ArticleMolecular therapy oncolytics2023
Development of a bicistronic anti-CD19/CD20 CAR construct including abrogation of unexpected nucleic acid sequence deletions.
Article in Molecular therapy oncolytics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 17 citations in OpenAlex.
- Axicabtagene ciloleucel in combination with rituximab for refractory large B cell lymphoma: the phase 2, single-arm ZUMA-14 trial.Nature cancer · 2026Trial
- Development of chimeric antigen receptors targeting the γδ T cell receptor.Molecular therapy. Oncology · 2026Article
- Trogocytosis in cancer immunity and cellular immunotherapy: mechanisms, therapeutic challenges, and translational opportunities.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Solid tumour CAR-T cells engineered with fusion proteins targeting PD-L1 for localized IL-12 delivery.Nature biomedical engineering · 2026Article
- Corticosteroids ameliorate CAR T-cell-induced cytokine-release syndrome without inhibiting multiple myeloma treatment.Journal for immunotherapy of cancer · 2026Article
- Can we cure autoimmunity?Current opinion in immunology · 2026Review
- Bioengineered T-cell therapies for precision immunotherapy in renal transplantation, autoimmune relapse, and sensitization.Clinical kidney journal · 2025Review
- Advancing CAR-based cell therapies for solid tumours: challenges, therapeutic strategies, and perspectives.Molecular cancer · 2025Review
- Targets for CAR Therapy in Multiple Myeloma.International journal of molecular sciences · 2025Review
- Chimeric antigen receptor T cell therapy for autoimmune disease.Nature reviews. Immunology · 2024Review
- Optimization of anti-CD19 CAR T cell production for treatment of patients with chronic lymphocytic leukemia.Molecular therapy. Methods & clinical development · 2024Article
- Rapid anti-myeloma activity by T cells expressing an anti-BCMA CAR with a human heavy-chain-only antigen-binding domain.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Logic-gated and contextual control of immunotherapy for solid tumors: contrasting multi-specific T cell engagers and CAR-T cell therapies.Frontiers in immunology · 2024Review
- Article
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
To address CD19 loss from lymphoma after anti-CD19 chimeric antigen receptor (CAR) T cell therapy, we designed a bicistronic construct encoding an anti-CD19 CAR and an anti-CD20 CAR. We detected deletions from the expected bicistronic construct sequence in a minority of transcripts by mRNA sequencing. Loss of bicistronic construct transgene DNA was also detected. Deletions of sequence were present at much higher frequencies in transduced T cell mRNA versus gamma-retroviral vector RNA. We concluded that these deletions were caused by intramolecular template switching of the reverse transcriptase enzyme during reverse transcription of gamma-retroviral vector RNA into transgene DNA of transduced T cells. Intramolecular template switching was driven by repeated regions of highly similar nucleic acid sequence within CAR sequences. We optimized the sequence of the bicistronic CAR construct to reduce repeated regions of highly similar sequences. This optimization nearly eliminated sequence deletions. This work shows that repeated regions of highly similar nucleic acid sequence must be avoided in complex CAR constructs. We further optimized the bicistronic construct by lengthening the linker of the anti-CD20 single-chain variable fragment. This modification increased CD20-specific interleukin-2 release and reduced CD20-specific activation-induced cell death. We selected an optimized anti-CD19/CD20 bicistronic construct for clinical development.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.