Intra-tumoral delivery of CXCL11 via a vaccinia virus, but not by modified T cells, enhances the efficacy of adoptive T cell therapy and vaccines
T cell trafficking into tumors depends on a “match” between chemokine receptors on effector cells (e.g., CXCR3 and CCR5) and tumor-secreted chemokines. There is often a chemokine/chemokine receptor “mismatch”, with tumors producing minute amounts of chemokines, resulting in inefficient targeting of...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2018-03-01
|
| Series: | OncoImmunology |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/2162402X.2017.1395997 |
| _version_ | 1819082746888192000 |
|---|---|
| author | Edmund K. Moon Liang-Chuan S. Wang Kheng Bekdache Rachel C. Lynn Albert Lo Stephen H. Thorne Steven M. Albelda |
| author_facet | Edmund K. Moon Liang-Chuan S. Wang Kheng Bekdache Rachel C. Lynn Albert Lo Stephen H. Thorne Steven M. Albelda |
| author_sort | Edmund K. Moon |
| collection | DOAJ |
| description | T cell trafficking into tumors depends on a “match” between chemokine receptors on effector cells (e.g., CXCR3 and CCR5) and tumor-secreted chemokines. There is often a chemokine/chemokine receptor “mismatch”, with tumors producing minute amounts of chemokines, resulting in inefficient targeting of effectors to tumors. We aimed to alter tumors to produce higher levels of CXCL11, a CXCR3 ligand, to attract more effector cells following immunotherapy. Mice bearing established subcutaneous tumors were studied. In our first approach, we used modified chimeric antigen receptor (CAR)-transduced human T cells to deliver CXCL11 (CAR/CXCL11) into tumors. In our second approach, we intravenously (iv) administered a modified oncolytic vaccinia virus (VV) engineered to produce CXCL11 (VV.CXCL11). The effect of these treatments on T cell trafficking into the tumors and anti-tumor efficacy after subsequent CAR T cell injections or anti-tumor vaccines was determined. CAR/CXCL11 and VV.CXCL11 significantly increased CXCL11 protein levels within tumors. For CAR/CXCL11, injection of a subsequent dose of CAR T cells did not result in increased intra-tumoral trafficking, and appeared to decrease the function of the injected CAR T cells. In contrast, VV.CXCL11 increased the number of total and antigen-specific T cells within tumors after CAR T cell injection or vaccination and significantly enhanced anti-tumor efficacy. Both approaches were successful in increasing CXCL11 levels within the tumors; however, only the vaccinia approach was successful in recruiting T cells and augmenting anti-tumor efficacy. VV.CXCL11 should be considered as a potential approach to augment adoptive T cell transfer or vaccine immunotherapy. |
| first_indexed | 2024-12-21T20:21:35Z |
| format | Article |
| id | doaj.art-1bef78f55bbf4dc486d1472a5d6e311d |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-12-21T20:21:35Z |
| publishDate | 2018-03-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-1bef78f55bbf4dc486d1472a5d6e311d2022-12-21T18:51:28ZengTaylor & Francis GroupOncoImmunology2162-402X2018-03-017310.1080/2162402X.2017.13959971395997Intra-tumoral delivery of CXCL11 via a vaccinia virus, but not by modified T cells, enhances the efficacy of adoptive T cell therapy and vaccinesEdmund K. Moon0Liang-Chuan S. Wang1Kheng Bekdache2Rachel C. Lynn3Albert Lo4Stephen H. Thorne5Steven M. Albelda6Perelman School of Medicine at the University of PennsylvaniaPerelman School of Medicine at the University of PennsylvaniaPerelman School of Medicine at the University of PennsylvaniaPerelman School of Medicine at the University of PennsylvaniaSchool of Veterinary Medicine at the University of PennsylvaniaUniversity of PittsburghPerelman School of Medicine at the University of PennsylvaniaT cell trafficking into tumors depends on a “match” between chemokine receptors on effector cells (e.g., CXCR3 and CCR5) and tumor-secreted chemokines. There is often a chemokine/chemokine receptor “mismatch”, with tumors producing minute amounts of chemokines, resulting in inefficient targeting of effectors to tumors. We aimed to alter tumors to produce higher levels of CXCL11, a CXCR3 ligand, to attract more effector cells following immunotherapy. Mice bearing established subcutaneous tumors were studied. In our first approach, we used modified chimeric antigen receptor (CAR)-transduced human T cells to deliver CXCL11 (CAR/CXCL11) into tumors. In our second approach, we intravenously (iv) administered a modified oncolytic vaccinia virus (VV) engineered to produce CXCL11 (VV.CXCL11). The effect of these treatments on T cell trafficking into the tumors and anti-tumor efficacy after subsequent CAR T cell injections or anti-tumor vaccines was determined. CAR/CXCL11 and VV.CXCL11 significantly increased CXCL11 protein levels within tumors. For CAR/CXCL11, injection of a subsequent dose of CAR T cells did not result in increased intra-tumoral trafficking, and appeared to decrease the function of the injected CAR T cells. In contrast, VV.CXCL11 increased the number of total and antigen-specific T cells within tumors after CAR T cell injection or vaccination and significantly enhanced anti-tumor efficacy. Both approaches were successful in increasing CXCL11 levels within the tumors; however, only the vaccinia approach was successful in recruiting T cells and augmenting anti-tumor efficacy. VV.CXCL11 should be considered as a potential approach to augment adoptive T cell transfer or vaccine immunotherapy.http://dx.doi.org/10.1080/2162402X.2017.1395997adoptive t cell transfercancer vaccinescar t cellschemokinescxcl11immunotherapymesotheliomalung cancervaccinia virus |
| spellingShingle | Edmund K. Moon Liang-Chuan S. Wang Kheng Bekdache Rachel C. Lynn Albert Lo Stephen H. Thorne Steven M. Albelda Intra-tumoral delivery of CXCL11 via a vaccinia virus, but not by modified T cells, enhances the efficacy of adoptive T cell therapy and vaccines OncoImmunology adoptive t cell transfer cancer vaccines car t cells chemokines cxcl11 immunotherapy mesothelioma lung cancer vaccinia virus |
| title | Intra-tumoral delivery of CXCL11 via a vaccinia virus, but not by modified T cells, enhances the efficacy of adoptive T cell therapy and vaccines |
| title_full | Intra-tumoral delivery of CXCL11 via a vaccinia virus, but not by modified T cells, enhances the efficacy of adoptive T cell therapy and vaccines |
| title_fullStr | Intra-tumoral delivery of CXCL11 via a vaccinia virus, but not by modified T cells, enhances the efficacy of adoptive T cell therapy and vaccines |
| title_full_unstemmed | Intra-tumoral delivery of CXCL11 via a vaccinia virus, but not by modified T cells, enhances the efficacy of adoptive T cell therapy and vaccines |
| title_short | Intra-tumoral delivery of CXCL11 via a vaccinia virus, but not by modified T cells, enhances the efficacy of adoptive T cell therapy and vaccines |
| title_sort | intra tumoral delivery of cxcl11 via a vaccinia virus but not by modified t cells enhances the efficacy of adoptive t cell therapy and vaccines |
| topic | adoptive t cell transfer cancer vaccines car t cells chemokines cxcl11 immunotherapy mesothelioma lung cancer vaccinia virus |
| url | http://dx.doi.org/10.1080/2162402X.2017.1395997 |
| work_keys_str_mv | AT edmundkmoon intratumoraldeliveryofcxcl11viaavacciniavirusbutnotbymodifiedtcellsenhancestheefficacyofadoptivetcelltherapyandvaccines AT liangchuanswang intratumoraldeliveryofcxcl11viaavacciniavirusbutnotbymodifiedtcellsenhancestheefficacyofadoptivetcelltherapyandvaccines AT khengbekdache intratumoraldeliveryofcxcl11viaavacciniavirusbutnotbymodifiedtcellsenhancestheefficacyofadoptivetcelltherapyandvaccines AT rachelclynn intratumoraldeliveryofcxcl11viaavacciniavirusbutnotbymodifiedtcellsenhancestheefficacyofadoptivetcelltherapyandvaccines AT albertlo intratumoraldeliveryofcxcl11viaavacciniavirusbutnotbymodifiedtcellsenhancestheefficacyofadoptivetcelltherapyandvaccines AT stephenhthorne intratumoraldeliveryofcxcl11viaavacciniavirusbutnotbymodifiedtcellsenhancestheefficacyofadoptivetcelltherapyandvaccines AT stevenmalbelda intratumoraldeliveryofcxcl11viaavacciniavirusbutnotbymodifiedtcellsenhancestheefficacyofadoptivetcelltherapyandvaccines |