Combination of a PD-1 antagonist and a listeria-based vaccine for treating prostate cancer

Patent metadata

Field	Value
Publication number	US-9907849-B2
Application number	US-201514802607-A
Country	US
Kind code	B2
Filing date	Jul 17, 2015
Priority date	Jul 18, 2014
Publication date	Mar 6, 2018
Grant date	Mar 6, 2018

Abstract

The present disclosure describes combination therapies comprising an antagonist of Programmed Death 1 receptor (PD-1) and a Listeria based strain that expresses prostate-tissue specific antigen (PSA), and the use of the combination therapies for the treatment of prostate cancer.

First claim

The invention claimed is:

1. A method for treating prostate cancer in a patient comprising administering to the patient a combination therapy which comprises an antagonist of a Programmed Death 1 protein (PD-1) and a bioengineered live-attenuated Listeria monocytogenes strain transformed with an expression vector to express a PSA antigen fused to a truncated Listeriolysin O (tLLO), and wherein the live-attenuated Listeria monocytogenes strain stimulates Antigen Presenting Cells (APCs) capable of driving a cellular immune response to PSA expressing cells.

2. A method for treating prostate cancer in a patient comprising administering to the patient a combination therapy which comprises an anti-PD-1 monoclonal antibody, comprising a heavy chain and a light chain, wherein the heavy and light chains comprise SEQ ID NO:21 and SEQ ID NO:22, respectively, and a bioengineered live-attenuated Listeria monocytogenes strain transformed with an expression vector to express a PSA antigen fused to a truncated Listeriolysin O (tLLO), wherein the live-attenuated Listeria monocytogenes strain stimulates Antigen Presenting Cells (APCs) capable of driving a cellular immune response to PSA expressing cells.

3. The method of claim 1 , wherein the PD-1 antagonist and the live-attenuated Listeria monocytogenes strain are administered simultaneously.

4. The method of claim 1 or 2 , wherein said tLLO-PSA fusion polypeptide consists of the sequence of SEQ ID NO: 54 or a sequence at least 99% homologous thereto, wherein said tLLO enhances the immunogenicity of the fusion polypeptide.

5. The method of claim 1 or 2 , wherein the live-attenuated Listeria monocytogenes strain comprises an LmddA-142 (10403S dal (−) dat (−) actA (−) pADV142) strain.

6. A method for treating prostate cancer in a patient comprising administering to the patient a combination therapy which comprises, an anti-PD-1 monoclonal antibody comprising a heavy chain and a light chain, wherein the heavy and light chains comprise SEQ ID NO:21 and SEQ ID NO:22, respectively, and a live-attenuated Listeria monocytogenes strain comprising a LmddA-143 (10403S dal (−) dat (−) actA (−) with klk3 fused to the hly gene in the chromosome) strain, wherein the live-attenuated Listeria monocytogenes strain stimulates Antigen Presenting Cells (APCs) capable of driving a cellular immune response to PSA expressing cells.

7. The method of claim 2 or 6 , wherein the anti-PD-1 monoclonal antibody and the live-attenuated Listeria monocytogenes strain are administered simultaneously.

8. The method of claim 1 , 2 or 6 , wherein the prostate cancer is metastatic Castration-Resistant Prostate Cancer (mCRPC).

9. The method of claim 1 , 2 or 6 , wherein said live attenuated Listeria monocytogenes strain is administered with an adjuvant, wherein said adjuvant comprises Montanide ISA 51, GM-CSF, KLH, a cytokine, a growth factor, a cell population, QS21, Freund's incomplete adjuvant, aluminum phosphate, aluminum hydroxide, BCG, alum, an interleukin, an unmethylated CpG oligonucleotide, quill glycosides, monophosphoryl lipid A, a liposomes, a bacterial mitogen, a bacterial toxin, or a chemokine, or any combination thereof.

10. The method of claim 2 or 6 , wherein the antibody is formulated as a liquid medicament which comprises 7% (w/v) sucrose, 0.02% (w/v) polysorbate 80 in 10 mM histidine buffer pH 5.5.

11. The method of claims 1 , 2 or 6 , wherein the prostate cancer tests positive for PD-L1 expression.

12. The method of claims 1 , wherein the PD-1 antagonist is pembrolizumab.

13. The method of claim 2 or 6 , wherein the anti-PD 1 monoclonal antibody is pembrolizumab.

14. The method of claim 1 , wherein the PD-1 antagonist and the live-attenuated Listeria monocytogenes strain are administered sequentially.

15. The method of claim 2 or 6 , wherein the anti-PD-1 monoclonal antibody and the live-attenuated Listeria monocytogenes strain are administered sequentially.

Assignees

• Advaxis Inc
• Merck Sharp & Dohme
• Merck Sharp & Dohme

Inventors

• Petit Robert
• Mauro David J
• Perini Rodolfo F

Classifications

• A61K2039/884

  prostate · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K2039/522

  avirulent or attenuated · CPC title

• A61K39/39558 Primary

  against tumor tissues, cells, antigens · CPC title

• A61K2039/572

  cytotoxic response · CPC title