Preclinical development of three novel CARs targeting CD79b for the treatment of non-Hodgkin’s lymphoma and characterization of the loss of the target antigen
Background Infusion of T cells modified with a chimeric antigen receptor (CAR) targeting CD19 has achieved exceptional responses in patients with non-Hodgkin’s lymphoma (NHL), which led to the approval of CAR targeting CD19 (CART19) (Axi-cel and Liso-cel) as second line of treatment for adult patien...
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BMJ Publishing Group
2024-12-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/12/e009485.full |
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| author | Manel Juan Beatriz Martín-Antonio Pablo Engel Narcis Fernandez-Fuentes Esperanza Esquinas Alvaro Moreno-Sanz Victor Sandá Damian Stodulski-Ciesla Jennifer Borregón Virginia Peña-Blanque Javier Fernández-Calles Juana Serrano-Lopez Pilar Llamas-Sillero Laura Solán-Blanco |
| author_facet | Manel Juan Beatriz Martín-Antonio Pablo Engel Narcis Fernandez-Fuentes Esperanza Esquinas Alvaro Moreno-Sanz Victor Sandá Damian Stodulski-Ciesla Jennifer Borregón Virginia Peña-Blanque Javier Fernández-Calles Juana Serrano-Lopez Pilar Llamas-Sillero Laura Solán-Blanco |
| author_sort | Manel Juan |
| collection | DOAJ |
| description | Background Infusion of T cells modified with a chimeric antigen receptor (CAR) targeting CD19 has achieved exceptional responses in patients with non-Hodgkin’s lymphoma (NHL), which led to the approval of CAR targeting CD19 (CART19) (Axi-cel and Liso-cel) as second line of treatment for adult patients with relapsed/refractory NHL. Unfortunately, 60% of patients still relapse after CART19 due to either a loss of expression of the target antigen (CD19) in the tumor cell, observed in 27% of relapsed patients, a limited CAR-T persistence, and additional mechanisms, including the suppression of the tumor microenvironment. Clinic strategies to prevent target antigen loss include sequential treatment with CARs directed at CD20 or CD22, which have caused loss of the second antigen, suggesting targeting other antigens less prone to disappear. CD79b, expressed in NHL, is a target in patients treated with antibody-drug conjugates (ADC). However, the limited efficacy of ADC suggests that a CAR therapy targeting CD79b might improve results.Methods We designed three new CARs against CD79b termed CAR for Lymphoma (CARLY)1, 2 and 3. We compared their efficacy, phenotype, and inflammatory profiles with CART19 (ARI0001) and CARTBCMA (ARI0002h), which can treat NHL. We also analyzed the target antigen’s expression loss (CD79b, CD19, and B-cell maturation antigen(BCMA)).Results We found that CARLY2 and CARLY3 had high affinity and specificity towards CD79b on B cells. In vitro, all CAR-T cells had similar anti-NHL efficacy, which was retained in an NHL model of CD19− relapse. In vivo, CARLY3 showed the highest efficacy. Analysis of the loss of the target antigen demonstrated that CARLY cells induced CD79b and CD19 downregulation on NHL cells with concomitant trogocytosis of these antigens to T cells, being most notorious in CARLY2, which had the highest affinity towards CD79b and CD19, and supporting the selection of CARLY3 to design a new treatment for patients with NHL. Finally, we created a CAR treatment based on dual targeting of CD79b and BCMA to avoid losing the target antigen. This treatment showed the highest efficacy and did not cause loss of the target antigen.Conclusions Based on specificity, efficacy, and loss of the target antigen, CARLY3 represents a potential novel CAR treatment for NHL. |
| format | Article |
| id | doaj-art-ff6dc5152f4a41099e2ebff259585dde |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-ff6dc5152f4a41099e2ebff259585dde2024-12-18T14:20:14ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-12-01121210.1136/jitc-2024-009485Preclinical development of three novel CARs targeting CD79b for the treatment of non-Hodgkin’s lymphoma and characterization of the loss of the target antigenManel Juan0Beatriz Martín-Antonio1Pablo Engel2Narcis Fernandez-Fuentes3Esperanza Esquinas4Alvaro Moreno-Sanz5Victor Sandá6Damian Stodulski-Ciesla7Jennifer Borregón8Virginia Peña-Blanque9Javier Fernández-Calles10Juana Serrano-Lopez11Pilar Llamas-Sillero12Laura Solán-Blanco13Department of Immunology and Immunotherapy, Hospital Clínic Barcelona, Barcelona, SpainDepartment of Experimental Hematology, Instituto de Investigación Sanitaria-Fundación Jiménez Diaz, Madrid, Spain6 Institut d`Investigacions Biomèdiques, August Pi i Sunyer, Barcelona, SpainJosep Carreras Leukaemia Research Institute, Barcelona, SpainDepartment of Experimental Hematology, Health Research Institute of the Jimenez Diaz Foundation, UAM, Madrid, Spain, UAM, Madrid, SpainDepartment of Experimental Hematology, Health Research Institute of the Jimenez Diaz Foundation, UAM, Madrid, Spain, UAM, Madrid, SpainDepartment of Experimental Hematology, Health Research Institute of the Jimenez Diaz Foundation, UAM, Madrid, Spain, UAM, Madrid, SpainDepartment of Experimental Hematology, Health Research Institute of the Jimenez Diaz Foundation, UAM, Madrid, Spain, UAM, Madrid, SpainDepartment of Experimental Hematology, Health Research Institute of the Jimenez Diaz Foundation, UAM, Madrid, Spain, UAM, Madrid, SpainDepartment of Immunology, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, UAM, Madrid, SpainDepartment of Biomedical Science, University of Barcelona Faculty of Medicine and Health Sciences, Barcelona, SpainDepartment of Experimental Hematology, Health Research Institute of the Jimenez Diaz Foundation, UAM, Madrid, Spain, UAM, Madrid, SpainDepartment of Experimental Hematology, Health Research Institute of the Jimenez Diaz Foundation, UAM, Madrid, Spain, UAM, Madrid, SpainDepartment of Experimental Hematology, Health Research Institute of the Jimenez Diaz Foundation, UAM, Madrid, Spain, UAM, Madrid, SpainBackground Infusion of T cells modified with a chimeric antigen receptor (CAR) targeting CD19 has achieved exceptional responses in patients with non-Hodgkin’s lymphoma (NHL), which led to the approval of CAR targeting CD19 (CART19) (Axi-cel and Liso-cel) as second line of treatment for adult patients with relapsed/refractory NHL. Unfortunately, 60% of patients still relapse after CART19 due to either a loss of expression of the target antigen (CD19) in the tumor cell, observed in 27% of relapsed patients, a limited CAR-T persistence, and additional mechanisms, including the suppression of the tumor microenvironment. Clinic strategies to prevent target antigen loss include sequential treatment with CARs directed at CD20 or CD22, which have caused loss of the second antigen, suggesting targeting other antigens less prone to disappear. CD79b, expressed in NHL, is a target in patients treated with antibody-drug conjugates (ADC). However, the limited efficacy of ADC suggests that a CAR therapy targeting CD79b might improve results.Methods We designed three new CARs against CD79b termed CAR for Lymphoma (CARLY)1, 2 and 3. We compared their efficacy, phenotype, and inflammatory profiles with CART19 (ARI0001) and CARTBCMA (ARI0002h), which can treat NHL. We also analyzed the target antigen’s expression loss (CD79b, CD19, and B-cell maturation antigen(BCMA)).Results We found that CARLY2 and CARLY3 had high affinity and specificity towards CD79b on B cells. In vitro, all CAR-T cells had similar anti-NHL efficacy, which was retained in an NHL model of CD19− relapse. In vivo, CARLY3 showed the highest efficacy. Analysis of the loss of the target antigen demonstrated that CARLY cells induced CD79b and CD19 downregulation on NHL cells with concomitant trogocytosis of these antigens to T cells, being most notorious in CARLY2, which had the highest affinity towards CD79b and CD19, and supporting the selection of CARLY3 to design a new treatment for patients with NHL. Finally, we created a CAR treatment based on dual targeting of CD79b and BCMA to avoid losing the target antigen. This treatment showed the highest efficacy and did not cause loss of the target antigen.Conclusions Based on specificity, efficacy, and loss of the target antigen, CARLY3 represents a potential novel CAR treatment for NHL.https://jitc.bmj.com/content/12/12/e009485.full |
| spellingShingle | Manel Juan Beatriz Martín-Antonio Pablo Engel Narcis Fernandez-Fuentes Esperanza Esquinas Alvaro Moreno-Sanz Victor Sandá Damian Stodulski-Ciesla Jennifer Borregón Virginia Peña-Blanque Javier Fernández-Calles Juana Serrano-Lopez Pilar Llamas-Sillero Laura Solán-Blanco Preclinical development of three novel CARs targeting CD79b for the treatment of non-Hodgkin’s lymphoma and characterization of the loss of the target antigen Journal for ImmunoTherapy of Cancer |
| title | Preclinical development of three novel CARs targeting CD79b for the treatment of non-Hodgkin’s lymphoma and characterization of the loss of the target antigen |
| title_full | Preclinical development of three novel CARs targeting CD79b for the treatment of non-Hodgkin’s lymphoma and characterization of the loss of the target antigen |
| title_fullStr | Preclinical development of three novel CARs targeting CD79b for the treatment of non-Hodgkin’s lymphoma and characterization of the loss of the target antigen |
| title_full_unstemmed | Preclinical development of three novel CARs targeting CD79b for the treatment of non-Hodgkin’s lymphoma and characterization of the loss of the target antigen |
| title_short | Preclinical development of three novel CARs targeting CD79b for the treatment of non-Hodgkin’s lymphoma and characterization of the loss of the target antigen |
| title_sort | preclinical development of three novel cars targeting cd79b for the treatment of non hodgkin s lymphoma and characterization of the loss of the target antigen |
| url | https://jitc.bmj.com/content/12/12/e009485.full |
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