Programmed cell death protein 1 activation preferentially inhibits CD28.CAR-T cells.

Abstract

Targeted adoptive immunotherapy with engineered T cells is a promising treatment for refractory hematologic malignancies. However, many patients achieving early complete remissions ultimately relapse. Immunosuppressive ligands are expressed on tumor and supportive cells in the tumor microenvironment (TME). When activated, T cells express associated "checkpoint" receptors. Binding of co-inhibitory ligands and receptors may directly contribute to T-cell functional exhaustion. It is not known whether all T cells engineered to express chimeric antigen receptors (CARs) are subject to checkpoint-mediated regulation. It is also unknown whether distinct CAR signaling moieties modulate T-cell responsiveness to these inhibitory pathways. We have, therefore, directly compared functional co-inhibition in engineered T cells identically targeted to the tumor-associated antigen CD123, but distinct in their mode of T-cell activation: via the endogenous T-cell receptor (ENG), or downstream of CD28 or 41BB-containing CARs. In all cases, we have observed antigen-independent T-cell activation associated with upregulation of the co-inhibitory receptors programmed cell death protein 1 (PD-1, CD279), Tim-3 and Lag-3. Notably, CD28.CAR T cells were uniquely susceptible to PD-1/PD-L1 mediated checkpoint inhibition. Together, our data indicate that PD-1/PD-L1 checkpoint blocking agents may be considered clinically when CD28.CAR T cells do not perform optimally in human trials.

• Authors: Sergey N Zolov, Skyler P Rietberg, Challice L Bonifant
• Journal: Cytotherapy (Cytotherapy) Vol. 20 Issue 10 Pg. 1259-1266 (10 2018) ISSN: 1477-2566 [Electronic] England
• PMID: 30309710 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• B7-H1 Antigen
• CD274 protein, human
• CD28 Antigens
• HAVCR2 protein, human
• Hepatitis A Virus Cellular Receptor 2
• IL3RA protein, human
• Interleukin-3 Receptor alpha Subunit
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• Receptors, Antigen, T-Cell
• Receptors, Chimeric Antigen

Topics

• B7-H1 Antigen (genetics, immunology, metabolism)
• CD28 Antigens (genetics, immunology)
• Cell Line, Tumor
• Cytotoxicity Tests, Immunologic (methods)
• Genetic Engineering
• Hepatitis A Virus Cellular Receptor 2 (immunology, metabolism)
• Humans
• Immunotherapy, Adoptive (methods)
• Interleukin-3 Receptor alpha Subunit (genetics)
• K562 Cells
• Leukemia, Myeloid, Acute (pathology, therapy)
• Lymphocyte Activation
• Programmed Cell Death 1 Receptor (immunology, metabolism)
• Receptors, Antigen, T-Cell (metabolism)
• Receptors, Chimeric Antigen (genetics, immunology)
• T-Lymphocytes (immunology, physiology)
• Tumor Microenvironment