title: Hematopoietic stem cells for cancer immunotherapy.
abstract: Hematopoietic stem cells (HSCs) provide an attractive target for immunotherapy of cancer and leukemia by the introduction of genes encoding T-cell receptors (TCRs) or chimeric antigen receptors (CARs) directed against tumor-associated antigens. HSCs engraft for long-term blood cell production and could provide a continuous source of targeted anti-cancer effector cells to sustain remissions. T cells produced de novo from HSCs may continuously replenish anti-tumor T cells that have become anergic or exhausted from ex vivo expansion or exposure to the intratumoral microenvironment. In addition, transgenic T cells produced in vivo undergo allelic exclusion, preventing co-expression of an endogenous TCR that could mis-pair with the introduced TCR chains and blunt activity or even cause off-target reactivity. CAR-engineered HSCs may produce myeloid and natural killer cells in addition to T cells expressing the CAR, providing broader anti-tumor activity that arises quickly after transplant and does not solely require de novo thymopoiesis. Use of TCR- or CAR-engineered HSCs would likely require cytoreductive conditioning to achieve long-term engraftment, and this approach may be used in clinical settings where autologous HSC transplant is being performed to add a graft-versus-tumor effect. Results of experimental and preclinical studies performed to date are reviewed.
authors: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA; Eli and Edythe Broad Center for Regenerative Medicine & Stem Cell Research, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA.
authors: Eric
authors: E
authors: Gschweng
authors: Satiro
authors: S
authors: De Oliveira
authors: Donald B
authors: DB
authors: Kohn
mesh_terms: D000818:Animals; D018014:Gene Transfer Techniques; D041722:Genes, Transgenic, Suicide; D005818:Genetic Engineering; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D016219:Immunotherapy, Adoptive / Q000379:methods; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D011948:Receptors, Antigen, T-Cell
keywords: T-cell receptor; chimeric antigen receptor; hematopoietic stem cells; immunotherapy