T cells dressed up with a dual HLA-restricted TCR targeting cathepsin G drive effective AML eradication
Despite immunosensitivity, genetic heterogeneity, low mutational burden and lack of tumor-specific antigens hinder immunotherapy success for acute myeloid leukemia (AML). T cell receptors (TCRs) offer a promising route by targeting tumor-relevant extra- and intracellular antigens shared across AML subtypes; however human leukocyte antigen (HLA) restriction limits their potential. We identified a potent TCR capable of recognizing peptides of Cathepsin G (CTSG), a serine protease confined to neutrophil granules but aberrantly localized in the cytoplasm of blasts, when presented by HLA-A*24:02 and HLA-C*07:02, highly frequent alleles. Leveraging TCR gene-editing and CD8 co-receptor transduction, we engineered a robust T cell population, comprising CD4+ CD8+ T lymphocytes with enhanced functionality, without altering subset identity. T cells expressing the CTSG-TCR exhibited strong and specific cytotoxicity against primary blasts, in vitro and in vivo. Noticeably, no alterations in peripheral blood cell populations, bone marrow hematopoiesis, or extramedullary hematopoietic organs (spleen and liver) were observed, demonstrating optimal on-target/off-tumor safety profile. Moreover, the absence of off-target cross-reactivity was proved by peptide mutagenesis, highlighting the specificity of the TCR for CTSG. These results reveal the potential of dual restricted TCRs, and of CTSG-TCR T cells as powerful therapeutics for a broad AML patient population.
Authors
- Samantha Scaramuzza (ORCID: https://orcid.org/0000-0003-2903-3650)
- Maria Teresa Lupo Stanghellini (ORCID: https://orcid.org/0000-0003-1382-6939)
- Erica Carnevale (ORCID: https://orcid.org/0000-0002-1455-830X)
- Zulma Magnani (ORCID: https://orcid.org/0000-0001-7612-6097)
- Cristina Toffalori (ORCID: https://orcid.org/0000-0002-8313-3057)
- Eliana Ruggiero (ORCID: https://orcid.org/0000-0002-2954-8278)
- Ivan Merelli (ORCID: https://orcid.org/0000-0003-3587-3680)
- Maria Themeli (ORCID: https://orcid.org/0000-0003-0585-7786)
- Rita El Khoury
- Francesca Sanvito (ORCID: https://orcid.org/0000-0002-4046-8420)
- Ciro Maria Improta
- Danilo Abbati (ORCID: https://orcid.org/0000-0001-8517-7937)
- Alessia Potenza (ORCID: https://orcid.org/0000-0003-0298-7315)
- Massimo Degano (ORCID: https://orcid.org/0000-0002-0787-1883)
- Monica Casucci (ORCID: https://orcid.org/0000-0003-4500-9060)
- Francesca Marzuttini
- Laura Conte (ORCID: https://orcid.org/0000-0003-4319-010X)
- Barbara Camisa (ORCID: https://orcid.org/0000-0002-3867-2457)
- Lucia Sergi Sergi (ORCID: https://orcid.org/0000-0002-8631-7433)
- L Vago
- Alessandra Scola
- Alessia Ugolini
- Anna Simioni
- Erica Remiddi
- Alice Grometto
- Maurilio Ponzoni
- Fabio Ciceri
- Vanessa Cavallaro
- Stefania Veronese
- Chiara Bonini
- Martina Spiga (ORCID: https://orcid.org/0000-0003-0038-6233)
Institutions
- Vita-Salute San Raffaele University (IT)
- San Raffaele University of Rome (IT)
- The San Raffaele Telethon Institute for Gene Therapy (IT)
- Amsterdam University Medical Centers (NL)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT)
- Vrije Universiteit Amsterdam (NL)
Publication Details
- Journal
- Blood
- Published
- 2026-04-14
- DOI
- https://doi.org/10.1182/blood.2025030579
- Primary Topic
- vaccines and immunoinformatics approaches
- Type
- article
- Field-Weighted Citation Impact
- 0.00