Rafael Blanco Domínguez
Delta One T cells in cancer immunotherapy
Abstract
Adoptive cell therapy has become a major avenue for cancer treatment. While already implemented as an autologous therapy for B-cell malignancies, next-generation therapies aim for “off-the-shelf” allogeneic products that may be safe and efficacious in other cancer types including solid tumors. By virtue of being MHC/HLA-independent and broadly reactive to many tumors (while sparing healthy cells), gd T cells are ideally placed to meet these goals. Critically, we have developed a clinical-grade protocol for expansion and differentiation of cytotoxic Vd1+ gd T cells, termed “Delta One T” (DOT) cells, and characterized their anti-tumor properties on the path to therapeutic application. Here we will discuss the pre-clinical data that led to an ongoing Phase 1 clinical trial with DOT cells in Acute Myeloid Leukemia (AML) patients. We have provided in vivo proof-of-principle data for DOT cells in patient-derived xenograft AML models; and dissected the molecular mechanisms of AML targeting by DOT cells. Moreover, using a CD123-directed Chimeric Antigen Receptor (CAR123), we have enhanced the intrinsic capacity of DOT cells to eliminate AML in vitro and in vivo.
Expanding beyond hematological malignancies, the natural tropism of Vδ1+ γδ T cells towards mucosal tissues and their ability to infiltrate tumor sites position DOT cells as promising candidates for exploration in solid tumors. Notably, we have demonstrated the efficacy of DOT cells in targeting colorectal cancer (CRC), a particularly challenging cancer type with limited response to current immunotherapies. Utilizing combinatorial approaches, including in vitro cytotoxic assays and orthotopic xenograft murine models, we have unveiled the mechanisms governing tumor infiltration, recognition, and response of DOT cells to the tumor microenvironment. Last, we will discuss ways to improve their tumoricidal function through either enhancement of cytotoxic receptors or blockade of inhibitory receptors. Overall, our findings support the clinical translation of DOT-based cellular products as next-generation allogeneic cancer therapies and underscore avenues for enhancing their efficacy.
Biography/Link
In 2022, he completed his PhD at the Spanish National Center for Cardiovascular Research (CNIC – Madrid, Spain) and the Universidad Autónoma de Madrid in the field of cardio-immunology under the mentorship of Prof. Pilar Martin. During this period, he conducted translational research from pre-clinical models to clinical studies, leading to the identification of significant T cell-derived regulatory molecules in cardiovascular diseases. His findings were published in prestigious journals and led to patent developments, resulting in multiple awards, including the ESC Young Investigator Award (2021), the Margarita Salas Award (2022), the Enrique Fuentes Quintana Award (2023), and the Premio Extraordinario UAM (2023).
Notable achievements include the discovery of a Th17-derived myocarditis biomarker (Blanco-Dominguez et al., New England Journal of Medicine 2021) and a population of anti-inflammatory Treg cells in the infarcted heart important to prevent heart failure development (Blanco-Dominguez et al., Journal of Clinical Investigations 2022). Research stays at La Jolla Institute for Immunology (CA, USA) and the Massachusetts General Hospital (MA, USA) significantly contributed to the achievements of his PhD work.
Recently, he secured an EMBO post-doctoral fellowship to join Prof. Bruno Silva-Santos’s team at the Instituto de Medicina Molecular (iMM – Lisbon, Portugal), where he has been working since 2022. His current focus lies in understanding the regulation of γδ T cells in the suppressive tumor microenvironment and expanding the application of a γδ T cell-derived immunotherapy, termed Delta One T cell, for solid tumors. Through ongoing collaboration with pharmaceutical companies his work feeds directly into the development of this adoptive cell therapy.