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Constitutively active MyD88/CD40 costimulation enhances expansion and efficacy of chimeric antigen receptor T cells targeting hematological malignancies.
- Source :
-
Leukemia [Leukemia] 2019 Sep; Vol. 33 (9), pp. 2195-2207. Date of Electronic Publication: 2019 Feb 28. - Publication Year :
- 2019
-
Abstract
- Successful adoptive chimeric antigen receptor (CAR) T-cell therapies against hematological malignancies require CAR-T expansion and durable persistence following infusion. Balancing increased CAR-T potency with safety, including severe cytokine-release syndrome (sCRS) and neurotoxicity, warrants inclusion of safety mechanisms to control in vivo CAR-T activity. Here, we describe a novel CAR-T cell platform that utilizes expression of the toll-like receptor (TLR) adaptor molecule, MyD88, and tumor-necrosis factor family member, CD40 (MC), tethered to the CAR molecule through an intentionally inefficient 2A linker system, providing a constitutive signal that drives CAR-T survival, proliferation, and antitumor activity against CD19 <superscript>+</superscript> and CD123 <superscript>+</superscript> hematological cancers. Robust activity of MC-enhanced CAR-T cells was associated with cachexia in animal models that corresponded with high levels of human cytokine production. However, toxicity could be successfully resolved by using the inducible caspase-9 (iC9) safety switch to reduce serum cytokines, by administration of a neutralizing antibody against TNF-α, or by selecting "low" cytokine-producing CD8 <superscript>+</superscript> T cells, without loss of antitumor activity. Interestingly, high basal activity was essential for in vivo CAR-T expansion. This study shows that co-opting novel signaling elements (i.e., MyD88 and CD40) and development of a unique CAR-T architecture can drive T-cell proliferation in vivo to enhance CAR-T therapies.
- Subjects :
- Animals
Antigens, CD19 immunology
Cell Proliferation drug effects
HEK293 Cells
Humans
Immunotherapy, Adoptive methods
Lymphocyte Activation immunology
Mice
Mice, Inbred NOD
Signal Transduction immunology
THP-1 Cells
CD40 Antigens immunology
CD8-Positive T-Lymphocytes immunology
Hematologic Neoplasms immunology
Hematologic Neoplasms therapy
Myeloid Differentiation Factor 88 immunology
Receptors, Antigen, T-Cell immunology
Receptors, Chimeric Antigen immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5551
- Volume :
- 33
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Leukemia
- Publication Type :
- Academic Journal
- Accession number :
- 30816327
- Full Text :
- https://doi.org/10.1038/s41375-019-0417-9