Strategies for enhancing adoptive T-cell immunotherapy against solid tumors using engineered cytokine signaling and other modalities
- 8 May 2018
- journal article
- review article
- Published by Informa UK Limited in Expert Opinion on Biological Therapy
- Vol. 18 (6), 653-664
- https://doi.org/10.1080/14712598.2018.1473368
Abstract
Introduction: Cancer therapy has been transformed by the demonstration that tumor-specific T-cells can eliminate tumor cells in a clinical setting with minimal long-term toxicity. However, significant success in the treatment of leukemia and lymphoma with T-cells using native receptors or redirected with chimeric antigen receptors (CARs) has not been recapitulated in the treatment of solid tumors. This lack of success is likely related to the paucity of costimulatory and cytokine signaling available in solid tumors, in addition to a range of inhibitory mechanisms. Areas covered: We summarize the latest developments in engineered T-cell immunotherapy, describe the limitations of these approaches in treating solid tumors, and finally highlight several strategies that may be useful in mediating solid tumor responses in the future, while also ensuring safety of engineered cells. Expert opinion: CAR-T therapies require further engineering to achieve their potential against solid tumors. Facilitating cytokine signaling in CAR T-cells appears to be essential in achieving better responses. However, the engineering of T-cells with potentially unchecked proliferation and potency raises the question of whether the simultaneous combination of enhancements will prove safe, necessitating continued advancements in regulating CAR-T activity at the tumor site and methods to safely switch off these engineered cells.Keywords
Funding Information
- National Institutes of Health (NIH-NCI P50 CA126752,NIH-NCI. PO1 CA94237)
- Alex’s Lemonade Foundation (Reach Award)
- Leukemia & Lymphoma Society (R7016-09 SCOR Grant #7018-10)
This publication has 102 references indexed in Scilit:
- Combinational Targeting Offsets Antigen Escape and Enhances Effector Functions of Adoptively Transferred T Cells in GlioblastomaMolecular Therapy, 2013
- Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid LeukemiaNew England Journal of Medicine, 2013
- Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in CancerNew England Journal of Medicine, 2012
- Inducible Apoptosis as a Safety Switch for Adoptive Cell TherapyNew England Journal of Medicine, 2011
- Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid LeukemiaNew England Journal of Medicine, 2011
- Improving Adoptive T Cell Therapy by Targeting and Controlling IL-12 Expression to the Tumor EnvironmentMolecular Therapy, 2011
- Therapeutic cell engineering with surface-conjugated synthetic nanoparticlesNature Medicine, 2010
- Case Report of a Serious Adverse Event Following the Administration of T Cells Transduced With a Chimeric Antigen Receptor Recognizing ERBB2Molecular Therapy, 2010
- Chimeric Antigen Receptors Combining 4-1BB and CD28 Signaling Domains Augment PI3kinase/AKT/Bcl-XL Activation and CD8+ T Cell–mediated Tumor EradicationMolecular Therapy, 2010
- Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastomaNature Medicine, 2008