Engineered T cells secreting αB7-H3-αCD3 bispecific engagers for enhanced anti-tumor activity against B7-H3 positive multiple myeloma: a novel therapeutic approach
Abstract Background Multiple myeloma (MM) is an incurable plasma cell malignancy with increasing global incidence. Chimeric antigen receptor (CAR) T-cell therapy targeting BCMA has shown efficacy in relapsed or refractory MM, but it faces resistance due to antigen loss and the tumor microenvironment...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-01-01
|
| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-024-05923-z |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832594493597024256 |
|---|---|
| author | Punchita Rujirachaivej Teerapong Siriboonpiputtana Kornkan Choomee Kamonlapat Supimon Thanich Sangsuwannukul Pucharee Songprakhon Krissada Natungnuy Piriya Luangwattananun Pornpimon Yuti Mutita Junking Pa-thai Yenchitsomanus |
| author_facet | Punchita Rujirachaivej Teerapong Siriboonpiputtana Kornkan Choomee Kamonlapat Supimon Thanich Sangsuwannukul Pucharee Songprakhon Krissada Natungnuy Piriya Luangwattananun Pornpimon Yuti Mutita Junking Pa-thai Yenchitsomanus |
| author_sort | Punchita Rujirachaivej |
| collection | DOAJ |
| description | Abstract Background Multiple myeloma (MM) is an incurable plasma cell malignancy with increasing global incidence. Chimeric antigen receptor (CAR) T-cell therapy targeting BCMA has shown efficacy in relapsed or refractory MM, but it faces resistance due to antigen loss and the tumor microenvironment. Bispecific T-cell engaging (BITE) antibodies also encounter clinical challenges, including short half-lives requiring continuous infusion and potential toxicities. Methods To address these issues, we developed a lentiviral system to engineer T cells that secrete αB7-H3-αCD3 bispecific engager molecules (αB7-H3-αCD3 ENG-T cells). We evaluated their effectiveness against MM cells with varying B7-H3 expression levels, from B7-H3neg to B7-H3high. Results The αB7-H3-αCD3 ENG-T cells demonstrated significant anti-tumor activity against MM cell lines expressing B7-H3. SupT-1 cells (B7-H3neg) served as controls and exhibited minimal cytotoxicity from αB7-H3-αCD3 ENG T cells. In contrast, these engineered T cells showed dose-dependent killing of B7-H3-expressing MM cells: NCI-H929 (B7-H3low), L-363 (B7-H3medium), and KMS-12-PE (B7-H3high). For NCI-H929 cells, cytotoxicity reached 38.5 ± 7.4% (p = 0.0212) and 54.0 ± 9.2% (p = 0.0317) at effector-to-target (E:T) ratios of 5:1 and 10:1, respectively. Against L-363 cells, cytotoxicity was 56.6 ± 3.2% (p < 0.0001) and 71.4 ± 5.2% (p = 0.0002) at E:T ratios of 5:1 and 10:1, respectively. For KMS-12-PE cells, significant cytotoxic effects were observed even at an E:T ratio of 1:1, with 27.2 ± 3.7% (p = 0.0004), 44.4 ± 3.7% (p < 0.0001), and 68.6 ± 9.2% (p = 0.0004) cytotoxicity at E:T ratios of 1:1, 5:1, and 10:1, respectively. Conclusions These results indicate that αB7-H3-αCD3 ENG T cells could be a promising therapy for B7-H3-positive MM. They may enhance current MM treatments and improve overall outcomes. Additional preclinical and clinical research is required to fully assess their therapeutic potential. |
| format | Article |
| id | doaj-art-8b54b4d5a63c4d5981282a39a2e5ad2c |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-8b54b4d5a63c4d5981282a39a2e5ad2c2025-01-19T12:37:10ZengBMCJournal of Translational Medicine1479-58762025-01-0123111910.1186/s12967-024-05923-zEngineered T cells secreting αB7-H3-αCD3 bispecific engagers for enhanced anti-tumor activity against B7-H3 positive multiple myeloma: a novel therapeutic approachPunchita Rujirachaivej0Teerapong Siriboonpiputtana1Kornkan Choomee2Kamonlapat Supimon3Thanich Sangsuwannukul4Pucharee Songprakhon5Krissada Natungnuy6Piriya Luangwattananun7Pornpimon Yuti8Mutita Junking9Pa-thai Yenchitsomanus10Graduate Program in Clinical Pathology, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol UniversityDepartment of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol UniversitySiriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol UniversitySiriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol UniversityDepartment of Molecular Medicine, Mayo Clinic RochesterSiriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol UniversitySiriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol UniversitySiriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol UniversitySiriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol UniversitySiriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol UniversitySiriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol UniversityAbstract Background Multiple myeloma (MM) is an incurable plasma cell malignancy with increasing global incidence. Chimeric antigen receptor (CAR) T-cell therapy targeting BCMA has shown efficacy in relapsed or refractory MM, but it faces resistance due to antigen loss and the tumor microenvironment. Bispecific T-cell engaging (BITE) antibodies also encounter clinical challenges, including short half-lives requiring continuous infusion and potential toxicities. Methods To address these issues, we developed a lentiviral system to engineer T cells that secrete αB7-H3-αCD3 bispecific engager molecules (αB7-H3-αCD3 ENG-T cells). We evaluated their effectiveness against MM cells with varying B7-H3 expression levels, from B7-H3neg to B7-H3high. Results The αB7-H3-αCD3 ENG-T cells demonstrated significant anti-tumor activity against MM cell lines expressing B7-H3. SupT-1 cells (B7-H3neg) served as controls and exhibited minimal cytotoxicity from αB7-H3-αCD3 ENG T cells. In contrast, these engineered T cells showed dose-dependent killing of B7-H3-expressing MM cells: NCI-H929 (B7-H3low), L-363 (B7-H3medium), and KMS-12-PE (B7-H3high). For NCI-H929 cells, cytotoxicity reached 38.5 ± 7.4% (p = 0.0212) and 54.0 ± 9.2% (p = 0.0317) at effector-to-target (E:T) ratios of 5:1 and 10:1, respectively. Against L-363 cells, cytotoxicity was 56.6 ± 3.2% (p < 0.0001) and 71.4 ± 5.2% (p = 0.0002) at E:T ratios of 5:1 and 10:1, respectively. For KMS-12-PE cells, significant cytotoxic effects were observed even at an E:T ratio of 1:1, with 27.2 ± 3.7% (p = 0.0004), 44.4 ± 3.7% (p < 0.0001), and 68.6 ± 9.2% (p = 0.0004) cytotoxicity at E:T ratios of 1:1, 5:1, and 10:1, respectively. Conclusions These results indicate that αB7-H3-αCD3 ENG T cells could be a promising therapy for B7-H3-positive MM. They may enhance current MM treatments and improve overall outcomes. Additional preclinical and clinical research is required to fully assess their therapeutic potential.https://doi.org/10.1186/s12967-024-05923-zMultiple myelomaBispecific T-cell engagerBITET cells secreting BITEENG T cellsB7-H3 |
| spellingShingle | Punchita Rujirachaivej Teerapong Siriboonpiputtana Kornkan Choomee Kamonlapat Supimon Thanich Sangsuwannukul Pucharee Songprakhon Krissada Natungnuy Piriya Luangwattananun Pornpimon Yuti Mutita Junking Pa-thai Yenchitsomanus Engineered T cells secreting αB7-H3-αCD3 bispecific engagers for enhanced anti-tumor activity against B7-H3 positive multiple myeloma: a novel therapeutic approach Journal of Translational Medicine Multiple myeloma Bispecific T-cell engager BITE T cells secreting BITE ENG T cells B7-H3 |
| title | Engineered T cells secreting αB7-H3-αCD3 bispecific engagers for enhanced anti-tumor activity against B7-H3 positive multiple myeloma: a novel therapeutic approach |
| title_full | Engineered T cells secreting αB7-H3-αCD3 bispecific engagers for enhanced anti-tumor activity against B7-H3 positive multiple myeloma: a novel therapeutic approach |
| title_fullStr | Engineered T cells secreting αB7-H3-αCD3 bispecific engagers for enhanced anti-tumor activity against B7-H3 positive multiple myeloma: a novel therapeutic approach |
| title_full_unstemmed | Engineered T cells secreting αB7-H3-αCD3 bispecific engagers for enhanced anti-tumor activity against B7-H3 positive multiple myeloma: a novel therapeutic approach |
| title_short | Engineered T cells secreting αB7-H3-αCD3 bispecific engagers for enhanced anti-tumor activity against B7-H3 positive multiple myeloma: a novel therapeutic approach |
| title_sort | engineered t cells secreting αb7 h3 αcd3 bispecific engagers for enhanced anti tumor activity against b7 h3 positive multiple myeloma a novel therapeutic approach |
| topic | Multiple myeloma Bispecific T-cell engager BITE T cells secreting BITE ENG T cells B7-H3 |
| url | https://doi.org/10.1186/s12967-024-05923-z |
| work_keys_str_mv | AT punchitarujirachaivej engineeredtcellssecretingab7h3acd3bispecificengagersforenhancedantitumoractivityagainstb7h3positivemultiplemyelomaanoveltherapeuticapproach AT teerapongsiriboonpiputtana engineeredtcellssecretingab7h3acd3bispecificengagersforenhancedantitumoractivityagainstb7h3positivemultiplemyelomaanoveltherapeuticapproach AT kornkanchoomee engineeredtcellssecretingab7h3acd3bispecificengagersforenhancedantitumoractivityagainstb7h3positivemultiplemyelomaanoveltherapeuticapproach AT kamonlapatsupimon engineeredtcellssecretingab7h3acd3bispecificengagersforenhancedantitumoractivityagainstb7h3positivemultiplemyelomaanoveltherapeuticapproach AT thanichsangsuwannukul engineeredtcellssecretingab7h3acd3bispecificengagersforenhancedantitumoractivityagainstb7h3positivemultiplemyelomaanoveltherapeuticapproach AT puchareesongprakhon engineeredtcellssecretingab7h3acd3bispecificengagersforenhancedantitumoractivityagainstb7h3positivemultiplemyelomaanoveltherapeuticapproach AT krissadanatungnuy engineeredtcellssecretingab7h3acd3bispecificengagersforenhancedantitumoractivityagainstb7h3positivemultiplemyelomaanoveltherapeuticapproach AT piriyaluangwattananun engineeredtcellssecretingab7h3acd3bispecificengagersforenhancedantitumoractivityagainstb7h3positivemultiplemyelomaanoveltherapeuticapproach AT pornpimonyuti engineeredtcellssecretingab7h3acd3bispecificengagersforenhancedantitumoractivityagainstb7h3positivemultiplemyelomaanoveltherapeuticapproach AT mutitajunking engineeredtcellssecretingab7h3acd3bispecificengagersforenhancedantitumoractivityagainstb7h3positivemultiplemyelomaanoveltherapeuticapproach AT pathaiyenchitsomanus engineeredtcellssecretingab7h3acd3bispecificengagersforenhancedantitumoractivityagainstb7h3positivemultiplemyelomaanoveltherapeuticapproach |