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

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.

1 .- 164 . (canceled) 
     
     
         165 . 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 deficient in at least one gene selected from the group consisting of a virulence gene, a metabolic gene and combinations thereof, wherein the live-attenuated  Listeria monocytogenes  stimulates Antigen Presenting Cells (APCs) capable of driving a cellular immune response to PSA expressing cells. 
     
     
         166 . The method of  claim 165 , wherein the at least one gene is deleted resulting in the deficiency. 
     
     
         167 . The method of  claim 165 , wherein the at least one gene is mutated resulting in the deficiency. 
     
     
         168 . The method of  claim 165 , wherein the live-attenuated  Listeria monocytogenes  strain is deficient in at least two genes selected from the group consisting of virulence genes, metabolic genes and combinations thereof. 
     
     
         169 . The method of  claim 165 , wherein the virulence gene is selected from the group consisting of actA gene, inlA gene, inlB gene, inlC gene, inlJ gene, bsh gene, prfA gene, plbC gene, plcA gene, plcB gene, and combinations thereof, and wherein the metabolic gene is selected from the group consisting of dal gene, dat gene and combinations thereof. 
     
     
         170 . The method of  claim 165 , wherein the virulence gene is actA. 
     
     
         171 . The method of  claim 165 , wherein the metabolic gene is selected from the group consisting of dal gene, dat gene and combinations thereof. 
     
     
         172 . The method of  claim 165 , wherein the live-attenuated  Listeria monocytogenes  strain is deficient in at least two virulence genes. 
     
     
         173 . The method of  claim 165 , wherein the PD-1 antagonist is an anti-PD-1 monoclonal antibody. 
     
     
         174 . The method of  claim 173 , wherein an anti-PD-1 monoclonal antibody comprises a heavy chain and a light chain, wherein the heavy and light chains comprise SEQ ID NO:21 and SEQ ID NO:22, respectively. 
     
     
         175 . The method of  claim 165 , wherein the PD-1 antagonist is pembrolizumab. 
     
     
         176 . The method of  claim 165 , wherein the PD-1 antagonist and the live-attenuated  Listeria monocytogenes  strain are administered simultaneously. 
     
     
         177 . The method of  claim 165 , wherein the PD-1 antagonist and the live-attenuated  Listeria monocytogenes  strain are administered sequentially. 
     
     
         178 . The method of  claim 165 , wherein said strain is administered with an adjuvant. 
     
     
         179 . The method of  claim 178 , 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. 
     
     
         180 . The method of  claim 165 , wherein the prostate cancer is metastatic Castration-Resistant Prostate Cancer (mCRPC). 
     
     
         181 . A kit comprising:
 a first container comprising at least one dose of a medicament comprising an antagonist of a Programmed Death 1 protein (PD-1);   a second container comprising at least one dose of a medicament comprising a bioengineered live-attenuated  Listeria monocytogenes  strain deficient in at least one gene selected from the group consisting of a virulence gene, a metabolic gene and combinations thereof; and   a package insert comprising instructions for treating a patient for prostate cancer using the medicaments.   
     
     
         182 . The kit of  claim 181 , wherein the second container comprises at least one dose of a medicament comprising a bioengineered live-attenuated  Listeria monocytogenes  comprising an LmddA-143 (10403 S dal (−)  dat (−)  actA (−)  with klk3 fused to the hly gene in the chromosome) strain. 
     
     
         183 . The kit of  claim 181 , wherein the second container comprises at least one dose of a medicament comprising a bioengineered live-attenuated  Listeria monocytogenes  comprising an LmddA-142 (10403 S dal (−)  dat (−)  actA (−)  pADV142) strain. 
     
     
         184 . A kit comprising:
 a first container comprising at least one dose of a medicament comprising an antagonist of a Programmed Death 1 protein (PD-1);   a second container comprising at least one dose of a medicament comprising 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   a package insert comprising instructions for treating a patient for prostate cancer using the medicaments.   
     
     
         185 . The kit of  claim 184 , wherein the PD-1 antagonist is 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. 
     
     
         186 . The kit of  claim 184 , 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 N-terminal LLO peptide enhances the immunogenicity of the fusion peptide. 
     
     
         187 . The kit of  claim 184 , wherein said kit further comprises 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. 
     
     
         188 . The kit of  claim 184 , wherein the prostate cancer is metastatic Castration-Resistant Prostate Cancer (mCRPC).