Restoring Immune tolerance through Cell and Gene Therapy

Immune mechanisms and curative treatments

Lab overview


About Maria Grazia Roncarolo

Dr. Maria Grazia Roncarolo is a pioneer in cell and gene therapy for genetic diseases and a world-renowned expert in immune regulation. Her breakthrough translational research intersects two distinct but interrelated areas: inducing immune tolerance following hematopoietic stem cell and progenitor cell transplantation (HSPCT) and designing novel gene and cell therapy approaches for patients with inborn errors of immunity and hematological malignancies.

Dr. Roncarolo discovered a subset of inducible regulatory T cells called type 1 regulatory T (Tr1) cells, which she brought into the clinic to support hematopoietic stem and progenitor cell (HSPC) engraftment and prevent graft-versus-host disease (GvHD), a major complication of otherwise life-saving allogeneic HSCT. She was the principal investigator for the first clinical trial using in vitro generated donor-derived Tr1 cells in adult leukemia patients undergoing haploidentical HSCT. Dr. Roncarolo is now the Sponsor of a new clinical trial (NTC03198234), in which patient alloantigen-specific Tr1 cells, called T-allo10, are infused to prevent GvHD in patients with hematological malignancies receiving allogeneic HSPCT. During this time, Dr. Roncarolo is also conducting pre-clinical studies on a 2nd generation of Tr1 cells, made by lentiviral insertion of the IL10 gene into human CD4+ T cells. Along with immunosuppressive properties, these engineered Tr1 cells are active against malignant myeloid cells, and are being explored as a potential novel cell therapy for acute myeloid leukemia (AML).

In addition, Dr. Roncarolo successfully led the first stem cell-based gene therapy trial for severe combined immunodeficiency (SCID) patients lacking adenosine deaminase (ADA-SCID; “bubble boy disease”), a life-threatening inborn error of immunity. The treatment, combining gene-corrected blood stem cells with low-dose chemotherapy, obtained orphan drug status from the FDA and EMEA. It was subsequently licensed to GlaxoSmithKline (GSK) as Strimvelis. This milestone in gene therapy was integral in the implementation of stem cell and gene therapies for other severe inherited diseases, including Wiskott-Aldrich syndrome (WAS) and metachromatic leukodystrophy (MLD). Currently, Dr. Roncarolo is designing a gene therapy strategy to correct mutations in IL-10 and IL-10 receptor genes, which cause devastating very early onset inflammatory bowel disease (VEO-IBD), by CRISPR-based gene correction of patient HSPCs.

At Stanford University School of Medicine, Dr. Roncarolo is a faculty member in the Pediatric Division of Stem Cell Transplantation and Regenerative Medicine, Co-Director of the Institute for Stem Cell Biology and Regenerative Medicine (ISCBRM), and Director of the Center for Definitive and Curative Medicine (CDCM).  As the founder of the CDCM, Dr. Roncarolo continues to lead clinical translation of cell and gene therapy approaches aimed at curing patients with incurable diseases. Dr. Roncarolo has more than 300 peer-reviewed publications and has received numerous honors  (see CAP profile), while also successfully mentoring over 20 students and postdoctoral scholars and has received numerous honors. Dr. Roncarolo is currently leading a small but vibrant lab comprised of three post-doctoral fellows, one graduate student in the Stem Cell Biology program, two life-science research professionals, one CIRM scholar and one Instructor of Pediatrics.


Research Interests

* Immunotolerance: Mechanisms underlying T-cell tolerance, induction of T-cell anergy and regulatory T cells; Immunomodulation: mAbs, proteins and low molecular weight compounds which can modulate T-cell activation;
*Primary immunodeficiencies: Characterization of molecular and immunological defects;
* Gene therapy: Gene transduction of hematopoietic cells for gene therapy in primary immunodeficiencies and metabolic diseases;
* Hematopoiesis: Mechanisms underlying growth and differentiation of hematopoietic stem cells;
* Transplantation: Immune reconstitution and T-cell tolerance after allogenic stem cell transplantation;
* Cytokines/Cytokine receptors: Role in regulation of immune and inflammatory responses.

Clinical Interests

 * Primary Immunodeficiencies
 * Monogenic Autoimmune Disorders
 * Allogenic Bone Marrow Transplantation 
 * Gene Therapy Clinical Trials 
 * Cell Therapy Clinical Trials
 * Clinical Trials in Autoimmune Diseases and Organ Transplantation
 * Clinical Trials in Hemoglobinopathies

Maria Grazia-Roncarolo, MD: Stanford Childx Conference

Maria Grazia Roncarolo, MD

Maria Grazia Roncarolo, MD is the George D. Smith Professor in Stem Cell and Regenerative Medicine, Professor of Pediatrics and of Medicine (blood and marrow transplantation), Co-Director of the Institute for Stem Cell Biology and Regenerative Medicine (ISCBRM), Director of the Center for Definitive and Curative Medicine (CDCM) and faculty member of the Pediatric Division of Stem Cell Transplantation and Regenerative Medicine.

Stanford Resources

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