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Article ; Online: SEAKER cells coordinate cellular immunotherapy with localized chemotherapy.

Lane, Isabel C / Jan, Max

2022 Volume 43, Issue 10, Page(s) 804–805

Abstract: 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- ...

Abstract	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.
MeSH term(s)	Antigens, Neoplasm ; Humans ; Immunotherapy ; Immunotherapy, Adoptive ; Neoplasms/drug therapy ; Tumor Escape
Chemical Substances	Antigens, Neoplasm
Language	English
Publishing date	2022-04-28
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Comment
ZDB-ID	282846-7
ISSN	1873-3735 ; 0165-6147
ISSN (online)	1873-3735
ISSN	0165-6147
DOI	10.1016/j.tips.2022.04.001
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Article ; Online: Targeting solid tumor antigens with chimeric receptors: cancer biology meets synthetic immunology.

Kembuan, Gabriele J / Kim, Joanna Y / Maus, Marcela V / Jan, Max

Trends in cancer

2024 Volume 10, Issue 4, Page(s) 312–331

Abstract: Chimeric antigen receptor (CAR) T cell therapy is a medical breakthrough in the treatment of B cell malignancies. There is intensive focus on developing solid tumor-targeted CAR-T cell therapies. Although clinically approved CAR-T cell therapies target B ...

Abstract	Chimeric antigen receptor (CAR) T cell therapy is a medical breakthrough in the treatment of B cell malignancies. There is intensive focus on developing solid tumor-targeted CAR-T cell therapies. Although clinically approved CAR-T cell therapies target B cell lineage antigens, solid tumor targets include neoantigens and tumor-associated antigens (TAAs) with diverse roles in tumor biology. Multiple early-stage clinical trials now report encouraging signs of efficacy for CAR-T cell therapies that target solid tumors. We review the landscape of solid tumor target antigens from the perspective of cancer biology and gene regulation, together with emerging clinical data for CAR-T cells targeting these antigens. We then discuss emerging synthetic biology strategies and their application in the clinical development of novel cellular immunotherapies.
MeSH term(s)	Humans ; Antigens, Neoplasm ; Receptors, Chimeric Antigen/genetics ; Receptors, Antigen, T-Cell/genetics ; T-Lymphocytes ; Neoplasms/genetics ; Neoplasms/therapy ; Biology
Chemical Substances	Antigens, Neoplasm ; Receptors, Chimeric Antigen ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2024-02-13
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2852626-0
ISSN	2405-8025 ; 2405-8033 ; 2405-8033
ISSN (online)	2405-8025 ; 2405-8033
ISSN	2405-8033
DOI	10.1016/j.trecan.2024.01.003
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Article ; Online: Photocatalysts for chemical-free PFOA degradation - What we know and where we go from here?

Juve, Jan-Max Arana / Donoso Reece, Juan A / Wong, Michael S / Wei, Zongsu / Ateia, Mohamed

Journal of hazardous materials

2023 Volume 462, Page(s) 132651

Abstract: Perfluorooctanoic acid (PFOA) is a toxic and recalcitrant perfluoroalkyl substance commonly detected in the environment. Its low concentration challenges the development of effective degradation techniques, which demands intensive chemical and energy ... ...

Abstract	Perfluorooctanoic acid (PFOA) is a toxic and recalcitrant perfluoroalkyl substance commonly detected in the environment. Its low concentration challenges the development of effective degradation techniques, which demands intensive chemical and energy consumption. The recent stringent health advisories and the upgrowth and advances in photocatalytic technologies claim the need to evaluate and compare the state-of-the-art. Among these systems, chemical-free photocatalysis emerges as a cost-effective and sustainable solution for PFOA degradation and potentially other perfluorinated carboxylic acids. This review (I) classifies the state-of-the-art of chemical-free photocatalysts for PFOA degradation in families of materials (Ti, Fe, In, Ga, Bi, Si, and BN), (II) describes the evolution of catalysts, identifies and discusses the strategies to enhance their performance, (III) proposes a simplified cost evaluation tool for simple techno-economical analysis of the materials; (IV) compares the features of the catalysts expanding the classic degradation focus to other essential parameters, and (V) identifies current research gaps and future research opportunities to enhance the photocatalyst performance. We aim that this critical review will assist researchers and practitioners to develop rational photocatalyst designs and identify research gaps for green and effective PFAS degradation.
Language	English
Publishing date	2023-09-29
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	1491302-1
ISSN	1873-3336 ; 0304-3894
ISSN (online)	1873-3336
ISSN	0304-3894
DOI	10.1016/j.jhazmat.2023.132651
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Article ; Online: Cancer therapies based on targeted protein degradation - lessons learned with lenalidomide.

Jan, Max / Sperling, Adam S / Ebert, Benjamin L

Nature reviews. Clinical oncology

2021 Volume 18, Issue 7, Page(s) 401–417

Abstract: For decades, anticancer targeted therapies have been designed to inhibit kinases or other enzyme classes and have profoundly benefited many patients. However, novel approaches are required to target transcription factors, scaffolding proteins and other ... ...

Abstract	For decades, anticancer targeted therapies have been designed to inhibit kinases or other enzyme classes and have profoundly benefited many patients. However, novel approaches are required to target transcription factors, scaffolding proteins and other proteins central to cancer biology that typically lack catalytic activity and have remained mostly recalcitrant to drug development. The selective degradation of target proteins is an attractive approach to expand the druggable proteome, and the selective oestrogen receptor degrader fulvestrant served as an early example of this concept. Following a long and tragic history in the clinic, the immunomodulatory imide drug (IMiD) thalidomide was discovered to exert its therapeutic activity via a novel and unexpected mechanism of action: targeting proteins to an E3 ubiquitin ligase for subsequent proteasomal degradation. This discovery has paralleled and directly catalysed myriad breakthroughs in drug development, leading to the rapid maturation of generalizable chemical platforms for the targeted degradation of previously undruggable proteins. Decades of clinical experience have established front-line roles for thalidomide analogues, including lenalidomide and pomalidomide, in the treatment of haematological malignancies. With a new generation of 'degrader' drugs currently in development, this experience provides crucial insights into class-wide features of degraders, including a unique pharmacology, mechanisms of resistance and emerging therapeutic opportunities. Herein, we review these past experiences and discuss their application in the clinical development of novel degrader therapies.
MeSH term(s)	Animals ; Antineoplastic Agents/therapeutic use ; Drug Development/methods ; Drug Development/trends ; Drugs, Investigational/isolation & purification ; Drugs, Investigational/therapeutic use ; Humans ; Lenalidomide/therapeutic use ; Molecular Targeted Therapy/adverse effects ; Molecular Targeted Therapy/methods ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Neoplasms/pathology ; Proteolysis/drug effects ; Proteome/drug effects ; Proteome/metabolism
Chemical Substances	Antineoplastic Agents ; Drugs, Investigational ; Proteome ; Lenalidomide (F0P408N6V4)
Language	English
Publishing date	2021-03-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2491410-1
ISSN	1759-4782 ; 1759-4774
ISSN (online)	1759-4782
ISSN	1759-4774
DOI	10.1038/s41571-021-00479-z
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Article ; Online: Concentrate and degrade PFOA with a photo-regenerable composite of In-doped TNTs@AC.

Arana Juve, Jan-Max / Li, Fan / Zhu, Yangmo / Liu, Wen / Ottosen, Lars D M / Zhao, Dongye / Wei, Zongsu

Chemosphere

2022 Volume 300, Page(s) 134495

Abstract: Concentrate-and-degrade" is an effective strategy to promote mass transfer and degradation of pollutants in photocatalytic systems, yet suitable and cost-effective photocatalysts are required to practice the new concept. In this study, we doped a post- ... ...

Abstract	"Concentrate-and-degrade" is an effective strategy to promote mass transfer and degradation of pollutants in photocatalytic systems, yet suitable and cost-effective photocatalysts are required to practice the new concept. In this study, we doped a post-transition metal of Indium (In) on a novel composite adsorptive photocatalyst, activated carbon-supported titanate nanotubes (TNTs@AC), to effectively degrade perfluorooctanoic acid (PFOA). In/TNTs@AC exhibited both excellent PFOA adsorption (>99% in 30 min) and photodegradation (>99% in 4 h) under optimal conditions (25 °C, pH 7, 1 atm, 1 g/L catalyst, 0.1 mg/L PFOA, 254 nm). The heterojunction structure of the composite facilitated a cooperative adsorption mode of PFOA, i.e., binding of the carboxylic head group of PFOA to the metal oxide and attachment of the hydrophobic tail to AC. The resulting side-on adsorption mode facilitates the electron (e
MeSH term(s)	Caprylates/chemistry ; Fluorocarbons/chemistry ; Indium ; Nanotubes, Carbon ; Titanium/chemistry ; Trinitrotoluene
Chemical Substances	Caprylates ; Fluorocarbons ; Nanotubes, Carbon ; Indium (045A6V3VFX) ; Trinitrotoluene (118-96-7) ; perfluorooctanoic acid (947VD76D3L) ; Titanium (D1JT611TNE)
Language	English
Publishing date	2022-04-04
Publishing country	England
Document type	Journal Article
ZDB-ID	120089-6
ISSN	1879-1298 ; 0045-6535 ; 0366-7111
ISSN (online)	1879-1298
ISSN	0045-6535 ; 0366-7111
DOI	10.1016/j.chemosphere.2022.134495
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Article: Concentrate and degrade PFOA with a photo-regenerable composite of In-doped TNTs@AC

Arana Juve, Jan-Max / Li, Fan / Zhu, Yangmo / Liu, Wen / Ottosen, Lars D.M. / Zhao, Dongye / Wei, Zongsu

Chemosphere. 2022 Aug., v. 300

2022

Abstract: Concentrate-and-degrade” is an effective strategy to promote mass transfer and degradation of pollutants in photocatalytic systems, yet suitable and cost-effective photocatalysts are required to practice the new concept. In this study, we doped a post- ... ...

Abstract	“Concentrate-and-degrade” is an effective strategy to promote mass transfer and degradation of pollutants in photocatalytic systems, yet suitable and cost-effective photocatalysts are required to practice the new concept. In this study, we doped a post-transition metal of Indium (In) on a novel composite adsorptive photocatalyst, activated carbon-supported titanate nanotubes (TNTs@AC), to effectively degrade perfluorooctanoic acid (PFOA). In/TNTs@AC exhibited both excellent PFOA adsorption (>99% in 30 min) and photodegradation (>99% in 4 h) under optimal conditions (25 °C, pH 7, 1 atm, 1 g/L catalyst, 0.1 mg/L PFOA, 254 nm). The heterojunction structure of the composite facilitated a cooperative adsorption mode of PFOA, i.e., binding of the carboxylic head group of PFOA to the metal oxide and attachment of the hydrophobic tail to AC. The resulting side-on adsorption mode facilitates the electron (e‒) transfer from the carboxylic head to the photogenerated hole (h⁺), which was the major oxidant verified by scavenger tests. Furthermore, the presence of In enables direct electron transfer and facilitates the subsequent stepwise defluorination. Finally, In/TNTs@AC was amenable to repeated uses in four consecutive adsorption-photodegradation runs. The findings showed that adsorptive photocatalysts can be prepared by hybridization of carbon and photoactive semiconductors and the enabled “concentrate-and-degrade” strategy is promising for the removal and degradation of trace levels of PFOA from polluted waters.
Keywords	adsorption ; carbon ; cost effectiveness ; electron transfer ; head ; hybridization ; indium ; mass transfer ; nanotubes ; oxidants ; pH ; perfluorooctanoic acid ; photocatalysis ; photocatalysts ; photolysis
Language	English
Dates of publication	2022-08
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	120089-6
ISSN	1879-1298 ; 0045-6535 ; 0366-7111
ISSN (online)	1879-1298
ISSN	0045-6535 ; 0366-7111
DOI	10.1016/j.chemosphere.2022.134495
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Article ; Online: Chemical genetic control of cytokine signaling in CAR-T cells using lenalidomide-controlled membrane-bound degradable IL-7.

Kann, Michael C / Schneider, Emily M / Almazan, Antonio J / Lane, Isabel C / Bouffard, Amanda A / Supper, Valentina M / Takei, Hana N / Tepper, Alexander / Leick, Mark B / Larson, Rebecca C / Ebert, Benjamin L / Maus, Marcela V / Jan, Max

Leukemia

2023 Volume 38, Issue 3, Page(s) 590–600

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Humans ; Lenalidomide/pharmacology ; Receptors, Antigen, T-Cell/genetics ; Interleukin-7/metabolism ; Cell Line, Tumor ; T-Lymphocytes/metabolism ; Immunotherapy, Adoptive ; Cytokines/metabolism
Chemical Substances	Lenalidomide (F0P408N6V4) ; Receptors, Antigen, T-Cell ; Interleukin-7 ; Cytokines
Language	English
Publishing date	2023-12-20
Publishing country	England
Document type	Journal Article
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-023-02113-6
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Article ; Online: Clonal hematopoiesis.

Jan, Max / Ebert, Benjamin L / Jaiswal, Siddhartha

Seminars in hematology

2016 Volume 54, Issue 1, Page(s) 43–50

Abstract: Cancer results from multistep pathogenesis, yet the pre-malignant states that precede the development of many hematologic malignancies have been difficult to identify. Recent genomic studies of blood DNA from tens of thousands of people have revealed the ...

Abstract	Cancer results from multistep pathogenesis, yet the pre-malignant states that precede the development of many hematologic malignancies have been difficult to identify. Recent genomic studies of blood DNA from tens of thousands of people have revealed the presence of remarkably common, age-associated somatic mutations in genes associated with hematologic malignancies. These somatic mutations drive the expansion from a single founding cell to a detectable hematopoietic clone. Owing to the admixed nature of blood that provides a sampling of blood cell production throughout the body, clonal hematopoiesis is a rare view into the biology of pre-malignancy and the direct effects of pre-cancerous lesions on organ dysfunction. Indeed, clonal hematopoiesis is associated not only with increased risk of hematologic malignancy, but also with cardiovascular disease and overall mortality. Here we review rapid advances in the genetic understanding of clonal hematopoiesis and nascent evidence implicating clonal hematopoiesis in malignant and non-malignant age-related disease.
MeSH term(s)	Cellular Senescence/genetics ; Hematopoiesis/genetics ; Humans ; Mutation
Language	English
Publishing date	2016-10-20
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	206923-4
ISSN	1532-8686 ; 0037-1963
ISSN (online)	1532-8686
ISSN	0037-1963
DOI	10.1053/j.seminhematol.2016.10.002
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Article ; Online: Proteolysis-targeting chimeras with reduced off-targets.

Nguyen, Tuan M / Sreekanth, Vedagopuram / Deb, Arghya / Kokkonda, Praveen / Tiwari, Praveen K / Donovan, Katherine A / Shoba, Veronika / Chaudhary, Santosh K / Mercer, Jaron A M / Lai, Sophia / Sadagopan, Ananthan / Jan, Max / Fischer, Eric S / Liu, David R / Ebert, Benjamin L / Choudhary, Amit

Nature chemistry

2023 Volume 16, Issue 2, Page(s) 218–228

Abstract: Proteolysis-targeting chimeras (PROTACs) are molecules that induce proximity between target proteins and E3 ligases triggering target protein degradation. Pomalidomide, a widely used E3 ligase recruiter in PROTACs, can independently degrade other ... ...

Abstract	Proteolysis-targeting chimeras (PROTACs) are molecules that induce proximity between target proteins and E3 ligases triggering target protein degradation. Pomalidomide, a widely used E3 ligase recruiter in PROTACs, can independently degrade other proteins, including zinc-finger (ZF) proteins, with vital roles in health and disease. This off-target degradation hampers the therapeutic applicability of pomalidomide-based PROTACs, requiring development of PROTAC design rules that minimize off-target degradation. Here we developed a high-throughput platform that interrogates off-target degradation and found that reported pomalidomide-based PROTACs induce degradation of several ZF proteins. We generated a library of pomalidomide analogues to understand how functionalizing different positions of the phthalimide ring, hydrogen bonding, and steric and hydrophobic effects impact ZF protein degradation. Modifications of appropriate size on the C5 position reduced off-target ZF degradation, which we validated through target engagement and proteomics studies. By applying these design principles, we developed anaplastic lymphoma kinase oncoprotein-targeting PROTACs with enhanced potency and minimal off-target degradation.
MeSH term(s)	Proteolysis ; Ubiquitin-Protein Ligases/metabolism ; Proteins/metabolism ; Thalidomide/pharmacology ; Thalidomide/analogs & derivatives
Chemical Substances	pomalidomide (D2UX06XLB5) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Proteins ; Thalidomide (4Z8R6ORS6L)
Language	English
Publishing date	2023-12-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2464596-5
ISSN	1755-4349 ; 1755-4330
ISSN (online)	1755-4349
ISSN	1755-4330
DOI	10.1038/s41557-023-01379-8
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Article ; Online: Genetic retargeting of E3 ligases to enhance CAR T cell therapy.

Lane, Isabel C / Kembuan, Gabriele / Carreiro, Jeannie / Kann, Michael C / Lin, William / Bouffard, Amanda A / Kreuzer, Johannes / Morris, Robert / Schneider, Emily M / Kim, Joanna Y / Zou, Charles / Salas-Benito, Diego / Gasser, Jessica A / Leick, Mark B / Słabicki, Mikołaj / Haas, Wilhelm / Maus, Marcela V / Jan, Max

Cell chemical biology

2023 Volume 31, Issue 2, Page(s) 338–348.e5

Abstract: 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 ... ...

Abstract	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 TGFβ 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 TGFβ 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.
MeSH term(s)	Humans ; Ubiquitin-Protein Ligases/metabolism ; Immunotherapy, Adoptive/methods ; Ubiquitination ; Neoplasms ; Transforming Growth Factor beta/genetics ; Transforming Growth Factor beta/metabolism
Chemical Substances	Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Transforming Growth Factor beta
Language	English
Publishing date	2023-11-20
Publishing country	United States
Document type	Journal Article
ISSN	2451-9448
ISSN (online)	2451-9448
DOI	10.1016/j.chembiol.2023.10.024
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