Method of delivery of fusogenic oncolytic virus and therapeutic molecules
AssigneeThe Brigham and Women's Hospital, Inc.
InventorFeng YAO
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Abstract
Malignant tumors that are resistant to conventional therapies represent significant therapeutic challenges. An embodiment of the present invention provides a method for treating cancer comprising administering to a subject in need thereof a checkpoint inhibitor in combination with a new generation regulatable fusogenic oncolytic herpes simplex virus-1 that is more effective at selective killing target cells, such as tumor cells. In various embodiments presented herein, the methods described herein is suitable for treatment of solid tumors, as well as other cancers.
Claims28
A method for treating cancer, the method comprising administering a subject in need thereof,
- i) a checkpoint inhibitor;
- and
- ii) an oncolytic Herpes Simplex Virus (HSV) comprising recombinant DNA, wherein the recombinant DNA comprises:
- a) a gene comprising a 5′ untranslated region and a HSV-1, or HSV-2, VP5 gene that is operably linked to an VP5 promoter comprising a TATA element;
- b) a tetracycline operator sequence positioned between 6 and 24 nucleotides 3′ to said TATA element, wherein the VP5 gene lies 3′ to said tetracycline operator sequence;
- c) a gene sequence encoding tetracycline repressor operably linked to an HSV immediate-early promoter, wherein the gene sequence is located at the ICP0 locus;
- d) a variant gene that increases syncytium formation as compared to wild type, wherein the HSV-1, or HSV-2, variant gene is selected from the group consisting of:
- a glycoprotein K (gK) variant;
- a glycoprotein B (gB) variant;
- a UL24 variant;
- and UL20 gene variant;
- and
- e) a gene sequence encoding a functional ICP34.5 protein;
- wherein said oncolytic HSV does not encode functional ICP0 and does not contain a ribozyme sequence located in said 5′ untranslated region of VP5.
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A method for treating cancer, the method comprising administering a subject in need thereof,
- i) a checkpoint inhibitor;
- and
- ii) an oncolytic Herpes Simplex Virus (HSV) comprising recombinant DNA, wherein the recombinant DNA does not encode functional ICP0;
- and encodes fusogenic activity.
-31. (canceled)
A composition comprising a
- i) a checkpoint inhibitor;
- and
- ii) an oncolytic Herpes Simplex Virus (HSV) comprising recombinant DNA, wherein the recombinant DNA comprises:
- a) a gene comprising a 5′ untranslated region and a HSV-1, or HSV-2, VP5 gene that is operably linked to an VP5 promoter comprising a TATA element;
- b) a tetracycline operator sequence positioned between 6 and 24 nucleotides 3′ to said TATA element, wherein the VP5 gene lies 3′ to said tetracycline operator sequence;
- c) a gene sequence encoding tetracycline repressor operably linked to an HSV immediate-early promoter, wherein the gene sequence is located at the ICP0 locus;
- d) a variant gene that increases syncytium formation as compared to wild type, wherein the HSV-1, or HSV-2, variant gene is selected from the group consisting of:
- a glycoprotein K (gK) variant;
- a glycoprotein B (gB) variant;
- a UL24 variant;
- and UL20 gene variant;
- and
- e) a gene sequence encoding a functional ICP34.5 protein;
- wherein said oncolytic HSV does not encode functional ICP0 and does not contain a ribozyme sequence located in said 5′ untranslated region of VP5.
A composition comprising
- i) a checkpoint inhibitor;
- and
- ii) an oncolytic Herpes Simplex Virus (HSV) comprising recombinant DNA, wherein the recombinant DNA does not encode functional ICP0;
- and encodes fusogenic activity.
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Dependencies are inferred from the claim text.