Lipid nanoparticle-based mRNA delivery systems for cancer immunotherapy

Han, Jieun; Lim, Jaesung; Wang, Chi-Pin James; Han, Jun-Hyeok; Shin, Ha Eun; Kim, Se-Na; Jeong, Dooyong; Lee, Sang Hwi; Chun, Bok-Hwan; Park, Chun Gwon; Park, Wooram

doi:10.1186/s40580-023-00385-3

Cited by 11 publications

(10 citation statements)

References 123 publications

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“…While our current study is focused on the directed evolution of nanoscale, decent PD-L1 binders and their application in CD19-SynNotch PDbody-CAR T cells, we are enthusiastic about the prospect of future research that delves into the integration of nanodelivery technologies. Specifically, we can foresee the future integration of nanoparticles for the tumor-specific delivery of antigens, , or in vivo genetic manipulation of CAR-T cells − would further achieve better T cell control, improve T cell function, and enhance the tumor elimination efficacy of our CD19-SynNotch PDbody-CAR T cells.…”

Section: Discussionmentioning

confidence: 99%

Engineering a Programmed Death-Ligand 1-Targeting Monobody Via Directed Evolution for SynNotch-Gated Cell Therapy

Zhu,

Man,

Harrison

et al. 2024

ACS Nano

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Programmed death-ligand 1 (PD-L1) is a promising target for cancer immunotherapy due to its ability to inhibit T cell activation; however, its expression on various noncancer cells may cause on-target off-tumor toxicity when designing PD-L1-targeting Chimeric Antigen Receptor (CAR) T cell therapies. Combining rational design and directed evolution of the human fibronectin-derived monobody scaffold, "PDbody" was engineered to bind to PD-L1 with a preference for a slightly lower pH, which is typical in the tumor microenvironment. PDbody was further utilized as a CAR to target the PD-L1expressing triple negative MDA-MB-231 breast cancer cell line. To mitigate on-target off-tumor toxicity associated with targeting PD-L1, a Cluster of Differentiation 19 (CD19)-recognizing SynNotch IF THEN gate was integrated into the system. This CD19-SynNotch PDbody-CAR system was then expressed in primary human T cells to target CD19-expressing MDA-MB-231 cancer cells. These CD19-SynNotch PDbody-CAR T cells demonstrated both specificity and efficacy in vitro, accurately eradicating cancer targets in cytotoxicity assays. Moreover, in an in vivo bilateral murine tumor model, they exhibited the capability to effectively restrain tumor growth. Overall, CD19-SynNotch PDbody-CAR T cells represent a distinct development over previously published designs due to their increased efficacy, proliferative capability, and mitigation of off-tumor toxicity for solid tumor treatment.

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Section: Discussionmentioning

confidence: 99%

Engineering a Programmed Death-Ligand 1-Targeting Monobody Via Directed Evolution for SynNotch-Gated Cell Therapy

Zhu,

Man,

Harrison

et al. 2024

ACS Nano

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“…This approach allows for the encoding of multiple neoantigens within a single mRNA molecule, thereby enhancing the vaccine's potency [ 235 ]. While there's still a need for definitive studies on cross‐species variations in mRNA delivery efficacy and cellular responses to lipid nanoparticles (LNPs), recent research has made strides in addressing these differences and introducing engineered animal models with predictable clinical outcomes to tackle challenges related to cross‐species variations [ 236 ]. Identifying the factors contributing to low transfection rates in lymphocytes or monocytes and developing strategies to enhance them is crucial for advancing LNP‐based mRNA delivery systems in cancer immunotherapy [ 236 ].…”

Section: Current and Future Directionsmentioning

confidence: 99%

“…As research and development in this field progress, it is anticipated that more effective, personalized, and safer therapeutic options will emerge. Ultimately, these advancements aim to not only enhance treatment outcomes but also improve the quality of life for individuals affected by cancer [ 236 ].…”

Section: Current and Future Directionsmentioning

confidence: 99%

Immunologic tumor microenvironment modulators for turning cold tumors hot

Khosravi,

Mostafavi,

Bastan

et al. 2024

Cancer Communications

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Tumors can be classified into distinct immunophenotypes based on the presence and arrangement of cytotoxic immune cells within the tumor microenvironment (TME). Hot tumors, characterized by heightened immune activity and responsiveness to immune checkpoint inhibitors (ICIs), stand in stark contrast to cold tumors, which lack immune infiltration and remain resistant to therapy. To overcome immune evasion mechanisms employed by tumor cells, novel immunologic modulators have emerged, particularly ICIs targeting cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) and programmed cell death protein 1/programmed death‐ligand 1(PD‐1/PD‐L1). These agents disrupt inhibitory signals and reactivate the immune system, transforming cold tumors into hot ones and promoting effective antitumor responses. However, challenges persist, including primary resistance to immunotherapy, autoimmune side effects, and tumor response heterogeneity. Addressing these challenges requires innovative strategies, deeper mechanistic insights, and a combination of immune interventions to enhance the effectiveness of immunotherapies. In the landscape of cancer medicine, where immune cold tumors represent a formidable hurdle, understanding the TME and harnessing its potential to reprogram the immune response is paramount. This review sheds light on current advancements and future directions in the quest for more effective and safer cancer treatment strategies, offering hope for patients with immune‐resistant tumors.

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“…100 While these DCs truly recapitulate features and functions of in vivo cDCs, the yield remains low, limiting their widespread use for vaccination purposes. With new technologies emerging to target cDCs in vivo using antibody-based strategies 7 or lipid nanoparticles (LNPs) as carriers to deliver tumor antigens to DCs, 101,102 in vivo targeting might become the preferred strategy for DC vaccination purposes. Broadly speaking, immunogenicity is determined by a combination of two properties: antigenicity and adjuvanticity.…”

Section: Box 1 DC Subsets In Vivo and In Vitromentioning

confidence: 99%

Decoding immunogenic cell death from a dendritic cell perspective

Janssens,

Rennen,

Agostinis

2023

Immunological Reviews

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SummaryDendritic cells (DCs) are myeloid cells bridging the innate and adaptive immune system. By cross‐presenting tumor‐associated antigens (TAAs) liberated upon spontaneous or therapy‐induced tumor cell death to T cells, DCs occupy a pivotal position in the cancer immunity cycle. Over the last decades, the mechanisms linking cancer cell death to DC maturation, have been the focus of intense research. Growing evidence supports the concept that the mere transfer of TAAs during the process of cell death is insufficient to drive immunogenic DC maturation unless this process is coupled with the release of immunomodulatory signals by dying cancer cells. Malignant cells succumbing to a regulated cell death variant called immunogenic cell death (ICD), foster a proficient interface with DCs, enabling their immunogenic maturation and engagement of adaptive immunity against cancer. This property relies on the ability of ICD to exhibit pathogen‐mimicry hallmarks and orchestrate the emission of a spectrum of constitutively present or de novo‐induced danger signals, collectively known as damage‐associated molecular patterns (DAMPs). In this review, we discuss how DCs perceive and decode danger signals emanating from malignant cells undergoing ICD and provide an outlook of the major signaling and functional consequences of this interaction for DCs and antitumor immunity.

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Lipid nanoparticle-based mRNA delivery systems for cancer immunotherapy

Cited by 11 publications

References 123 publications

Engineering a Programmed Death-Ligand 1-Targeting Monobody Via Directed Evolution for SynNotch-Gated Cell Therapy

Engineering a Programmed Death-Ligand 1-Targeting Monobody Via Directed Evolution for SynNotch-Gated Cell Therapy

Immunologic tumor microenvironment modulators for turning cold tumors hot

Decoding immunogenic cell death from a dendritic cell perspective

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