleural catheter on one, two or four occasions each dose given one week apart, in three separate patient cohorts. To date 11 patients have been treated, 3 in each 1 and 2 dose cohorts and 5 in the 4 dose cohort and SEPREHVIR® has been well-tolerated with few adverse events in any patients. An exploratory objective, to assess tumor responses by CT using modified RECIST criteria, has demonstrated disease stabilisation in 6 / 10 evaluable patients.

[0585]Pleural fluid and plasma samples h...

example 2

i-Tumor Serum IgG Response

[0630]Patient serum samples were used to probe cell extracts in order to investigate the possibility of an anti-tumor antibody response to treatment with SEPREHVIR®. Cell extracts were prepared from cell lines: MSTO-211H (mesothelioma; ATCC CRL-2081), SPC111 (mesothelioma), and HuH7 (hepatic carcinoma), and contacted with patient sera. IgG:target complexes were detected using an anti-human IgG antibody by standard Western Blotting procedures (FIG. 15).

[0631]Analysis of plasma samples indicated a strong anti-HSV IgG responses post SEPREHVIR® administration, particularly after 2 and 4 doses. Intrapleural administration of SEPREHVIR® was found to induce a novel anti-tumor IgG response against an antigen present on MSTO-211H cells but not on SPC111 or HuH7 cells (FIG. 16-18) more so in patients receiving 4 doses of Seprehvir.

[0632]Thus, SEPREHVIR® has immunotherapeutic potential capable of inducing novel anti-tumor immune responses in patients. This result is c...

example 3

t Blockade Enhances Oncolytic Herpes Virotherapy in Immunosuppressive Sarcoma Models

[0633]Most solid tumors are characterized by an immunosuppressive microenvironment, limiting the effectiveness of antitumor immunotherapeutics. Programmed cell death protein (PD)-1-mediated T cell suppression via engagement of its ligand, PD-L1, is of particular interest due to recent successes in selected adult cancers. The utility of PD1-directed therapy for pediatric cancers is unknown, especially given the paucity of mutations and thus infrequent neoantigens in many types of childhood tumors. Oncolytic virotherapy induces tumor shrinkage via a multistep process including direct tumor cell lysis, induction of cytotoxic or apoptosis-sensitizing cytokines, and induction of antitumor T cell responses. We have demonstrated that intratumoral injection of an oncolytic herpes virus induced growth delays and in some cases durable remissions in several mouse models of rhabdomyosarcoma. The effects were T c...

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Abstract

An oncolytic herpes simplex virus is disclosed for use in a method of treating cancer in a human subject, the method comprising administering to the human subject at least one dose of oncolytic herpes simplex virus by infusion to the blood, wherein the oncolytic herpes simplex virus reaches cells of the cancer in which it replicates.

Description

RELATED APPLICATIONS[0001]This application is a continuation of International Patent Application No. PCT / GB2016 / 052177, filed Jul. 19, 2016, which claims priority to and the benefit of United Kingdom patent application No. 1512723.6 filed on 20 Jul. 2015 and United Kingdom patent application No. 1523091.5 filed on 30 Dec. 2015. The entire contents of these applications are incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention relates to methods of treatment of human cancers involving administration of an oncolytic herpes simplex virus to a human subject by infusion of the virus to the blood.BACKGROUND TO THE INVENTION[0003]Oncolytic virotherapy concerns the use of lytic viruses which selectively infect and kill cancer cells. Some oncolytic viruses are promising therapies as they display exquisite selection for replication in cancer cells and their self-limiting propagation within tumors results in fewer toxic side effects. Several oncolytic viruses have ...

Claims

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Application Information

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IPC IPC(8): A61K35/763A61P35/00C07K16/28A61K39/395
CPCA61K2039/505A61K35/763A61P35/00C07K16/2818A61K39/3955C07K2317/76A61K9/0019A61K45/06A61K35/768A61K2039/57A61K47/12A61K9/08C07K2317/73A61K2300/00A61K39/39566
Inventor CONNER, JOE
Owner VIRTTU BIOLOGICS
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