Master checkpoint Cbl-b inhibition: Anti-tumour efficacy in a murine colorectal cancer model following siRNA-based cell therapy

Thell, Kathrin; Urban, Maria Cristina Cocenza; Harrauer, J.; Haslinger, Isabella; Kuttke, Mario; Brunner, Julia; Vogel, Andrea; Schabbauer, Gernot; Penninger, Josef; Gaweco, Anderson S.

doi:10.1093/annonc/mdz253.057

Cited by 5 publications

(6 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 133 Given this immune suppressive role, APN401, a small interfering RNA‐based cellular immunotherapy that specifically targets and silences Cbl‐b is currently in clinical studies in patients with advanced solid tumours. 134 …”

Section: Roles Of E3 Ligases In Cancer Hallmarksmentioning

confidence: 99%

“…133 Given this immune suppressive role, APN401, a small interfering RNA-based cellular immunotherapy that specifically targets and silences Cbl-b is currently in clinical studies in patients with advanced solid tumours. 134 Tumour-promoting inflammation is mainly regulated via nuclear factor-kappa B (NF-κB) signalling. NF-κB is the key mediator of downstream inflammatory response and is composed of five members (RelA/p65, RelB, c-Rel, NF-κB1/p50 and NF-κB2/p52), from which p52 and p50 are generated from p105 and p100 precursors, respectively.…”

Section: Roles Of E3 Ubiquitin Ligases In Immune Response and Inflamm...mentioning

confidence: 99%

See 1 more Smart Citation

The roles of E3 ubiquitin ligases in cancer progression and targeted therapy

Sampson

Wang

Otkur

et al. 2023

Clinical & Translational Med

View full text Add to dashboard Cite

Ubiquitination is one of the most important post‐translational modifications which plays a significant role in conserving the homeostasis of cellular proteins. In the ubiquitination process, ubiquitin is conjugated to target protein substrates for degradation, translocation or activation, dysregulation of which is linked to several diseases including various types of cancers. E3 ubiquitin ligases are regarded as the most influential ubiquitin enzyme owing to their ability to select, bind and recruit target substrates for ubiquitination. In particular, E3 ligases are pivotal in the cancer hallmarks pathways where they serve as tumour promoters or suppressors. The specificity of E3 ligases coupled with their implication in cancer hallmarks engendered the development of compounds that specifically target E3 ligases for cancer therapy. In this review, we highlight the role of E3 ligases in cancer hallmarks such as sustained proliferation via cell cycle progression, immune evasion and tumour promoting inflammation, and in the evasion of apoptosis. In addition, we summarise the application and the role of small compounds that target E3 ligases for cancer treatment along with the significance of targeting E3 ligases as potential cancer therapy.

show abstract

Section: Roles Of E3 Ligases In Cancer Hallmarksmentioning

confidence: 99%

Section: Roles Of E3 Ubiquitin Ligases In Immune Response and Inflamm...mentioning

confidence: 99%

The roles of E3 ubiquitin ligases in cancer progression and targeted therapy

Sampson

Wang

Otkur

et al. 2023

Clinical & Translational Med

View full text Add to dashboard Cite

show abstract

“…In a murine model of colon cancer, strong anti‐tumorigenic immune responses were observed in Cbl‐b‐silenced animals in vivo , providing pre‐clinical proof for the effectiveness of Cbl‐b silencing by siRN as a practical approach for cellular immunotherapy [156]. Thus, modulating the Cbl‐b E3 ligase activity together with other immune‐activating approaches, such as DNA‐based vaccines, DC vaccines and anti‐checkpoint mAbs, could be introduced as a novel immunotherapy strategy, which boosts the immunity against tumors without predisposing the signs of autoimmunity [91,134,143].…”

Section: Cbl‐b In Immune‐related Diseasesmentioning

confidence: 99%

E3 ubiquitin ligase Casitas B lineage lymphoma-b and its potential therapeutic implications for immunotherapy

Jafari

Mousavi

Shahbaz

et al. 2021

Clinical and Experimental Immunology

View full text Add to dashboard Cite

Summary The distinction of self from non‐self is crucial to prevent autoreactivity and ensure protection from infectious agents and tumors. Maintaining the balance between immunity and tolerance of immune cells is strongly controlled by several sophisticated regulatory mechanisms of the immune system. Among these, the E3 ligase ubiquitin Casitas B cell lymphoma‐b (Cbl‐b) is a newly identified component in the ubiquitin‐dependent protein degradation system, which is thought to be an important negative regulator of immune cells. An update on the current knowledge and new concepts of the relevant immune homeostasis program co‐ordinated by Cbl‐b in different cell populations could pave the way for future immunomodulatory therapies of various diseases, such as autoimmune and allergic diseases, infections, cancers and other immunopathological conditions. In the present review, the latest findings are comprehensively summarized on the molecular structural basis of Cbl‐b and the suppressive signaling mechanisms of Cbl‐b in physiological and pathological immune responses, as well as its emerging potential therapeutic implications for immunotherapy in animal models and human diseases.

show abstract

“…Importantly, no signs of autoimmune toxicity have been reported in Cbl-b-deficient mice challenged with tumors, neither short-term, while rejecting tumors, nor long-term, up to 1 year after tumor rejection [ 125 , 126 , 127 , 129 , 138 ]. Similarly, no autoimmune injury was ever described in wild-type mice receiving Cbl-b knockout or knockdown CD8 + T-cell-based adoptive transfer immunotherapy [ 125 , 126 , 128 , 130 , 139 , 140 ], not even when the same tumor antigens are expressed in distal organs [ 128 ]. Thus, for its multiple checkpoint inhibitory roles and minimal autoimmune toxicities, Cbl-b is a strong candidate for future targeted cancer immunotherapies.…”

Section: Ubiquitination Is Essential To Regulate T Cell Activating and Inhibitory Signalingmentioning

confidence: 99%

“…Unfortunately, selective small molecules inhibitors targeting Cbl-b, a RING-type of E3, have not yet been possible. Nevertheless, scientists have successfully down-regulated Cbl-b levels in T cells using RNA interference, which has yielded excellent in vitro and preclinical results in different adoptive T-cell transfer tumor models [ 139 , 140 , 249 , 250 ], and being well tolerated by cancer patients [ 251 , 252 ], it has now moved on to clinical trials (NCT02166255 and NCT03087591). Small peptides and small molecule inhibitors have been able to efficiently block in vivo Cbl-b interactions with a specific substrate [ 253 ] or inhibit directly the function of the Cbl-b relevant substrate [ 129 ]; yet, these approaches depend on substrate identification, which is often challenging.…”

Section: Exploiting Ubiquitin-dependent Pathways For Cancer Treatmentmentioning

confidence: 99%

Ubiquitination in T-Cell Activation and Checkpoint Inhibition: New Avenues for Targeted Cancer Immunotherapy

Gavali

Liu

Paolino

2021

IJMS

View full text Add to dashboard Cite

The advent of T-cell-based immunotherapy has remarkably transformed cancer patient treatment. Despite their success, the currently approved immunotherapeutic protocols still encounter limitations, cause toxicity, and give disparate patient outcomes. Thus, a deeper understanding of the molecular mechanisms of T-cell activation and inhibition is much needed to rationally expand targets and possibilities to improve immunotherapies. Protein ubiquitination downstream of immune signaling pathways is essential to fine-tune virtually all immune responses, in particular, the positive and negative regulation of T-cell activation. Numerous studies have demonstrated that deregulation of ubiquitin-dependent pathways can significantly alter T-cell activation and enhance antitumor responses. Consequently, researchers in academia and industry are actively developing technologies to selectively exploit ubiquitin-related enzymes for cancer therapeutics. In this review, we discuss the molecular and functional roles of ubiquitination in key T-cell activation and checkpoint inhibitory pathways to highlight the vast possibilities that targeting ubiquitination offers for advancing T-cell-based immunotherapies.

show abstract

Master checkpoint Cbl-b inhibition: Anti-tumour efficacy in a murine colorectal cancer model following siRNA-based cell therapy

Cited by 5 publications

References 0 publications

The roles of E3 ubiquitin ligases in cancer progression and targeted therapy

The roles of E3 ubiquitin ligases in cancer progression and targeted therapy

E3 ubiquitin ligase Casitas B lineage lymphoma-b and its potential therapeutic implications for immunotherapy

Ubiquitination in T-Cell Activation and Checkpoint Inhibition: New Avenues for Targeted Cancer Immunotherapy

Contact Info

Product

Resources

About