Steering CAR T cell epigenetic programs by tweaking manufacturing protocol DOI Creative Commons
Meghan W. Dukes, Giedre Krenciute

Cell Reports Medicine, Journal Year: 2023, Volume and Issue: 4(6), P. 101080 - 101080

Published: June 1, 2023

CAR T cell persistence remains a significant roadblock to effective clinical translation of cells for solid and brain tumors. Jung et al.1Jung I.Y. Noguera-Ortega E. Bartoszek R. Collins S.M. Williams Davis M. Jadlowsky J.K. Plesa G. Siegel D.L. Chew A. al.Tissue-resident memory with stem-like characteristics display enhanced efficacy against liquid tumors.Cell Rep. Med. 2023; 4: 101053https://doi.org/10.1016/j.xcrm.2023.101053Abstract Full Text PDF Google Scholar demonstrate enrichment resident phenotypes through simple changes the manufacturing process. Chimeric antigen receptor (CAR) are gaining momentum as safe treatments tumors; however, improving anti-tumor challenge field. The mechanism by which kill tumor is straightforward. Synthetic molecules designed recognize specific antigens redirect cytotoxic machinery antigen-expressing cells, kill. subsequently activate expand, promoting further killing. However, it well established that progressively lose effector function after repeat exposure resulting in incomplete clearance recurrence. This gradual functional loss inability expand persist collectively defined exhaustion. To overcome exhaustion, field exploring strategies manipulating programs so sustained long term. Targeting epigenetic has emerged potential way accomplish this. Indeed, several groups have explored methods re-programming long-term targeting programs. In human deletion TET2,2Jain N. Zhao Z. Feucht J. Koche Iyer Dobrin Mansilla-Soto Yang Zhan Y. Lopez al.TET2 guards unchecked BATF3-induced expansion.Nature. 615: 315-322Crossref PubMed Scopus (0) DNMT3A,3Prinzing B. Zebley C.C. Petersen C.T. Fan Anido A.A. Yi Nguyen P. Houke H. Bell Haydar D. al.Deleting DNMT3A prevents exhaustion enhances antitumor activity.Sci. Transl. 2021; 13eabh0272Crossref (56) or SUV39H14Jain Gozlan Brocks Raveh-Sadka T. Wells Shi al.Abstract 5583: SUV39H1 disruption CD28-costimulated cells.Cancer Res. 2022; 82: 5583Crossref significantly survival, proliferation, function. these examples, requires regulators via gene editing cells. While knockout approaches now field, clinic still highly tedious, time consuming, expensive due regulatory requirements. Thus, alternative simplistic needed. One strategy been tweaking protocol addition chemical reagents. Multiple studies demonstrated dasatinib during not only primes adopt memory-like phenotype, reprograms transcriptional profiles, vitro vivo,5Weber, W.; Parker, K. R.; Sotillo, E.; Lynn, C.; Anbunathan, H.; Lattin, J.; Good, Z.; Belk, A.; Daniel, B.; Klysz, D., al, Transient rest restores functionality exhausted CAR-T remodeling. Science (New York, N.Y.) 2021, 372.Google but also overcomes fratricide.6Watanabe Mo F. Zheng Ma Bray V.C. van Leeuwen D.G. Sritabal-Ramirez Hu Wang S. Mehta al.Feasibility preclinical CD7-unedited CD7 malignancies.Mol. Ther. 31: 24-34Abstract Addition decitabine, an DNA methyltransferase (DNMT) inhibitor, shows promise priming improved function.7Wang Li Chen L. Bian X. Q. Xu Liu al.Low-dose decitabine endows persistent antitumour reprogramming.Nat. Commun. 6: 409Crossref (75) current study published Cell Reports Medicine, Jung. developed method products can be enriched tissue-resident (TRM) encourage accumulation tissue. many blood cancers benefit from actively circulate bloodstream bone marrow, treatment tumors cellular programming encourages cytolytic at location resist recirculation. this, al. optimized production activated generated presence exogenous transforming growth factor β (TGF-β) (Figure 1). TGF-β numerous functions on including maintenance naive/stem-like populations implication preserved tissue retention,8Mackay L.K. Rahimpour J.Z. Stock A.T. Hafon M.L. Vega-Ramos Lauzurica Mueller S.N. Stefanovic al.The developmental pathway CD103(+)CD8+ skin.Nat. Immunol. 2013; 14: 1294-1301Crossref (824) reduction CD8+ function.9Oh S.A. M.O. TGF-β: guardian function.J. 191 (1950): 3973-3979Crossref (202) Mesothelin (M5)-targeted interleukin-2 (IL-2) (CAR-TRM cells) were analyzed surface markers (via flow cytometry), profiles bulk single-cell RNA sequencing), chromatin accessibility assay transposase-accessible using sequencing [ATAC-seq]) confirm CAR-TRM phenotypes. indeed showed increased expression regulation TRM phenotype compared IL-2 alone. Importantly, analysis revealed downregulation KLF2 loci dictates commitment recirculation, suggesting residence discourage circulation. associated stemness, self-renewal, early traditional markers. superior cytokine upon stimulation control reduced genes responsible terminal differentiation dysfunction. suggests exhaustive decoupled terminally exhausted. produced vivo models both (pancreatic prostate) (B leukemia) cancers. Specifically, administration resulted higher overall number tissues two weeks following treatment. Improved was observed days administration. animals received successfully cleared rechallenges, residency Due known inhibitory attempted enrich overexpressing RUNX3 activation CD25, they ultimately failed induce exciting promising results, there some questions remain addressed. For example, this performed B leukemia settings. It would interesting see whether results consistent more challenging hematological malignancies such acute myeloid leukemia. addition, multiple try block signaling because its immunosuppressive effect cells.10de Folmont Bourhis J.-H. Chouaib Terry Multifaceted Role Transforming Growth Factor Therapy.Immuno. 1: 160-173Crossref know suppressive effects TME where secreted infiltrating immune immune-competent animal warranted. summary, demonstrates small tweaks generate ability penetrate additional pre-clinical testing warranted, shown easily manipulate potentially easy clinic. G.K. one-time consultant Kineticos (2022).

Language: Английский

Unlocking T cell exhaustion: Insights and implications for CAR-T cell therapy DOI Creative Commons

Dian Xiong,

Haijun Yu, Zhi‐Jun Sun

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(8), P. 3416 - 3431

Published: April 24, 2024

Chimeric antigen receptor T (CAR-T) cell therapy as a form of adoptive (ACT) has shown significant promise in cancer treatment, demonstrated by the FDA-approved CAR-T therapies targeting CD19 or B maturation (BCMA) for hematological malignancies, albeit with moderate outcomes solid tumors. However, despite these advancements, efficacy is often compromised exhaustion, phenomenon that impedes persistence and effector function cells, leading to relapse rate up 75% patients treated CD22 cells malignancies. Strategies overcome exhaustion employ state-of-the-art genomic engineering tools single-cell sequencing technologies. In this review, we provide comprehensive understanding latest mechanistic insights into their implications current efforts optimize therapy. These insights, combined lessons learned from benchmarking based products recent clinical trials, aim address challenges posed potentially setting stage development tailored next-generation approaches treatment.

Language: Английский

Citations

2
Navigating the landscape of the unfolded protein response in CD8+ T cells DOI Creative Commons

Keith Alan Nair,

Bei Liu

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: July 4, 2024

Endoplasmic reticulum stress occurs due to large amounts of misfolded proteins, hypoxia, nutrient deprivation, and more. The unfolded protein is a complex intracellular signaling network designed operate under this stress. Composed three individual arms, inositol-requiring enzyme 1, kinase RNA-like ER kinase, activating transcription factor-6, the response looks resolve return proteostasis. CD8 + T cell critical type for adaptive immune system. has been shown have wide-ranging spectrum effects on cells. cells undergo cellular during activation environmental insults. However, magnitude still understudied. Thus, studying these pathways important unraveling inner machinations powerful In review, we will highlight recent literature in field, summarize response, discuss their roles biology functionality.

Language: Английский

Citations

2
In vivo gene editing and in situ generation of chimeric antigen receptor cells for next-generation cancer immunotherapy DOI Creative Commons
Weiyue Zhang, Xin Huang

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: Nov. 13, 2024

Chimeric antigen receptor (CAR) cell therapy has achieved groundbreaking success in treating hematological malignancies. However, its application to solid tumors remains challenging due complex manufacturing processes, limited vivo persistence, and transient therapeutic effects. In CAR-immune cells induced by gene delivery systems loaded with CAR genes gene-editing tools have shown efficiency for anti-tumor immunotherapy. situ programming of autologous immune avoids the safety concerns allogeneic cells, manufacture could be standardized. Therefore, editing generation might potentially overcome abovementioned limitations current therapy. This review mainly focuses on structures, tools, techniques applied immunotherapy help design develop The recent applications both hematologic malignancies are investigated. To sum up, holds promise offering a practical, cost-effective, efficient, safe, widely applicable approach next-generation

Language: Английский

Citations

2
Exploring the potential of the convergence between extracellular vesicles and CAR technology as a novel immunotherapy approach DOI Creative Commons

O. Bar,

Angel Porgador, Tomer Cooks

et al.

Journal of Extracellular Biology, Journal Year: 2024, Volume and Issue: 3(9)

Published: Sept. 1, 2024

Abstract Cancer therapy is a dynamically evolving field, witnessing the emergence of innovative approaches that offer promising outlook for patients grappling with persistent disease. Within realm therapeutic exploration, chimeric antigen receptor (CAR) T cells as well CAR NK cells, have surfaced novel approaches, each possessing unique attributes and transformative potential. Immune engineered to express CARs recognizing tumour‐specific antigens, shown remarkable promise in treating terminal cancers by combining precision antibody specificity potent cytotoxic function cells. However, their application solid tumours still its nascent stages, presenting major challenges. On same note, distinct immunotherapeutic approach, utilizing on providing advantages safety, manufacturing simplicity, broader scope cancer treatment. Extracellular vesicles (EVs) emerged agents due ability carry crucial biomarkers biologically active molecules, serving vital messengers intercellular communication network. In context cancer, potential EVs lies delivering tumour‐suppressing proteins, nucleic acid components, or targeting drugs precision, thereby redefining paradigm medicine. The fusion technology capabilities has given rise new frontier. EVs, leveraging power alleviate challenges associated live‐cell therapies. are suggested reduce side effects linked cell hold revolutionize penetrance tumours. act carriers pro‐apoptotic molecules RNA enhancing immune responses expanding this review article, we navigate dynamic landscapes, our objective being evaluate comparative efficacy, safety profiles, complexities, clinical applicability.

Language: Английский

Citations

1
Steering CAR T cell epigenetic programs by tweaking manufacturing protocol DOI Creative Commons
Meghan W. Dukes, Giedre Krenciute

Cell Reports Medicine, Journal Year: 2023, Volume and Issue: 4(6), P. 101080 - 101080

Published: June 1, 2023

CAR T cell persistence remains a significant roadblock to effective clinical translation of cells for solid and brain tumors. Jung et al.1Jung I.Y. Noguera-Ortega E. Bartoszek R. Collins S.M. Williams Davis M. Jadlowsky J.K. Plesa G. Siegel D.L. Chew A. al.Tissue-resident memory with stem-like characteristics display enhanced efficacy against liquid tumors.Cell Rep. Med. 2023; 4: 101053https://doi.org/10.1016/j.xcrm.2023.101053Abstract Full Text PDF Google Scholar demonstrate enrichment resident phenotypes through simple changes the manufacturing process. Chimeric antigen receptor (CAR) are gaining momentum as safe treatments tumors; however, improving anti-tumor challenge field. The mechanism by which kill tumor is straightforward. Synthetic molecules designed recognize specific antigens redirect cytotoxic machinery antigen-expressing cells, kill. subsequently activate expand, promoting further killing. However, it well established that progressively lose effector function after repeat exposure resulting in incomplete clearance recurrence. This gradual functional loss inability expand persist collectively defined exhaustion. To overcome exhaustion, field exploring strategies manipulating programs so sustained long term. Targeting epigenetic has emerged potential way accomplish this. Indeed, several groups have explored methods re-programming long-term targeting programs. In human deletion TET2,2Jain N. Zhao Z. Feucht J. Koche Iyer Dobrin Mansilla-Soto Yang Zhan Y. Lopez al.TET2 guards unchecked BATF3-induced expansion.Nature. 615: 315-322Crossref PubMed Scopus (0) DNMT3A,3Prinzing B. Zebley C.C. Petersen C.T. Fan Anido A.A. Yi Nguyen P. Houke H. Bell Haydar D. al.Deleting DNMT3A prevents exhaustion enhances antitumor activity.Sci. Transl. 2021; 13eabh0272Crossref (56) or SUV39H14Jain Gozlan Brocks Raveh-Sadka T. Wells Shi al.Abstract 5583: SUV39H1 disruption CD28-costimulated cells.Cancer Res. 2022; 82: 5583Crossref significantly survival, proliferation, function. these examples, requires regulators via gene editing cells. While knockout approaches now field, clinic still highly tedious, time consuming, expensive due regulatory requirements. Thus, alternative simplistic needed. One strategy been tweaking protocol addition chemical reagents. Multiple studies demonstrated dasatinib during not only primes adopt memory-like phenotype, reprograms transcriptional profiles, vitro vivo,5Weber, W.; Parker, K. R.; Sotillo, E.; Lynn, C.; Anbunathan, H.; Lattin, J.; Good, Z.; Belk, A.; Daniel, B.; Klysz, D., al, Transient rest restores functionality exhausted CAR-T remodeling. Science (New York, N.Y.) 2021, 372.Google but also overcomes fratricide.6Watanabe Mo F. Zheng Ma Bray V.C. van Leeuwen D.G. Sritabal-Ramirez Hu Wang S. Mehta al.Feasibility preclinical CD7-unedited CD7 malignancies.Mol. Ther. 31: 24-34Abstract Addition decitabine, an DNA methyltransferase (DNMT) inhibitor, shows promise priming improved function.7Wang Li Chen L. Bian X. Q. Xu Liu al.Low-dose decitabine endows persistent antitumour reprogramming.Nat. Commun. 6: 409Crossref (75) current study published Cell Reports Medicine, Jung. developed method products can be enriched tissue-resident (TRM) encourage accumulation tissue. many blood cancers benefit from actively circulate bloodstream bone marrow, treatment tumors cellular programming encourages cytolytic at location resist recirculation. this, al. optimized production activated generated presence exogenous transforming growth factor β (TGF-β) (Figure 1). TGF-β numerous functions on including maintenance naive/stem-like populations implication preserved tissue retention,8Mackay L.K. Rahimpour J.Z. Stock A.T. Hafon M.L. Vega-Ramos Lauzurica Mueller S.N. Stefanovic al.The developmental pathway CD103(+)CD8+ skin.Nat. Immunol. 2013; 14: 1294-1301Crossref (824) reduction CD8+ function.9Oh S.A. M.O. TGF-β: guardian function.J. 191 (1950): 3973-3979Crossref (202) Mesothelin (M5)-targeted interleukin-2 (IL-2) (CAR-TRM cells) were analyzed surface markers (via flow cytometry), profiles bulk single-cell RNA sequencing), chromatin accessibility assay transposase-accessible using sequencing [ATAC-seq]) confirm CAR-TRM phenotypes. indeed showed increased expression regulation TRM phenotype compared IL-2 alone. Importantly, analysis revealed downregulation KLF2 loci dictates commitment recirculation, suggesting residence discourage circulation. associated stemness, self-renewal, early traditional markers. superior cytokine upon stimulation control reduced genes responsible terminal differentiation dysfunction. suggests exhaustive decoupled terminally exhausted. produced vivo models both (pancreatic prostate) (B leukemia) cancers. Specifically, administration resulted higher overall number tissues two weeks following treatment. Improved was observed days administration. animals received successfully cleared rechallenges, residency Due known inhibitory attempted enrich overexpressing RUNX3 activation CD25, they ultimately failed induce exciting promising results, there some questions remain addressed. For example, this performed B leukemia settings. It would interesting see whether results consistent more challenging hematological malignancies such acute myeloid leukemia. addition, multiple try block signaling because its immunosuppressive effect cells.10de Folmont Bourhis J.-H. Chouaib Terry Multifaceted Role Transforming Growth Factor Therapy.Immuno. 1: 160-173Crossref know suppressive effects TME where secreted infiltrating immune immune-competent animal warranted. summary, demonstrates small tweaks generate ability penetrate additional pre-clinical testing warranted, shown easily manipulate potentially easy clinic. G.K. one-time consultant Kineticos (2022).

Language: Английский

Citations

1