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