Priming systemic anti-tumor immunity via in situ immunomodulation of the tumor microenvironment
Systemic cancer immunotherapies including checkpoint blockade antibodies targeting the PD-1/PD-L1 axis and CTLA-4 have improved survival outcomes in a subset of cancer patients by driving tumor-directed immune responses. However, many patients do not benefit from such immunotherapies due to immune r...
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| Format: | Thesis |
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Massachusetts Institute of Technology
2022
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| Online Access: | https://hdl.handle.net/1721.1/139220 |
| _version_ | 1826191844351934464 |
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| author | Milling, Lauren Elizabeth |
| author2 | Irvine, Darrell J. |
| author_facet | Irvine, Darrell J. Milling, Lauren Elizabeth |
| author_sort | Milling, Lauren Elizabeth |
| collection | MIT |
| description | Systemic cancer immunotherapies including checkpoint blockade antibodies targeting the PD-1/PD-L1 axis and CTLA-4 have improved survival outcomes in a subset of cancer patients by driving tumor-directed immune responses. However, many patients do not benefit from such immunotherapies due to immune resistance mechanisms or severe inflammatory adverse events resulting in treatment discontinuation. Direct intratumoral injection of immunomodulatory agents has been successfully implemented to maximize immune stimulation at the site of the tumor while minimizing drug concentrations in systemic circulation. By focusing the immune response within a tumor of interest, immune cell killing of cancer cells releases tumor debris to which the immune system can be educated – effectively generating a tumor-specific vaccine. Localized inflammation in the tumor microenvironment additionally serves to adjuvant the in situ vaccination response. Ultimately, immune cells primed after intratumoral immunomodulation can traffic to distant sites of metastasis leading to tumor regressions at injected and non-injected lesions. The intratumoral in situ vaccination approach is amenable to a variety of therapeutic modalities ranging from small molecules, to proteins, and cell-based therapies. In this thesis, we present two combination immunotherapy regimen that take advantage of intratumoral injection. First, we describe an “off-the-shelf” in situ vaccine featuring locally administered small molecule activators of the STimulator of INterferon Genes (STING) pathway combined with systemically administered interleukin-2 and anti-PD-1 towards the generation of anti-tumor immunity in spontaneously metastatic breast tumor models. In this setting we detail the integration of immunotherapy with surgical resection and define the immune cell types mediating metastasis clearance. Taking a more personalized vaccine approach, we secondly demonstrate that in vitro treatment of tumor cells with DNA-damaging chemotherapy can promote tumor antigen-specific T cell activation by dendritic cells. Intratumoral injection of these chemotherapy-damaged cells synergizes with immune checkpoint blockade to promote tumor regression. Together, these studies underscore the versatility of intratumoral immunomodulation and highlight the wholistic activation of both innate and adaptive immune cells, hopefully contributing to more patients benefiting from cancer immunotherapy. |
| first_indexed | 2024-09-23T09:02:09Z |
| format | Thesis |
| id | mit-1721.1/139220 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T09:02:09Z |
| publishDate | 2022 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/1392202022-01-15T04:02:39Z Priming systemic anti-tumor immunity via in situ immunomodulation of the tumor microenvironment Milling, Lauren Elizabeth Irvine, Darrell J. Massachusetts Institute of Technology. Department of Biological Engineering Systemic cancer immunotherapies including checkpoint blockade antibodies targeting the PD-1/PD-L1 axis and CTLA-4 have improved survival outcomes in a subset of cancer patients by driving tumor-directed immune responses. However, many patients do not benefit from such immunotherapies due to immune resistance mechanisms or severe inflammatory adverse events resulting in treatment discontinuation. Direct intratumoral injection of immunomodulatory agents has been successfully implemented to maximize immune stimulation at the site of the tumor while minimizing drug concentrations in systemic circulation. By focusing the immune response within a tumor of interest, immune cell killing of cancer cells releases tumor debris to which the immune system can be educated – effectively generating a tumor-specific vaccine. Localized inflammation in the tumor microenvironment additionally serves to adjuvant the in situ vaccination response. Ultimately, immune cells primed after intratumoral immunomodulation can traffic to distant sites of metastasis leading to tumor regressions at injected and non-injected lesions. The intratumoral in situ vaccination approach is amenable to a variety of therapeutic modalities ranging from small molecules, to proteins, and cell-based therapies. In this thesis, we present two combination immunotherapy regimen that take advantage of intratumoral injection. First, we describe an “off-the-shelf” in situ vaccine featuring locally administered small molecule activators of the STimulator of INterferon Genes (STING) pathway combined with systemically administered interleukin-2 and anti-PD-1 towards the generation of anti-tumor immunity in spontaneously metastatic breast tumor models. In this setting we detail the integration of immunotherapy with surgical resection and define the immune cell types mediating metastasis clearance. Taking a more personalized vaccine approach, we secondly demonstrate that in vitro treatment of tumor cells with DNA-damaging chemotherapy can promote tumor antigen-specific T cell activation by dendritic cells. Intratumoral injection of these chemotherapy-damaged cells synergizes with immune checkpoint blockade to promote tumor regression. Together, these studies underscore the versatility of intratumoral immunomodulation and highlight the wholistic activation of both innate and adaptive immune cells, hopefully contributing to more patients benefiting from cancer immunotherapy. Ph.D. 2022-01-14T14:57:31Z 2022-01-14T14:57:31Z 2021-06 2021-08-23T21:43:34.298Z Thesis https://hdl.handle.net/1721.1/139220 In Copyright - Educational Use Permitted Copyright MIT http://rightsstatements.org/page/InC-EDU/1.0/ application/pdf Massachusetts Institute of Technology |
| spellingShingle | Milling, Lauren Elizabeth Priming systemic anti-tumor immunity via in situ immunomodulation of the tumor microenvironment |
| title | Priming systemic anti-tumor immunity via in situ immunomodulation of the tumor microenvironment |
| title_full | Priming systemic anti-tumor immunity via in situ immunomodulation of the tumor microenvironment |
| title_fullStr | Priming systemic anti-tumor immunity via in situ immunomodulation of the tumor microenvironment |
| title_full_unstemmed | Priming systemic anti-tumor immunity via in situ immunomodulation of the tumor microenvironment |
| title_short | Priming systemic anti-tumor immunity via in situ immunomodulation of the tumor microenvironment |
| title_sort | priming systemic anti tumor immunity via in situ immunomodulation of the tumor microenvironment |
| url | https://hdl.handle.net/1721.1/139220 |
| work_keys_str_mv | AT millinglaurenelizabeth primingsystemicantitumorimmunityviainsituimmunomodulationofthetumormicroenvironment |