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CAR-macrophages for the Treatment of HER2 Overexpressing Solid Tumors

ABSTRACT: Phase 1, first-in-human, open label study of CAR macrophages in HER2 overexpressing solid tumors.

DISEASE(S): Adenocarcinoma,Endometrial Cancer,Her-2 Gene Amplification,Carcinoma,Carcinoma, Transitional Cell,Breast Neoplasm,Biliary Tract Neoplasms,Her-2 Protein Overexpression,Colorectal Cancer,Her2-positive Gastric Cancer,Head And Neck Neoplasms,Endometrial Neoplasms,Breast Neoplasms,Lung Neoplasms,Neoplasms,Her2-positive,Prostatic Neoplasms,Carcinoma, Small Cell,Bile Duct Cancer,Carcinoma, Non-small-cell Lung,Her2-positive Breast Cancer,Ovarian Neoplasms,Lung Cancer, Non-small-cell,Stomach Neoplasms,Malignant Neoplasms,Small Cell Lung Carcinoma,Advanced Cancer,Bladder Cancer,Pancreatic Cancer,Inflammatory Breast Cancer,Breast Cancer,Carcinoma, Squamous Cell,Her2-positive Solid Tumors,Esophagogastric Junction Neoplasms,Lung Cancer, Small Cell,Biliary Tract Cancer,Carcinoma, Ductal,Carcinoma, Ovarian Epithelial,Bile Duct Neoplasms,Prostate Cancer,Inflammatory Breast Neoplasms,Carcinoma, Hepatocellular,Head And Neck Cancer,Cancer,Carcinoma, Squamous

PROVIDER: 2360169 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Anti-cancer immunotherapy approaches are increasingly coveted. Chimeric antigen receptor (CAR)-T cell therapy has been shown to be an effective treatment for hematological tumors, but the treatment of solid tumors still lacks effectiveness, due to lower intra-tumor infiltration of CAR-T cells and tumor-induced immunosuppression. Macrophages represent a very large proportion of the tumor environment, participate in many aspects to tumor development and therefore represent interesting therapeutic targets. Macrophages can infiltrate solid tumor tissue and interact with almost all cellular components in the tumor microenvironment. In addition, macrophages can also promote a direct anti-tumor response by phagocyting tumor cells. We have developed macrophages expressing a CAR receptor against the HER2 antigen. The CAR receptor possesses an intracellular domain CD3ζ having homology with the protein FcεRI-γ, which once activated by the recognition antibody-antigen, induces the phagocytic activity of macrophages. 72% of macrophages express the CAR after transduction. CAR-M can specifically phagocyte HER2 coated-beads in a much more effective way than WT macrophages. We have then confirmed the capacity of CAR-M to phagocyte HER2+ cancer cell lines. Co-culture of CAR-M with breast cancer tumoroids (HER2+ or HER2-) has also been performed demonstrating their efficacy in a more complex environment. However, in the tumor microenvironment, due to their plasticity, macrophages tend to adopt an anti-inflammatory phenotype losing their anti-tumor activities. We have therefore developed a combined strategy by inhibiting two proprotein convertases, Furin and PC1/3 in CAR-M. The inhibition of furin or PC1/3 induces an increase in pro-inflammatory markers and maintains macrophage activation in the presence of cancer cells. In addition, HER2+ CAR-M with shFurin or shPC1/3 greatly increases the phagocytic activity on Her2+ beads or Her2+ tumors. These enzymes are therefore phenotypic regulators of macrophages. Our strategy is therefore based on a double activation of tumor-infiltrating macrophages. The first one consists in boosting the phagocytic activity of macrophages by having them express a CAR receptor targeting a tumor antigen. The second allows their reprogramming towards a pro- inflammatory phenotype by the inhibition of Furin and/or PC1/3 proprotein convertases

Project description:Purpose: To compare cell states between control Her2-BBz and JUN-overexpression Her2-BBz human CAR T cells in a mouse model of osteosarcoma. Methods: 8-week old NSG mice were implanted with 1 million 143B osteosarcoma tumor cells intramuscularly in the right leg. 14 days post tumor implantation, mice were infused intravenously with 10 million human CAR+ T cells via tail vein injection. Before T cell transfer, mice were randomized for tumor size and treated with either control Her2-BBz or JUN-overexpressing Her2-BBz CAR T cells. T cells were 70% CAR+ at infusion for both groups. 14 days post T cell treatment (day 28 post tumor engraftment), 6 mice per group were euthanized, solid tumor tissue was collected, mechanically dissociated, and single cell suspensions were labeled with human-CD45 antibody and viability dye. Live hCD45+ tumor-infiltrating lymphocytes were sorted from each tumor and 6 samples were pooled for each group. ~35,000-40,000 sorted live cells (counted post sort) for each group were delivered to the Stanford Functional Genomics Facility for 3' single-cell RNA-sequencing on the 10X Genomics platform. Results: We found that substantially more JUN-overexpressing Her2-BBz CAR T cells were within the G2/M and S phases of the cell cycle than control Her2-BBz CAR T cells, consistent with increased in vivo proliferation of JUN-Her2-BBz CAR T cells. Furthermore, JUN-Her2-BBz CAR T cells also demonstrated a more activated transcriptional program (as measured by IL2RA and CD38), while many exhaustion-associated genes were downregulated (PDCD1, BTLA, TIGIT, CD200, ENTPD1, NR4A2) compared to control Her2-BBz CAR T cells. Finally, a small cluster of cells characterized by high IL7R expression (IL7R+ KLF2+ CD27+ TCF7+ SELL+) was apparent in JUN-overexpressing but not in control Her2-BBz CAR T cells, consistent with maintenance of a memory-like population capable of self-renewal. Conclusions: This study provides insights into cell states that could explain the improved efficacy of JUN-overexpression Her2-BBz CAR T cells compared to control Her2-BBz CAR T cells in a mouse model of osteosarcoma.

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CAR-macrophages for the Treatment of HER2 Overexpressing Solid Tumors

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