Bicistronic CAR T Cell against BCMA and CD229 Effectively Controls Myeloma Even When BCMA Expression Is Limited

Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy has revolutionized the prognosis of patients with relapsed/refractory multiple myeloma. Regrettably, despite unprecedented overall response rates achieved with this approach, most patients eventually relapse. One of the primary reasons for this is the complete loss or reduced expression of BCMA on the malignant plasma cell surface. Consequently, new therapeutic targets are under investigation. Another potential therapeutic approach involves the use of CAR T cells targeting two tumor antigens. In this study, we developed and validated a monospecific CAR targeting CD229, which was effective in in vitro and in vivo NOD.Cg-Prkdcscid Il2rdtm1Wjl/SzJ mouse models with both homogeneous and heterogeneous BCMA expression. Additionally, we created a bicistronic CAR T cell targeting both CD229 and BCMA, which demonstrated efficacy in models with homogeneous BCMA expression, in heterogeneous models featuring small clonal populations with biallelic BCMA deletion, and in cases with reduced BCMA expression both in vivo and in vitro. Regarding "on-target off-tumor toxicity," no fratricide was observed among CAR T cells, but there was a limited elimination of nonactivated T cells. The immune pressure exerted by anti-CD229 CAR T cells led to the loss of the CD229 antigen expression in some instances. In summary, this work underscores the potential utility of CD229 alone or in combination with BCMA as an immunotherapeutic target in multiple myeloma, especially in cases marked by diminished or absent BCMA expression.

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Publication Details

Journal
Cancer Immunology Research
Published
2025-06-27
DOI
https://doi.org/10.1158/2326-6066.cir-24-1313
Citations
2
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
2.09
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article

Bicistronic CAR T Cell against BCMA and CD229 Effectively Controls Myeloma Even When BCMA Expression Is Limited

Álvaro Urbano-Ispizúa, Laura Rosiñol, Ester Lozano, María Queralt Salas et al.
2 citations
Cancer Immunology Research
CAR-T cell therapy research
2.09
article

Bicistronic CAR T Cell against BCMA and CD229 Effectively Controls Myeloma Even When BCMA Expression Is Limited

Álvaro Urbano-Ispizúa, Laura Rosiñol, Ester Lozano, María Queralt Salas, Joan Mañé-Pujol, Luis Gerardo Rodríguez‐Lobato, Joan Bladé, Natalia Tovar, Carlos Fernández de Larrea, Valentín Ortiz‐Maldonado, Aina Oliver‐Caldés, Hugo Calderón, Anthony M. Battram, David F. Moreno, Oriol Cardús, Manel Juan, Beatriz Martín-Antonio, Anna de Daniel, Pablo Engel, Lorena Pérez-Amill, M. Teresa Cibeira, Judith Carpio, Sergi Vaqué-Salsench
article en
2 citations

Abstract

Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy has revolutionized the prognosis of patients with relapsed/refractory multiple myeloma. Regrettably, despite unprecedented overall response rates achieved with this approach, most patients eventually relapse. One of the primary reasons for this is the complete loss or reduced expression of BCMA on the malignant plasma cell surface. Consequently, new therapeutic targets are under investigation. Another potential therapeutic approach involves the use of CAR T cells targeting two tumor antigens. In this study, we developed and validated a monospecific CAR targeting CD229, which was effective in in vitro and in vivo NOD.Cg-Prkdcscid Il2rdtm1Wjl/SzJ mouse models with both homogeneous and heterogeneous BCMA expression. Additionally, we created a bicistronic CAR T cell targeting both CD229 and BCMA, which demonstrated efficacy in models with homogeneous BCMA expression, in heterogeneous models featuring small clonal populations with biallelic BCMA deletion, and in cases with reduced BCMA expression both in vivo and in vitro. Regarding "on-target off-tumor toxicity," no fratricide was observed among CAR T cells, but there was a limited elimination of nonactivated T cells. The immune pressure exerted by anti-CD229 CAR T cells led to the loss of the CD229 antigen expression in some instances. In summary, this work underscores the potential utility of CD229 alone or in combination with BCMA as an immunotherapeutic target in multiple myeloma, especially in cases marked by diminished or absent BCMA expression.

Cancer Immunology ResearchVol. 13(9)
Instituto de Salud Carlos III (ES), Escuela Nacional de Sanidad (ES), Hospital Clínic de Barcelona (ES), Hospital Universitario Fundación Jiménez Díaz (ES), Municipal Institute for Medical Research (ES), Fundació Clínic per a la Recerca Biomèdica (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (ES), Universitat de Barcelona (ES)
Good health and well-being
Openalex Percentile: Top 12%
CAR-T cell therapy research
2.09
DOISourceOpenAlex
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