An oncolytic virus expressing a T-cell engager simultaneously targets cancer and immunosuppressive stromal cells
Effective immunotherapy of stromal-rich tumors requires simultaneous targeting of cancer cells and immunosuppressive elements of the microenvironment. Here, we modified the oncolytic group B adenovirus enadenotucirev to express a stroma-targeted bispecific T-cell engager (BiTE). This BiTE bound fibr...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
American Association for Cancer Research
2018
|
| _version_ | 1797100903373733888 |
|---|---|
| author | Freedman, J Duffy, M Lei-Rossmann, J Muntzer, A Scott, E Hagel, J Campo, L Bryant, R Verrill, C Lambert, A Miller, P Champion, B Seymour, L Fisher, K |
| author_facet | Freedman, J Duffy, M Lei-Rossmann, J Muntzer, A Scott, E Hagel, J Campo, L Bryant, R Verrill, C Lambert, A Miller, P Champion, B Seymour, L Fisher, K |
| author_sort | Freedman, J |
| collection | OXFORD |
| description | Effective immunotherapy of stromal-rich tumors requires simultaneous targeting of cancer cells and immunosuppressive elements of the microenvironment. Here, we modified the oncolytic group B adenovirus enadenotucirev to express a stroma-targeted bispecific T-cell engager (BiTE). This BiTE bound fibroblast activation protein on cancer-associated fibroblasts (CAF) and CD3ε on T cells, leading to potent T-cell activation and fibroblast death. Treatment of fresh clinical biopsies, including malignant ascites and solid prostate cancer tissue, with FAP-BiTE–encoding virus induced activation of tumor-infiltrating PD1+ T cells to kill CAFs. In ascites, this led to depletion of CAF-associated immunosuppressive factors, upregulation of proinflammatory cytokines, and increased gene expression of markers of antigen presentation, T-cell function, and trafficking. M2-like ascites macrophages exhibited a proinflammatory repolarization, indicating spectrum-wide alteration of the tumor microenvironment. With this approach, we have actively killed both cancer cells and tumor fibroblasts, reversing CAF-mediated immunosuppression and yielding a potent single-agent therapeutic that is ready for clinical assessment. |
| first_indexed | 2024-03-07T05:44:18Z |
| format | Journal article |
| id | oxford-uuid:e6a9d616-d1c3-4259-9f54-2546dbcd7bed |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:44:18Z |
| publishDate | 2018 |
| publisher | American Association for Cancer Research |
| record_format | dspace |
| spelling | oxford-uuid:e6a9d616-d1c3-4259-9f54-2546dbcd7bed2022-03-27T10:32:52ZAn oncolytic virus expressing a T-cell engager simultaneously targets cancer and immunosuppressive stromal cellsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:e6a9d616-d1c3-4259-9f54-2546dbcd7bedEnglishSymplectic Elements at OxfordAmerican Association for Cancer Research2018Freedman, JDuffy, MLei-Rossmann, JMuntzer, AScott, EHagel, JCampo, LBryant, RVerrill, CLambert, AMiller, PChampion, BSeymour, LFisher, KEffective immunotherapy of stromal-rich tumors requires simultaneous targeting of cancer cells and immunosuppressive elements of the microenvironment. Here, we modified the oncolytic group B adenovirus enadenotucirev to express a stroma-targeted bispecific T-cell engager (BiTE). This BiTE bound fibroblast activation protein on cancer-associated fibroblasts (CAF) and CD3ε on T cells, leading to potent T-cell activation and fibroblast death. Treatment of fresh clinical biopsies, including malignant ascites and solid prostate cancer tissue, with FAP-BiTE–encoding virus induced activation of tumor-infiltrating PD1+ T cells to kill CAFs. In ascites, this led to depletion of CAF-associated immunosuppressive factors, upregulation of proinflammatory cytokines, and increased gene expression of markers of antigen presentation, T-cell function, and trafficking. M2-like ascites macrophages exhibited a proinflammatory repolarization, indicating spectrum-wide alteration of the tumor microenvironment. With this approach, we have actively killed both cancer cells and tumor fibroblasts, reversing CAF-mediated immunosuppression and yielding a potent single-agent therapeutic that is ready for clinical assessment. |
| spellingShingle | Freedman, J Duffy, M Lei-Rossmann, J Muntzer, A Scott, E Hagel, J Campo, L Bryant, R Verrill, C Lambert, A Miller, P Champion, B Seymour, L Fisher, K An oncolytic virus expressing a T-cell engager simultaneously targets cancer and immunosuppressive stromal cells |
| title | An oncolytic virus expressing a T-cell engager simultaneously targets cancer and immunosuppressive stromal cells |
| title_full | An oncolytic virus expressing a T-cell engager simultaneously targets cancer and immunosuppressive stromal cells |
| title_fullStr | An oncolytic virus expressing a T-cell engager simultaneously targets cancer and immunosuppressive stromal cells |
| title_full_unstemmed | An oncolytic virus expressing a T-cell engager simultaneously targets cancer and immunosuppressive stromal cells |
| title_short | An oncolytic virus expressing a T-cell engager simultaneously targets cancer and immunosuppressive stromal cells |
| title_sort | oncolytic virus expressing a t cell engager simultaneously targets cancer and immunosuppressive stromal cells |
| work_keys_str_mv | AT freedmanj anoncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT duffym anoncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT leirossmannj anoncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT muntzera anoncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT scotte anoncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT hagelj anoncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT campol anoncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT bryantr anoncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT verrillc anoncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT lamberta anoncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT millerp anoncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT championb anoncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT seymourl anoncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT fisherk anoncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT freedmanj oncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT duffym oncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT leirossmannj oncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT muntzera oncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT scotte oncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT hagelj oncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT campol oncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT bryantr oncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT verrillc oncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT lamberta oncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT millerp oncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT championb oncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT seymourl oncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells AT fisherk oncolyticvirusexpressingatcellengagersimultaneouslytargetscancerandimmunosuppressivestromalcells |