Abstract: Myelodysplastic syndrome (MDS) hematopoietic stem and progenitor cells (HSPC) translocate endosomal Toll-Like receptor (TLR)-9 to the plasma membrane, thereby sensitizing these clonal propagating cells to respective ligands in the microenvironment. TLR9 is the cognate receptor for RNA:DNA hybrids (R-loops) and unmethylated CpG oligonucleotides in oxidized mitochondrial DNA, the latter of which is abundant in the bone marrow microenvironment as a result of massive medullary pyroptotic cytolytic cell death. Both ligands are important danger-associated molecular patterns (DAMPs) triggering innate immune activation and chronic inflammation that contributes to MDS pathogenesis. In an effort to neutralize these DAMPs and disrupt this feed-forward inflammatory cascade, a chimeric protein was designed fusing the external epitopes of TLR9 to the Fc domain of human IgG4 to serve as a decoy receptor or ligand trap recognizing extracellular RNA:DNA hybrids (R-loops) and oxidized mitochondrial DNA.

Abstract: Disclosed are compositions and methods for treating disease or condition caused or exacerbated by S100A9 activity, such as myelodysplastic syndromes (MDS) using a composition comprising an effective amount of a CD33/S100A9 inhibitor.

Abstract: The present invention encompasses methods for reducing the number of target cells in a subject, such as cancer cells. The methods include administration of genetically-modified human immune cells expressing a chimeric antigen receptor or exogenous T cell receptor, which have specificity for an antigen on the target cells Administration of the genetically-modified immune cells can be preceded by the administration of a lymphodepletion region and/or an immunosuppression regimen, to improve efficacy of the therapy and persistence of the cells in vivo.

Abstract: The present invention encompasses methods for reducing the number of target cells in a subject, such as cancer cells. The methods include administration of genetically-modified human immune cells expressing a chimeric antigen receptor or exogenous T cell receptor, which have specificity for an antigen on the target cells. Administration of the genetically-modified immune cells is preceded by the administration of a tolerance regimen, followed by administration of a lymphodepletion regimen, to improve efficacy of the therapy and persistence of the cells in vivo.

Abstract: Disclosed are compositions and methods for treating disease or condition caused or exacerbated by S100A9 activity, such as myelodysplastic syndromes (MDS) using a composition comprising an effective amount of a CD33/S100A9 inhibitor.

Abstract: This invention provides a method of treating myelodysplastic syndrome in a human subject afflicted therewith comprising administering to the subject an amount from 0.1 mg/m2 to 5 mg/m2 of a compound having the structure or a salt, zwitterion, or ester thereof.

Abstract: This invention provides a method of treating myelodysplastic syndrome in a human subject afflicted therewith comprising administering to the subject an amount from 0.1 mg/m2 to 5 mg/m2 of a compound having the structure or a salt, zwitterion, or ester thereof.

Abstract: Methods, systems, and apparatus, including computer programs encoded on a computer storage medium are provided, including a method for presenting information for treating patients. The method comprises presenting, in a user interface, a pathway for use in treating a patient with a disease and including a combination of therapeutic and diagnostic pathway elements including an integration of diagnostic, radiation, chemotherapy, surgical and other elements. The method further comprises augmenting the pathway including providing controls for accessing additional information associated with a given pathway element, augmenting pathway elements to include indicators for pricing, efficacy and/or toxicity of a treatment associated with a given treatment element, and augmenting the pathway with a connection to another pathway including providing a link to another pathway at a point in a given pathway that provides information for a related pathway.

Abstract: Disclosed herein are chimeric antigen receptor (CAR) polypeptides that can be used with adoptive cell transfer to target and kill cancer cells that express TLR9 on their surface. Also disclosed are immune effector cells, such as T cells or Natural Killer (NK) cells that are engineered to express these CARs. Therefore, also disclosed are methods of providing an anti-tumor immunity in a subject with a TLR9-expressing cancer that involves adoptive transfer of the disclosed immune effector cells engineered to express the disclosed CARs.

Abstract: Disclosed herein are CAR-T cells with enhanced tumor infiltration. As disclosed herein, infiltrating lymphocytes (T and NK) within tumor tissue are absent of CX3CR1, a key chemokine receptor specific for lymphocytes. Therefore, disclosed herein are CAR-T cells that co-express CX3CR1 to enhance the infiltration of CAR-T cells into the tumor tissue. Also disclosed herein are CAR-T cells that co-express IL-15 in order to activate infiltration of NK cell. In some embodiments, the disclosed CAR-T cells express both CX3CR1 and IL-15 in combination with the CAR polypeptide. In some embodiments, the disclosed CAR-T cells further express EGFR in combination with the CAR polypeptide.

Abstract: Disclosed are methods for diagnosing a myelodysplastic syndrome (MDS) in a subject. In some embodiments, the method involves assaying a sample from the subject to detect inflammasome activation, wherein an increase in inflammasome activation in the sample compared to a control is an indication of MDS in the subject. The disclosed methods can further involve treating the subject for MDS if an increase in inflammasome activation is detected.

Abstract: Disclosed herein is a companion diagnostic to predict efficacy of combination lenalidomide and erythropoietin treatment in patients with a erythropoietin (Epo)-refractory, Lower Risk (LR) Non-deletion 5q [Del(5q)] myelodysplastic syndrome (MDS). The method involves assaying erythroid precursors from a biological sample from the subject for a CD45 isoform profile, and treating the subject with a combination of lenalidomide and erythropoietin if the erythroid precursors have a predominance of large CD45RA and CD45RB isoforms compared to small CD45RO isoform.

Abstract: Myelodysplastic syndrome (MDS) hematopoietic stem and progenitor cells (HSPC) translocate endosomal Toll-Like receptor (TLR)-9 to the plasma membrane, thereby sensitizing these clonal propagating cells to respective ligands in the microenvironment. TLR9 is the cognate receptor for RNA:DNA hybrids (R-loops) and unmethylated CpG oligonucleotides in oxidized mitochondrial DNA, the latter of which is abundant in the bone marrow microenvironment as a result of massive medullary pyroptotic cytolytic cell death. Both ligands are important danger-associated molecular patterns (DAMPs) triggering innate immune activation and chronic inflammation that contributes to MDS pathogenesis. In an effort to neutralize these DAMPs and disrupt this feed-forward inflammatory cascade, a chimeric protein was designed fusing the external epitopes of TLR9 to the Fc domain of human IgG4 to serve as a decoy receptor or ligand trap recognizing extracellular RNA:DNA hybrids (R-loops) and oxidized mitochondrial DNA.

Abstract: Disclosed are compositions and methods for targeted treatment of TLR9-expressing cancers, such as primary human MDS progenitors and hematopoietic stem cell (HSC), as well as lung and breast cancers. In particular, multispecific, multivalent antibodies are disclosed that are able to engage T-cells to destroy TLR9-expressing malignant cells.

Abstract: A method is disclosed for diagnosing multiple myeloma or myelodysplastic syndrome (MDS) in a subject and/or predicting the responsiveness of a patient with a multiple myeloma or MDS to lenalidomide treatment, erythropoietin treatment, or a combination thereof. The method involves assaying a biological sample from the subject, such as a blood, serum, or plasma sample, for s100A9 protein levels, TNF? levels, or a combination thereof wherein elevated levels of s100A9 in the biological sample and/or reduced levels of TNF? levels is an indication of MDS in the subject and/or that the patient will be responsive.

Abstract: Disclosed are methods for diagnosing a myelodysplastic syndrome (MDS) in a subject. In some embodiments, the method involves assaying a sample from the subject to detect inflammasome activation, wherein an increase in inflammasome activation in the sample compared to a control is an indication of MDS in the subject. The disclosed methods can further involve treating the subject for MDS if an increase in inflammasome activation is detected.

Abstract: Disclosed are compositions and methods for treating disease or condition caused or exacerbated by S100A9 activity, such as myelodysplastic syndromes (MDS) using a composition comprising an effective amount of a CD33/S100A9 inhibitor.

Abstract: Disclosed are methods for diagnosing a myelodysplastic syndrome (MDS) in a subject. In some embodiments, the method involves assaying a sample from the subject to detect inflammasome activation, wherein an increase in inflammasome activation in the sample compared to a control is an indication of MDS in the subject. The disclosed methods can further involve treating the subject for MDS if an increase in inflammasome activation is detected.

Abstract: Disclosed herein are chimeric antigen receptor (CAR) polypeptides that can be used with adoptive cell transfer to target and kill cancer cells that express TLR9 on their surface. Also disclosed are immune effector cells, such as T cells or Natural Killer (NK) cells that are engineered to express these CARs. Therefore, also disclosed are methods of providing an anti-tumor immunity in a subject with a TLR9-expressing cancer that involves adoptive transfer of the disclosed immune effector cells engineered to express the disclosed CARs.

Abstract: Disclosed are methods for treating a meylodysplastic syndrome (MDS) in a subject that involves administering to the subject a therapeutically effective amount of a protein phosphatase 2A (PP2A) inhibitor.