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1.
Cell Chem Biol ; 31(2): 338-348.e5, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-37989314

RESUMO

Chimeric antigen receptor (CAR) T cell therapies are medical breakthroughs in cancer treatment. However, treatment failure is often caused by CAR T cell dysfunction. Additional approaches are needed to overcome inhibitory signals that limit anti-tumor potency. Here, we developed bifunctional fusion "degrader" proteins that bridge one or more target proteins and an E3 ligase complex to enforce target ubiquitination and degradation. Conditional degradation strategies were developed using inducible degrader transgene expression or small molecule-dependent E3 recruitment. We further engineered degraders to block SMAD-dependent TGFß signaling using a domain from the SARA protein to target both SMAD2 and SMAD3. SMAD degrader CAR T cells were less susceptible to suppression by TGFß and demonstrated enhanced anti-tumor potency in vivo. These results demonstrate a clinically suitable synthetic biology platform to reprogram E3 ligase target specificity for conditional, multi-specific endogenous protein degradation, with promising applications including enhancing the potency of CAR T cell therapy.


Assuntos
Neoplasias , Ubiquitina-Proteína Ligases , Humanos , Ubiquitina-Proteína Ligases/metabolismo , Imunoterapia Adotiva/métodos , Ubiquitinação , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
2.
Leukemia ; 38(3): 590-600, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38123696

RESUMO

CAR-T cell therapy has emerged as a breakthrough therapy for the treatment of relapsed and refractory hematologic malignancies. However, insufficient CAR-T cell expansion and persistence is a leading cause of treatment failure. Exogenous or transgenic cytokines have great potential to enhance CAR-T cell potency but pose the risk of exacerbating toxicities. Here we present a chemical-genetic system for spatiotemporal control of cytokine function gated by the off-patent anti-cancer molecular glue degrader drug lenalidomide and its analogs. When co-delivered with a CAR, a membrane-bound, lenalidomide-degradable IL-7 fusion protein enforced a clinically favorable T cell phenotype, enhanced antigen-dependent proliferative capacity, and enhanced in vivo tumor control. Furthermore, cyclical pharmacologic combined control of CAR and cytokine abundance enabled the deployment of highly active, IL-7-augmented CAR-T cells in a dual model of antitumor potency and T cell hyperproliferation.


Assuntos
Interleucina-7 , Receptores de Antígenos de Linfócitos T , Humanos , Lenalidomida/farmacologia , Receptores de Antígenos de Linfócitos T/genética , Interleucina-7/metabolismo , Linhagem Celular Tumoral , Linfócitos T/metabolismo , Imunoterapia Adotiva , Citocinas/metabolismo
3.
Trends Pharmacol Sci ; 43(10): 804-805, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35491262

RESUMO

Tumor antigen escape and T cell dysfunction limit the effectiveness of chimeric antigen receptor (CAR) T cell therapies. To overcome these challenges, Gardner et al. engineered synthetic enzyme-armed killer (SEAKER) cells to coexpress a CAR and a prodrug-activating enzyme to orchestrate a dual immunologic and pharmacologic attack at the tumor site.


Assuntos
Imunoterapia , Neoplasias , Antígenos de Neoplasias , Humanos , Imunoterapia Adotiva , Neoplasias/tratamento farmacológico , Evasão Tumoral
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