Abstract: Provided are delivery immunostimulatory bacteria that have enhanced colonization of tumors, the tumor microenvironment and/or tumor-resident immune cells, and enhanced anti-tumor activity. The immunostimulatory bacteria are modified by deletion of genes encoding the flagella, or by modification of the genes so that functional flagella are not produced, and/or are modified by deletion of pagP or modification of pagP to produce inactive PagP product. As a result, the immunostimulatory bacteria are flagellin? and/or pagP?. The immunostimulatory bacteria optionally have additional genomic modifications so that the bacteria are adenosine or purine auxotrophs. The bacteria optionally are one or more of asd?, purI?, and msbB?.

Abstract: Provided are delivery immunostimulatory bacteria that have enhanced colonization of tumors, the tumor microenvironment and/or tumor-resident immune cells, and enhanced anti-tumor activity. The immunostimulatory bacteria are modified by deletion of genes encoding the flagella, or by modification of the genes so that functional flagella are not produced, and/or are modified by deletion of pagP or modification of pagP to produce inactive PagP product. As a result, the immunostimulatory bacteria are flagellin? and/or pagP?. The immunostimulatory bacteria optionally have additional genomic modifications so that the bacteria are adenosine or purine auxotrophs. The bacteria optionally are one or more of asd?, purI?, and msbB?.

Abstract: Provided are delivery immunostimulatory bacteria that have enhanced colonization of tumors, the tumor microenvironment and/or tumor-resident immune cells, and enhanced anti-tumor activity. The immunostimulatory bacteria are modified by deletion of genes encoding the flagella, or by modification of the genes so that functional flagella are not produced, and/or are modified by deletion of pagP or modification of pagP to produce inactive PagP product. As a result, the immunostimulatory bacteria are flagellin? and/or pagP?. The immunostimulatory bacteria optionally have additional genomic modifications so that the bacteria are adenosine or purine auxotrophs. The bacteria optionally are one or more of asd?, purI?, and msbB?.

Abstract: Provided are methods for treating cancer by converting tumor-resident macrophages into a hybrid M1/M2 macrophage phenotype; this phenotype has attributes that are advantageous for cancer therapy. Hybrid markers include (lower than M2, higher than M1): SPP1, CD209, and CD206, and induced markers include MERTK, C1QC, IFNa, IFNb, CXCL10, 4-1BBL, and MYC. The methods include administering a therapeutic that effects the phenotypic conversion. Therapeutics, such as delivery vehicles, including immunostimulatory bacteria with genome modifications, are designed so that they do not induce or result in a sufficient TLR2, TLR4, TLR5 response to inhibit type I IFN. The therapeutics also encode a payload that encodes immunostimulatory proteins, such as a cytokine and a modified cytosolic DNA/RNA sensor that constitutively induces type I IFN, such as a modified STING protein.

Abstract: Provided are delivery immunostimulatory bacteria that have enhanced colonization of tumors, the tumor microenvironment and/or tumor-resident immune cells, and enhanced anti-tumor activity. The immunostimulatory bacteria are modified by deletion of genes encoding the flagella or by modification of the genes so that functional flagella are not produced, and/or are modified by deletion of pagP or modification of pagP to produce inactive PagP product. As a result, the immunostimulatory bacteria are flagellin? and/or pagP?. The immunostimulatory bacteria optionally have additional genomic modifications so that the bacteria are adenosine and/or purine auxotrophs. The bacteria optionally are one or more of asd?, purI? and msbB?.

Abstract: Provided are immunostimulatory bacteria and oncolytic viruses, and pharmaceutical compositions containing the bacteria and/or viruses, that act as three prime repair exonuclease 1 (TREX1) antagonists. The bacteria and viruses are for treating tumors that are human papillomavirus (HPV) positive or that have a high tumor mutational burden (TMB). The immunostimulatory bacteria and oncolytic viruses encode therapeutic products such RNAi, such as shRNA and microRNA, that mediate gene disruption and/or inhibit expression of TREX1, or that inhibit TREX1. The bacteria contain additional modifications to enhance their anti-tumor activity. The bacteria and viruses are used for treatment of tumors in which TREX1 expression correlates with the presence of the tumor or properties of the tumor, such that inhibition of TREX1 advantageously treats the tumor.

Abstract: Provided are delivery immunostimulatory bacteria that have enhanced colonization of tumors, the tumor microenvironment and/or tumor-resident immune cells, and enhanced anti-tumor activity. The immunostimulatory bacteria are modified by deletion of genes encoding the flagella or modification of the genes so that functional flagella are not produced, and/or are modified by deletion of pagP or modification of pagP to produce inactive PagP product. As a result, the immunostimulatory bacteria are flagellin? and/or pagP?. The immunostimulatory bacteria optionally have additional genomic modifications so that the bacteria are adenosine or purine auxotrophs. The bacteria optionally are one or more of asd?, purI? and msbB?.

Abstract: Provided are delivery immunostimulatory bacteria that have enhanced colonization of tumors, the tumor microenvironment and/or tumor-resident immune cells, and enhanced anti-tumor activity. The immunostimulatory bacteria are modified by deletion of genes encoding the flagella, or by modification of the genes so that functional flagella are not produced, and/or are modified by deletion of pagP or modification of pagP to produce inactive PagP product. As a result, the immunostimulatory bacteria are flagellin? and/or pagP?. The immunostimulatory bacteria optionally have additional genomic modifications so that the bacteria are adenosine or purine auxotrophs. The bacteria optionally are one or more of asd?, purI?, and msbB?.

Abstract: Provided are attenuated immunostimulatory bacteria with genomes that are modified to, for example, reduce toxicity and improve the anti-tumor activity, such as by increasing accumulation in the tumor microenvironment, particularly in tumor-resident myeloid cells, improving resistance to complement inactivation, reducing immune cell death, promoting adaptive immunity, and enhancing T-cell function. The increase in colonization of phagocytic cells improves the delivery of encoded therapeutic products to the tumor microenvironment and tumors, and permits, among other routes, systemic administration of the immunostimulatory bacteria.

Abstract: Provided are delivery immunostimulatory bacteria that have enhanced colonization of tumors, the tumor microenvironment and/or tumor-resident immune cells, and enhanced anti-tumor activity. The immunostimulatory bacteria are modified by deletion of genes encoding the flagella, or by modification of the genes so that functional flagella are not produced, and/or are modified by deletion of pagP or modification of pagP to produce inactive PagP product. As a result, the immunostimulatory bacteria are flagellin? and/or pagP?. The immunostimulatory bacteria optionally have additional genomic modifications so that the bacteria are adenosine or purine auxotrophs. The bacteria optionally are one or more of asd?, purI?, and msbB?.

Abstract: Provided are modified STING proteins that have constitutive activity, and also can have lower NF-?B signaling activity compared to unmodified human STING. Combinations and compositions containing the modified STING proteins with immunostimulatory proteins also are provided. Also provided are immunostimulatory bacteria that encode the STING proteins and the combinations, where the immunostimulatory proteins are encoded as a polycistronic message. The immunostimulatory bacteria have genomes that are modified to, for example, reduce toxicity and improve the anti-tumor activity, such as by increasing accumulation in the tumor microenvironment, particularly in tumor-resident myeloid cells, improving resistance to complement inactivation, reducing immune cell death, promoting adaptive immunity, and enhancing T-cell function.

Abstract: Provided are delivery immunostimulatory bacteria that have enhanced colonization of tumors, the tumor microenvironment and/or tumor-resident immune cells, and enhanced anti-tumor activity. The immunostimulatory bacteria are modified by deletion of genes encoding the flagella or by modification of the genes so that functional flagella are not produced, and/or are modified by deletion of pagP or modification of pagP to produce inactive PagP product. As a result, the immunostimulatory bacteria are flagellin? and/or pagP?. The immunostimulatory bacteria optionally have additional genomic modifications so that the bacteria are adenosine and/or purine auxotrophs. The bacteria optionally are one or more of asd?, purI? and msbB?.

Abstract: Provided are immunostimulatory bacteria with genomes that are modified to, for example, reduce toxicity and improve the anti-tumor activity, such as by increasing accumulation in the tumor microenvironment, particularly in tumor-resident myeloid cells, improving resistance to complement inactivation, reducing immune cell death, promoting adaptive immunity, and enhancing T-cell function. Also provided are immunostimulatory bacteria for use as vaccines, and for delivery of mRNA. The immunostimulatory bacterium comprise genome modifications resulting in an increase in colonization of phagocytic cells, which delivers encoded therapeutic products to phagocytic cells, and permits, among other routes, systemic administration of the immunostimulatory bacteria. The increase in colonization of phagocytic cells also provides for use of immunostimulatory bacteria for direct tissue administration for use as vaccines.

Abstract: Provided are immunostimulatory bacteria and oncolytic viruses, and pharmaceutical compositions containing the bacteria and/or viruses, that act as three prime repair exonuclease 1 (TREX1) antagonists. The bacteria and viruses are for treating tumors that are human papillomavirus (HPV) positive or that have a high tumor mutational burden (TMB). The immunostimulatory bacteria and oncolytic viruses encode therapeutic products such RNAi, such as shRNA and microRNA, that mediate gene disruption and/or inhibit expression of TREX1, or that inhibit TREX1. The bacteria contain additional modifications to enhance their anti-tumor activity. The bacteria and viruses are used for treatment of tumors in which TREX1 expression correlates with the presence of the tumor or properties of the tumor, such that inhibition of TREX1 advantageously treats the tumor.

Abstract: Provided are immunostimulatory bacteria and oncolytic viruses, and pharmaceutical compositions containing the bacteria and/or viruses, that act as three prime repair exonuclease 1 (TREX1) antagonists. The bacteria and viruses are for treating tumors that are human papillomavirus (HPV) positive or that have a high tumor mutational burden (TMB). The immunostimulatory bacteria and oncolytic viruses encode therapeutic products such RNAi, such as shRNA and microRNA, that mediate gene disruption and/or inhibit expression of TREX1, or that inhibit TREX1. The bacteria contain additional modifications to enhance their anti-tumor activity. The bacteria and viruses are used for treatment of tumors in which TREX1 expression correlates with the presence of the tumor or properties of the tumor, such that inhibition of TREX1 advantageously treats the tumor.

Abstract: Provided are immunostimulatory bacteria and pharmaceutical compositions containing the bacteria. The immunostimulatory bacteria provided herein contain one or more modalities that enhance the anti-tumor activity of the immunostimulatory bacteria. Among the immunostimulatory bacteria provided are bacteria, such as Salmonella species, which are modified to be auxotrophic or are auxotrophic for adenosine and/or contain plasmids encoding RNAi, such as shRNA and microRNA, that mediate gene disruption and/or expression of immune checkpoints, such as TREX1, VISTA, PD-L1 and, genes that influence the immune system. The bacteria contain additional modifications to enhance their anti-tumor activity. Also provided are methods of inhibiting the growth or reducing the volume of a solid tumor by administering the pharmaceutical compositions.

Abstract: Provided are immunostimulatory bacteria and pharmaceutical compositions containing the bacteria. The immunostimulatory bacteria provided herein contain one or more modalities that enhance the anti-tumor activity of the immunostimulatory bacteria. Among the immunostimulatory bacteria provided are bacteria, such as Salmonella species, which are modified to be auxotrophic or are auxotrophic for adenosine and/or contain plasmids encoding RNAi, such as shRNA and microRNA, that mediate gene disruption and/or expression of immune checkpoints, such as TREX1, VISTA, PD-L1 and, genes that influence the immune system. The bacteria contain additional modifications to enhance their anti-tumor activity. Also provided are methods of inhibiting the growth or reducing the volume of a solid tumor by administering the pharmaceutical compositions.

Abstract: The present invention provides highly active cyclic-di-nucleotide (CDN) immune stimulators that activate DCs via a recently discovered cytoplasmic receptor known as STING (Stimulator of Interferon Genes). In particular, the CDNs of the present invention are provided in the form of a composition comprising one or more cyclic purine dinucleotides induce human STING-dependent type I interferon production, wherein the cyclic purine dinucleotides present in the composition are 2?-fluoro substituted, bis-3?,5? CDNs, and most preferably one or more 2?,2?-diF-Rp,Rp, bis-3?,5?CDNs.

Abstract: Provided are delivery immunostimulatory bacteria that have enhanced colonization of tumors, the tumor microenvironment and/or tumor-resident immune cells, and enhanced anti-tumor activity. The immunostimulatory bacteria are modified by deletion of genes encoding the flagella, or by modification of the genes so that functional flagella are not produced, and/or are modified by deletion of pagP or modification of pagP to produce inactive PagP product. As a result, the immunostimulatory bacteria are flagellin? and/or pagP?. The immunostimulatory bacteria optionally have additional genomic modifications so that the bacteria are adenosine or purine auxotrophs. The bacteria optionally are one or more of asd?, purI?, and msbB?.

Abstract: The present invention provides highly active cyclic-di-nucleotide (CDN) immune stimulators that activate DCs via a recently discovered cytoplasmic receptor known as STING (Stimulator of Interferon Genes). In particular, the CDNs of the present invention are provided in the form of a composition comprising one or more cyclic purine dinucleotides induce human STING-dependent type I interferon production, wherein the cyclic purine dinucleotides present in the composition are 2?- or 3?-mono-fluoro substituted, or 2?3?-di-fluoro substituted mixed linkage 2?,5?-3?,5? CDNs.