Cabozantinib Enhances Anti-PD1 Activity and Elicits a Neutrophil-Based Immune Response in Hepatocellular Carcinoma

Esteban-Fabró, Roger; Willoughby, Catherine E.; Piqué-Gili, Marta; Montironi, Carla; Abril-Fornaguera, Jordi; Peix, Judit; Torrens, Laura; Mesropian, Agavni; Balaseviciute, Ugne; Miró-Mur, Francesc; Mazzaferro, Vincenzo; Pinyol, Roser; Llovet, Josep M.

doi:10.1158/1078-0432.ccr-21-2517

Cited by 42 publications

(33 citation statements)

References 48 publications

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“…In clinical practice, some patients are sensitive to a specific drug therapy, while some patients are suffering from drug side effects ( 48 ). Previous studies suggested that the combination of anti-angiogenic therapy and immunotherapy has a huge potential to improve prognosis and facilitate clinical efficacy ( 49 , 50 ). To deliver a precise treatment, the potential therapeutic drugs for C2 were identified by pRRophetic algorithm, such as nilotinib and bosutinib.…”

Section: Discussionmentioning

confidence: 99%

CD8+ T cell trajectory subtypes decode tumor heterogeneity and provide treatment recommendations for hepatocellular carcinoma

et al. 2022

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IntroductionMounting evidence has revealed that the interactions and dynamic alterations among immune cells are critical in shaping the tumor microenvironment and ultimately map onto heterogeneous clinical outcomes. Currently, the underlying clinical significance of immune cell evolutions remains largely unexplored in hepatocellular carcinoma (HCC).MethodsA total of 3,817 immune cells and 1,750 HCC patients of 15 independent public datasets were retrieved. The Seurat and Monocle algorithms were used to depict T cell evolution, and nonnegative matrix factorization (NMF) was further applied to identify the molecular classification. Subsequently, the prognosis, biological characteristics, genomic variations, and immune landscape among distinct clusters were decoded. The clinical efficacy of multiple treatment approaches was further investigated.ResultsAccording to trajectory gene expression, three heterogeneous clusters with different clinical outcomes were identified. C2, with a more advanced pathological stage, presented the most dismal prognosis relative to C1 and C3. Eight independent external cohorts validated the robustness and reproducibility of the three clusters. Further explorations elucidated C1 to be characterized as lipid metabolic HCC, and C2 was referred to as cell-proliferative HCC, whereas C3 was defined as immune inflammatory HCC. Moreover, C2 also displayed the most conspicuous genomic instability, and C3 was deemed as “immune-hot”, having abundant immune cells and an elevated expression of immune checkpoints. The assessments of therapeutic intervention suggested that patients in C1 were suitable for transcatheter arterial chemoembolization treatment, and patients in C2 were sensitive to tyrosine kinase inhibitors, while patients in C3 were more responsive to immunotherapy. We also identified numerous underlying therapeutic agents, which might be conducive to clinical transformation in the future.ConclusionsOur study developed three clusters with distinct characteristics based on immune cell evolutions. For specifically stratified patients, we proposed individualized treatment strategies to improve the clinical outcomes and facilitate the clinical management.

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Section: Discussionmentioning

confidence: 99%

CD8+ T cell trajectory subtypes decode tumor heterogeneity and provide treatment recommendations for hepatocellular carcinoma

et al. 2022

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“…In several preclinical studies, angiogenesis inhibitors improved the efficacy of α-PD-1/PD-L1 in mouse tumor models ( 123 – 125 ). In the IMBrave150 study, atezolizumab combined with bevacizumab was shown to significantly improve the prognosis of patients and to maintain a clinically significant survival benefit after a longer follow-up compared to sorafenib ( 126 ).…”

Section: Combined Application Of Pd-1/pd-l1 Blockadementioning

confidence: 99%

PD-1/PD-L1 checkpoint inhibitors in advanced hepatocellular carcinoma immunotherapy

Han

Yang

et al. 2022

Front. Immunol.

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Hepatocellular carcinoma (HCC) has a high prevalence and mortality rate worldwide. Sorafenib monotherapy has been the standard of first-line treatment for advanced HCC for a long time, but there are still many shortcomings. In recent years, with the deepening of research on tumor immune microenvironment, researchers have begun to explore new approaches in immunotherapy, and the introduction of immune checkpoint inhibitors has brought fundamental changes to the treatment of HCC. Programmed cell death protein 1 (PD-1) is an immune checkpoint molecule that plays an important role in down-regulating immune system function and promoting tolerance. Programmed cell death ligand 1 (PDL-1) is involved in tumor immune evasion by binding to PD-1, resulting in failure of treatment. Currently, immunotherapy targeting the PD-1/PD-L1 axis has achieved unprecedented success in HCC, but it also faces great challenges, with its low remission rate still to be solved. For most patients with HCC, the PD-1/PD-L1 pathway is not the only rate limiting factor of antitumor immunity, and blocking only the PD-1/PD-L1 axis is not enough to stimulate an effective antitumor immune response; thus, combination therapy may be a better option. In this study, changes in the immune microenvironment of HCC patients were reviewed to clarify the feasibility of anti-PD-1/PD-L1 therapy, and a series of monotherapy and combination therapy clinical trials were summarized to verify the safety and efficacy of this newly developed treatment in patients with advanced HCC. Furthermore, we focused on hyperprogressive disease and drug resistance to gain a better understanding of PD-1/PD-L1 blockade as a promising treatment.

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“…The combination of radiotherapy and ICIs can effectively treat aggressive pituitary tumors and metastatic Merkel cell carcinoma (Kleinendorst et al, 2022). ICIs combined with antiangiogenic agents produce beneficial effects in the treatment of advanced hepatocellular carcinoma (HCC; Esteban-Fabr o et al, 2022). The success of clinical trials has greatly inspired the research enthusiasm of scholars, at present, a large quantity of preclinical studies are also devoted to improving the efficacy of anti-PD-1 antibodies by combining with chemotherapy, radiotherapy, and gene therapy.…”

Section: The Necessity Of Pharmaceutics In Improving the Immunotherap...mentioning

confidence: 99%

New advances in pharmaceutical strategies for sensitizing anti‐PD‐1 immunotherapy and clinical research

Jiang

Qin

et al. 2022

WIREs Nanomed Nanobiotechnol

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Attempts have been made continuously to use nano-drug delivery system (NDDS) to improve the effect of antitumor therapy. In recent years, especially in the application of immunotherapy represented by antiprogrammed death receptor 1 (anti-PD-1), it has been vigorously developed. Nanodelivery systems are significantly superior in a number of aspects including increasing the solubility of insoluble drugs, enhancing their targeting ability, prolonging their half-life, and reducing side effects. It can not only directly improve the efficacy of anti-PD-1 immunotherapy, but also indirectly enhance the antineoplastic efficacy of immunotherapy by boosting the effectiveness of therapeutic modalities such as chemotherapy, radiotherapy, photothermal, and photodynamic therapy (PTT/PDT). Here, we summarize the studies published in recent years on the use of nanotechnology in pharmaceutics to improve the efficacy of anti-PD-1 antibodies, analyze their characteristics and shortcomings, and combine with the current clinical research on anti-PD-1 antibodies to provide a reference for the design of future nanocarriers, so as to further expand the clinical application prospects of NDDSs.

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Cabozantinib Enhances Anti-PD1 Activity and Elicits a Neutrophil-Based Immune Response in Hepatocellular Carcinoma

Cited by 42 publications

References 48 publications

CD8+ T cell trajectory subtypes decode tumor heterogeneity and provide treatment recommendations for hepatocellular carcinoma

CD8+ T cell trajectory subtypes decode tumor heterogeneity and provide treatment recommendations for hepatocellular carcinoma

PD-1/PD-L1 checkpoint inhibitors in advanced hepatocellular carcinoma immunotherapy

New advances in pharmaceutical strategies for sensitizing anti‐PD‐1 immunotherapy and clinical research

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