Anti-CS1 × Anti-CD3 Bispecific Antibody (BiAb)-Armed Anti-CD3 Activated T Cells (CS1-BATs) Kill CS1+ Myeloma Cells and Release Type-1 Cytokines
Background: Multiple myeloma (MM) remains incurable despite significant advances in chemotherapy, targeted therapies, and immunotherapy. Bispecific antibody (BiAb)-armed activated T cells (BATs) have been developed for targeting and treatment of solid and hematologic malignancies. BATs are serial ki...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-05-01
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| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2020.00544/full |
| _version_ | 1818299371973771264 |
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| author | Lawrence G. Lum Archana Thakur Abdalla Elhakiem Lena Alameer Emily Dinning Manley Huang |
| author_facet | Lawrence G. Lum Archana Thakur Abdalla Elhakiem Lena Alameer Emily Dinning Manley Huang |
| author_sort | Lawrence G. Lum |
| collection | DOAJ |
| description | Background: Multiple myeloma (MM) remains incurable despite significant advances in chemotherapy, targeted therapies, and immunotherapy. Bispecific antibody (BiAb)-armed activated T cells (BATs) have been developed for targeting and treatment of solid and hematologic malignancies. BATs are serial killers of tumor cells, secrete Th1 cytokines, and induce adaptive cellular and humoral immune responses in patients (pts). This study provides preclinical data using bispecific anti-CS1 (elotuzumab) × anti-CD3 (OKT3) antibody (CS1Bi)-armed activated T cells (CS1- BATs) that provide a strong rationale for applying CS1-BATs to pts with MM.Methods: CS1-BATs and unarmed activated T cells (ATC) were incubated with MM cell targets at various effector to target ratios (E:T) in a quantitative flow cytometry-based assay to determine the degree of cell loss relative to target cells incubated without ATC. ATC from up to 8 normal donors were armed with various concentrations of CS1 BiAb and tested against 5 myeloma cells lines for CS1-BATs-mediated killing and release of Th1 cytokines, chemokines and granzyme B.Results: CS1-BATs from normal donors killed each of 5 MM cell lines proportional to E:T ratios ranging between 1:1 and 10:1 and arming concentrations of 12.5 to 50 ng/million ATC, which was accompanied by release of Th1 cytokines, chemokines and granzyme B. CS1-BATs prepared from MM pts' peripheral blood mononuclear cells (PBMC) showed increasing cytotoxicity and T cell expansion over time against ARH77 MM cells. The optimal arming dose of CS1Bi is 50 ng/106 ATC.Conclusions: These data demonstrate the therapeutic potential of CS1-BATs-mediated cytotoxicity and Th1 cytokines release at low E:T and support advancing their clinical development in pts with MM. |
| first_indexed | 2024-12-13T04:50:10Z |
| format | Article |
| id | doaj.art-472608a65f2841468b0959ec0fb19b27 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-13T04:50:10Z |
| publishDate | 2020-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-472608a65f2841468b0959ec0fb19b272022-12-21T23:59:02ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2020-05-011010.3389/fonc.2020.00544514132Anti-CS1 × Anti-CD3 Bispecific Antibody (BiAb)-Armed Anti-CD3 Activated T Cells (CS1-BATs) Kill CS1+ Myeloma Cells and Release Type-1 CytokinesLawrence G. LumArchana ThakurAbdalla ElhakiemLena AlameerEmily DinningManley HuangBackground: Multiple myeloma (MM) remains incurable despite significant advances in chemotherapy, targeted therapies, and immunotherapy. Bispecific antibody (BiAb)-armed activated T cells (BATs) have been developed for targeting and treatment of solid and hematologic malignancies. BATs are serial killers of tumor cells, secrete Th1 cytokines, and induce adaptive cellular and humoral immune responses in patients (pts). This study provides preclinical data using bispecific anti-CS1 (elotuzumab) × anti-CD3 (OKT3) antibody (CS1Bi)-armed activated T cells (CS1- BATs) that provide a strong rationale for applying CS1-BATs to pts with MM.Methods: CS1-BATs and unarmed activated T cells (ATC) were incubated with MM cell targets at various effector to target ratios (E:T) in a quantitative flow cytometry-based assay to determine the degree of cell loss relative to target cells incubated without ATC. ATC from up to 8 normal donors were armed with various concentrations of CS1 BiAb and tested against 5 myeloma cells lines for CS1-BATs-mediated killing and release of Th1 cytokines, chemokines and granzyme B.Results: CS1-BATs from normal donors killed each of 5 MM cell lines proportional to E:T ratios ranging between 1:1 and 10:1 and arming concentrations of 12.5 to 50 ng/million ATC, which was accompanied by release of Th1 cytokines, chemokines and granzyme B. CS1-BATs prepared from MM pts' peripheral blood mononuclear cells (PBMC) showed increasing cytotoxicity and T cell expansion over time against ARH77 MM cells. The optimal arming dose of CS1Bi is 50 ng/106 ATC.Conclusions: These data demonstrate the therapeutic potential of CS1-BATs-mediated cytotoxicity and Th1 cytokines release at low E:T and support advancing their clinical development in pts with MM.https://www.frontiersin.org/article/10.3389/fonc.2020.00544/fullbispecific antibodyelotuzumabactivated T cellsOKT3multiple myelomacytotoxicity |
| spellingShingle | Lawrence G. Lum Archana Thakur Abdalla Elhakiem Lena Alameer Emily Dinning Manley Huang Anti-CS1 × Anti-CD3 Bispecific Antibody (BiAb)-Armed Anti-CD3 Activated T Cells (CS1-BATs) Kill CS1+ Myeloma Cells and Release Type-1 Cytokines Frontiers in Oncology bispecific antibody elotuzumab activated T cells OKT3 multiple myeloma cytotoxicity |
| title | Anti-CS1 × Anti-CD3 Bispecific Antibody (BiAb)-Armed Anti-CD3 Activated T Cells (CS1-BATs) Kill CS1+ Myeloma Cells and Release Type-1 Cytokines |
| title_full | Anti-CS1 × Anti-CD3 Bispecific Antibody (BiAb)-Armed Anti-CD3 Activated T Cells (CS1-BATs) Kill CS1+ Myeloma Cells and Release Type-1 Cytokines |
| title_fullStr | Anti-CS1 × Anti-CD3 Bispecific Antibody (BiAb)-Armed Anti-CD3 Activated T Cells (CS1-BATs) Kill CS1+ Myeloma Cells and Release Type-1 Cytokines |
| title_full_unstemmed | Anti-CS1 × Anti-CD3 Bispecific Antibody (BiAb)-Armed Anti-CD3 Activated T Cells (CS1-BATs) Kill CS1+ Myeloma Cells and Release Type-1 Cytokines |
| title_short | Anti-CS1 × Anti-CD3 Bispecific Antibody (BiAb)-Armed Anti-CD3 Activated T Cells (CS1-BATs) Kill CS1+ Myeloma Cells and Release Type-1 Cytokines |
| title_sort | anti cs1 anti cd3 bispecific antibody biab armed anti cd3 activated t cells cs1 bats kill cs1 myeloma cells and release type 1 cytokines |
| topic | bispecific antibody elotuzumab activated T cells OKT3 multiple myeloma cytotoxicity |
| url | https://www.frontiersin.org/article/10.3389/fonc.2020.00544/full |
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