Adjuvante Instillationstherapie des nicht muskelinvasiven Harnblasenkarzinoms – neue Optionen abseits von BCG und Mitomycin

Gakis, Georgios

doi:10.1055/a-1677-0952

Cited by 2 publications

(1 citation statement)

References 21 publications

(21 reference statements)

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“…The biological effects of IL-15 are mediated through interaction with a receptor complex comprising three distinct chains: CD122 (IL-2/IL-15Rβ), CD132 (IL-2/IL-15Rγc), and the high-affinity-specific chain IL-15Rα (3). IL-15 currently has garnered considerable attention as a promising immunotherapeutic candidate for cancer treatment (4,5), exemplified by the advancement of the IL-15 analogue and agonist complex agent nogapendekin alfa (N-803) (6)(7)(8)(9), as well as the ongoing clinical trials of similar agents (10)(11)(12). However, potential toxicity remains due to the mechanism by which IL-15 superagonists activate T/NK cells (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Targeted LNPs deliver mRNA encoding IL-15 superagonists to balance efficacy and toxicity in cancer therapy

Yu,

Li,

Luo

et al. 2024

Preprint

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Interleukin-15 (IL-15) emerges as a promising immunotherapeutic candidate in oncology because of its pivotal role in modulating both innate and adaptive immunity. However, the therapeutic utility remains concern due to the unexpected toxicity. We propose here that the mRNA lipid nanoparticle (mRNA-LNP) system can balance the issue through targeted delivery to increase IL-15 concentration in the tumor area and reduce leakage into the circulation. Utilizing the Structure-driven TARgeting (STAR) platform, we acquired intellectual property LNP vectors for effective and selective mRNA delivery to local (LNPLocal) and to pulmonary (LNPLung). Then the promising IL-15 superagonists mRNAs were obtained through structural optimization and sequence screening, showing better activity compared with benchmarker N-803. Subsequently, the anti-tumor efficacy of IL-15 superagonists mRNAs were evaluated by intratumoural (i.t.) injection and intravenous (i.v.) injection via LNPLocal and LNPLung, respectively. As a result, such superagonists exhibited better anti-tumor activity, less systematic exposure, and less cytokine related risks than N-803. We finally verified the selective delivery and well tolerability of LNPLung in non-human primates (NHPs), confirming the potential for clinical application. This finding may open up new possibilities for the treatment of lung cancers and lung metastasis cancers.

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Section: Introductionmentioning

confidence: 99%

Targeted LNPs deliver mRNA encoding IL-15 superagonists to balance efficacy and toxicity in cancer therapy

Yu,

Li,

Luo

et al. 2024

Preprint

View full text Add to dashboard Cite

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ALT-803 in the treatment of non-muscle-invasive bladder cancer: Preclinical and clinical evidence and translational potential

et al. 2022

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Bladder cancer (BCa) is one of the most common malignant tumors that cause death. Approximately 75%–85% of BCa develop into non-muscle-invasive bladder cancer (NMIBC). Bacillus Calmette-Guérin (BCG) is the gold standard for avoiding cystectomy in the treatment of NMIBC. Unfortunately, up to 30% of patients do not respond to BCG treatment, and up to 70% of BCG responders relapse. The United States Food and Drug Administration (FDA) approved valrubicin (1998) and pembrolizumab (2020) for the treatment of BCG-unresponsive (BCGu) NMBIC. However, the complete remission rate for valrubicin and pembrolizumab was only 16% and 40.6%, respectively. ALT-803 (N-803) is an IL-15 superagonist and reduces tumor burden by promoting the proliferation and activation of NK cells and CD8+ T cells. The FDA received (23 May 2022) and accepted to review (28 July 2022) the marketing submission of ALT-803 plus BCG for the treatment of BCGu NMIBC. However, the FDA previously rejected the application for oportuzumab monatox (OM) due to a lack of data comparing it with pembrolizumab on August 20, 2021. Interestingly, the clinical efficacy and safety of ALT-803 were higher than that of pembrolizumab and OM, suggesting that ALT-803 may be approved by FDA. This review aims to further knowledge of the preclinical and clinical evidence of ALT-803 in the treatment of NMIBC and discuss its translational potential.

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Adjuvante Instillationstherapie des nicht muskelinvasiven Harnblasenkarzinoms – neue Optionen abseits von BCG und Mitomycin

Cited by 2 publications

References 21 publications

Targeted LNPs deliver mRNA encoding IL-15 superagonists to balance efficacy and toxicity in cancer therapy

Targeted LNPs deliver mRNA encoding IL-15 superagonists to balance efficacy and toxicity in cancer therapy

ALT-803 in the treatment of non-muscle-invasive bladder cancer: Preclinical and clinical evidence and translational potential

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