2026-10-05 マサチューセッツ大学アマースト校
＜関連情報＞
- https://www.umass.edu/news/article/umass-amherst-leads-131m-research-effort-treat-breast-cancer-bacteria
- https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(26)00256-9
- https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1228532/full
- https://www.nature.com/articles/s41467-021-26367-9
サルモネラベクターは、固形腫瘍を縮小させ、抗腫瘍免疫記憶を形成する新規パルボウイルスを生成する Salmonella vector creates de novo parvovirus that reduces solid tumors and forms antitumor immune memory
Shradha Khanduja ∙ Vishnu Raman ∙ Christopher L. Hall ∙ Lars M. Howell ∙ Nele Van Dessel ∙ Neil S. Forbes
Cell Reports Medicine Published:June 3, 2026
DOI:https://doi.org/10.1016/j.xcrm.2026.102839
Highlights
- Engineered Salmonella preserves H-1PV hairpin structures required for virion formation
- Engineered Salmonella safely colonizes and delivers functional virus in tumors in vivo
- Virus-delivering Salmonella (VDS) reduces tumors beyond standard of care or virus alone
- VDS activates innate and adaptive immunity, generating durable antitumor immune memory
Summary
We have created a Salmonella vector that delivers oncolytic viruses (OVs) into solid tumors. Despite their potential, OVs are cleared after systemic injection and are not effective against internal tumors. When injected intravenously, virus-delivering Salmonella (VDS) is safe and colonizes tumors 50 million times more than clearance organs. After colonization, VDS invades cancer cells, releases a virus-encoding plasmid, and initiates virion formation. Bacterial delivery of the H-1 parvovirus reduces both hepatocellular and pancreatic tumors, increases survival, and triggers the formation of tumor-specific splenocytes that prevent re-implantation. Treating with VDS increases dendritic cells, infiltration of CD8 T cells, and polarized macrophages. Intravenous injection of VDS produces the same responses as an intratumoral injection, and outperforms direct injection of H-1 parvovirus (H-1PV), which minimally affects immune responses and tumor volume. Combining bacteria and OVs creates a therapy that activates the immune system, generates antitumor immunity, and provides a promising platform for treating solid tumors.
細胞内へのサルモネラ菌による外来性免疫抗原の送達は、CD8 T細胞を癌細胞に向け直し、膵臓腫瘍を排除し、抗腫瘍免疫を形成する Intracellular Salmonella delivery of an exogenous immunization antigen refocuses CD8 T cells against cancer cells, eliminates pancreatic tumors and forms antitumor immunity
Vishnu Raman,Lars M. Howell,Shoshana M. K. Bloom,Christopher L. Hall,Victoria E. Wetherby,Lisa M. Minter,Ashish A. Kulkarni,Neil S. Forbes
Frontiers in Immunology Published:05 October 2023
DOI:https://doi.org/10.3389/fimmu.2023.1228532
Abstract
Introduction:
Immunotherapies have shown great promise, but are not effective for all tumors types and are effective in less than 3% of patients with pancreatic ductal adenocarcinomas (PDAC). To make an immune treatment that is effective for more cancer patients and those with PDAC specifically, we genetically engineered Salmonella to deliver exogenous antigens directly into the cytoplasm of tumor cells. We hypothesized that intracellular delivery of an exogenous immunization antigen would activate antigen-specific CD8 T cells and reduce tumors in immunized mice.
Methods:
To test this hypothesis, we administered intracellular delivering (ID) Salmonella that deliver ovalbumin as a model antigen into tumor-bearing, ovalbumin-vaccinated mice. ID Salmonella delivers antigens by autonomously lysing in cells after the induction of cell invasion.
Results:
We showed that the delivered ovalbumin disperses throughout the cytoplasm of cells in culture and in tumors. This delivery into the cytoplasm is essential for antigen cross-presentation. We showed that co-culture of ovalbumin-recipient cancer cells with ovalbumin-specific CD8 T cells triggered a cytotoxic T cell response. After the adoptive transfer of OT-I CD8 T cells, intracellular delivery of ovalbumin reduced tumor growth and eliminated tumors. This effect was dependent on the presence of the ovalbumin-specific T cells. Following vaccination with the exogenous antigen in mice, intracellular delivery of the antigen cleared 43% of established KPC pancreatic tumors, increased survival, and prevented tumor re-implantation.
Discussion:
This response in the immunosuppressive KPC model demonstrates the potential to treat tumors that do not respond to checkpoint inhibitors, and the response to re-challenge indicates that new immunity was established against intrinsic tumor antigens. In the clinic, ID Salmonella could be used to deliver a protein antigen from a childhood immunization to refocus pre-existing T cell immunity against tumors. As an off-the-shelf immunotherapy, this bacterial system has the potential to be effective in a broad range of cancer patients.
自律的に溶解する細菌システムを用いたタンパク質薬剤の細胞内送達は、腫瘍の増殖と転移を抑制する Intracellular delivery of protein drugs with an autonomously lysing bacterial system reduces tumor growth and metastases
Vishnu Raman, Nele Van Dessel, Christopher L. Hall, Victoria E. Wetherby, Samantha A. Whitney, Emily L. Kolewe, Shoshana M. K. Bloom, Abhinav Sharma, Jeanne A. Hardy, Mathieu Bollen, Aleyde Van Eynde & Neil S. Forbes
Nature Communications Published:21 October 2021
DOI:https://doi.org/10.1038/s41467-021-26367-9
Abstract
Critical cancer pathways often cannot be targeted because of limited efficiency crossing cell membranes. Here we report the development of a Salmonella-based intracellular delivery system to address this challenge. We engineer genetic circuits that (1) activate the regulator flhDC to drive invasion and (2) induce lysis to release proteins into tumor cells. Released protein drugs diffuse from Salmonella containing vacuoles into the cellular cytoplasm where they interact with their therapeutic targets. Control of invasion with flhDC increases delivery over 500 times. The autonomous triggering of lysis after invasion makes the platform self-limiting and prevents drug release in healthy organs. Bacterial delivery of constitutively active caspase-3 blocks the growth of hepatocellular carcinoma and lung metastases, and increases survival in mice. This success in targeted killing of cancer cells provides critical evidence that this approach will be applicable to a wide range of protein drugs for the treatment of solid tumors.
