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T-Cell Receptor/CD28-Targeted Immunotherapeutics: Parallel Pathways to Expand Naive HIV- or Melanoma-Specific T Cells and Develop TCR Transgenic CD8+ T Cells /

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	T-Cell Receptor/CD28-Targeted Immunotherapeutics: Parallel Pathways to Expand Naive HIV- or Melanoma-Specific T Cells and Develop TCR Transgenic CD8+ T Cells // April Lynn Mueller.
作者:	Mueller, April Lynn,
面頁冊數:	1 electronic resource (316 pages)
附註:	Source: Dissertations Abstracts International, Volume: 86-11, Section: B.
Contained By:	Dissertations Abstracts International86-11B.
標題:	Immunology. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31847507
ISBN:	9798314862407

T-Cell Receptor/CD28-Targeted Immunotherapeutics: Parallel Pathways to Expand Naive HIV- or Melanoma-Specific T Cells and Develop TCR Transgenic CD8+ T Cells /
Mueller, April Lynn,

T-Cell Receptor/CD28-Targeted Immunotherapeutics: Parallel Pathways to Expand Naive HIV- or Melanoma-Specific T Cells and Develop TCR Transgenic CD8+ T Cells /April Lynn Mueller. - 1 electronic resource (316 pages)

Source: Dissertations Abstracts International, Volume: 86-11, Section: B.

In this dissertation, I investigate the capacity of Immuno-STAT™ (Selective Targeting and Alteration of T cells; IST)-a novel immunotherapeutic scaffold platform that functions as an artificial antigen-presenting cell (aAPC)-to enhance immunotherapeutic strategies by stimulating naive CD8+ T cells and facilitating targeted gene modification. To test this hypothesis, I explore two interrelated applications of IST: first, generating de novo immune responses by priming naive CD8+ T cells against viral and cancer antigens to produce functional effector cells; and second, enabling antigen-specific lentiviral transduction of memory-inflated cells to generate dual-T cell receptor (TCR) T cells with potentially enhanced functionality and longevity compared to those produced by conventional transduction methods.Aim I evaluates the ability of IST constructs, incorporating a costimulatory agonistic anti-CD28 (αCD28) antibody domain, to activate, expand, and differentiate naive CD8+ T cells into cytotoxic T lymphocytes (CTLs) specific for clinically relevant antigens. Using peripheral blood from healthy human donors, I demonstrate that IST constructs presenting the melanoma-associated MART-1 antigen or the HIV-associated SL9 antigen effectively prime naive CD8+ T cells in vitro. These IST-treated T cells expand and differentiate into antigen-specific CTLs capable of producing effector cytokines and mediating cytotoxicity. While MART-1 serves as a widely used model antigen to study naive CD8+ T cell priming, SL9 presents a unique challenge due to the difficulty in eliciting robust SL9-specific CTL responses ex vivo. IST treatment overcomes this hurdle, generating polyfunctional and cytotoxic SL9-specific CD8+ T cells across multiple donors. This finding addresses a significant obstacle in the development of adoptive T cell therapies aimed at achieving durable HIV control.To assess the quality of IST-generated CTLs, I compare them to CTLs produced by peptide-loaded autologous dendritic cells, the current gold standard for naive CD8+ T cell priming. Despite lower overall yields, IST-derived CTLs display similar or superior functional attributes, including potent cytotoxicity, high levels of IFNγ and TNFα production, and a focused TCR repertoire with limited clonotypic diversity. Epigenetic analyses reveal that IST-primed CTLs exhibit a more differentiated phenotype, marked by expression of genes associated with effector function, although this may have implications for in vivo persistence. These results establish IST as a robust tool for generating functional, antigen-specific CD8+ T cells from the naive repertoire, with the potential for further optimization to enhance long-term functionality and persistence.Aim II extends the application of IST to antigen-specific gene delivery, leveraging its ability to selectively activate antigen-specific CD8+ T cells as a means to enable targeted lentiviral transduction. Since effective lentiviral transduction requires prior T cell activation, I use IST to selectively activate CD8+ T cells specific for the cytomegalovirus-derived memory-inflation generating NLV peptide which may be resistant to T cell exhaustion. These cells are then transduced with a lentiviral vector encoding a high-affinity SL9- specific murinized TCR. This approach generates a population of dual-TCR CD8+ T cells capable of recognizing both NLV and SL9 antigens. Functionally, these dual-antigen reactive T cells exhibit superior cytotoxicity and elevated SL9-induced expression of IFNγ and TNFα compared to TCR cells generated by conventional anti-CD3/anti-CD28 activation. Importantly, antigen-specific activation via IST minimizes off-target transduction, potentially improving safety and therapeutic efficacy. These findings offer a novel strategy for the selective generation of dual-antigen reactive T cells with enhanced functionality and suggest that IST can serve as a platform for targeted gene editing beyond TCRs, including the generation of chimeric antigen receptor (CAR) T cells or delivery of gene-editing tools.Together, the results from both projects support the hypothesis that IST functions as a versatile aAPC capable of priming naive CD8+ T cells and facilitating antigen-specific gene delivery, enabling the generation of enhanced TCR-transgenic T cells. This work highlights IST as a promising platform to overcome key challenges in the development of next-generation adoptive T cell therapies. The ability to both initiate de novo immune responses and enable precise, antigen-directed gene modification offers broad potential to expand the efficacy, safety, and applicability of cellular immunotherapies for cancer, chronic viral infections, and other diseases. Future studies aim to validate these strategies in larger cohorts and explore their extension to other transgenic constructs and disease models.

English

ISBN: 9798314862407Subjects--Topical Terms:

611031
Immunology.
Subjects--Index Terms:

CD8+ T cells

T-Cell Receptor/CD28-Targeted Immunotherapeutics: Parallel Pathways to Expand Naive HIV- or Melanoma-Specific T Cells and Develop TCR Transgenic CD8+ T Cells /
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520 $a In this dissertation, I investigate the capacity of Immuno-STAT™ (Selective Targeting and Alteration of T cells; IST)-a novel immunotherapeutic scaffold platform that functions as an artificial antigen-presenting cell (aAPC)-to enhance immunotherapeutic strategies by stimulating naive CD8+ T cells and facilitating targeted gene modification. To test this hypothesis, I explore two interrelated applications of IST: first, generating de novo immune responses by priming naive CD8+ T cells against viral and cancer antigens to produce functional effector cells; and second, enabling antigen-specific lentiviral transduction of memory-inflated cells to generate dual-T cell receptor (TCR) T cells with potentially enhanced functionality and longevity compared to those produced by conventional transduction methods.Aim I evaluates the ability of IST constructs, incorporating a costimulatory agonistic anti-CD28 (αCD28) antibody domain, to activate, expand, and differentiate naive CD8+ T cells into cytotoxic T lymphocytes (CTLs) specific for clinically relevant antigens. Using peripheral blood from healthy human donors, I demonstrate that IST constructs presenting the melanoma-associated MART-1 antigen or the HIV-associated SL9 antigen effectively prime naive CD8+ T cells in vitro. These IST-treated T cells expand and differentiate into antigen-specific CTLs capable of producing effector cytokines and mediating cytotoxicity. While MART-1 serves as a widely used model antigen to study naive CD8+ T cell priming, SL9 presents a unique challenge due to the difficulty in eliciting robust SL9-specific CTL responses ex vivo. IST treatment overcomes this hurdle, generating polyfunctional and cytotoxic SL9-specific CD8+ T cells across multiple donors. This finding addresses a significant obstacle in the development of adoptive T cell therapies aimed at achieving durable HIV control.To assess the quality of IST-generated CTLs, I compare them to CTLs produced by peptide-loaded autologous dendritic cells, the current gold standard for naive CD8+ T cell priming. Despite lower overall yields, IST-derived CTLs display similar or superior functional attributes, including potent cytotoxicity, high levels of IFNγ and TNFα production, and a focused TCR repertoire with limited clonotypic diversity. Epigenetic analyses reveal that IST-primed CTLs exhibit a more differentiated phenotype, marked by expression of genes associated with effector function, although this may have implications for in vivo persistence. These results establish IST as a robust tool for generating functional, antigen-specific CD8+ T cells from the naive repertoire, with the potential for further optimization to enhance long-term functionality and persistence.Aim II extends the application of IST to antigen-specific gene delivery, leveraging its ability to selectively activate antigen-specific CD8+ T cells as a means to enable targeted lentiviral transduction. Since effective lentiviral transduction requires prior T cell activation, I use IST to selectively activate CD8+ T cells specific for the cytomegalovirus-derived memory-inflation generating NLV peptide which may be resistant to T cell exhaustion. These cells are then transduced with a lentiviral vector encoding a high-affinity SL9- specific murinized TCR. This approach generates a population of dual-TCR CD8+ T cells capable of recognizing both NLV and SL9 antigens. Functionally, these dual-antigen reactive T cells exhibit superior cytotoxicity and elevated SL9-induced expression of IFNγ and TNFα compared to TCR cells generated by conventional anti-CD3/anti-CD28 activation. Importantly, antigen-specific activation via IST minimizes off-target transduction, potentially improving safety and therapeutic efficacy. These findings offer a novel strategy for the selective generation of dual-antigen reactive T cells with enhanced functionality and suggest that IST can serve as a platform for targeted gene editing beyond TCRs, including the generation of chimeric antigen receptor (CAR) T cells or delivery of gene-editing tools.Together, the results from both projects support the hypothesis that IST functions as a versatile aAPC capable of priming naive CD8+ T cells and facilitating antigen-specific gene delivery, enabling the generation of enhanced TCR-transgenic T cells. This work highlights IST as a promising platform to overcome key challenges in the development of next-generation adoptive T cell therapies. The ability to both initiate de novo immune responses and enable precise, antigen-directed gene modification offers broad potential to expand the efficacy, safety, and applicability of cellular immunotherapies for cancer, chronic viral infections, and other diseases. Future studies aim to validate these strategies in larger cohorts and explore their extension to other transgenic constructs and disease models.
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