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Multifunctional nanocomposites modulating the tumor microenvironment for enhanced cancer immunotherapy.

ABSTRACT: Cancer immunotherapy has gained momentum for treating malignant tumors over the past decade. Checkpoint blockade and chimeric antigen receptor cell therapy (CAR-T) have shown considerable potency against liquid and solid cancers. However, the tumor microenvironment (TME) is highly immunosuppressive and hampers the effect of currently available cancer immunotherapies on overall treatment outcomes. Advancements in the design and engineering of nanomaterials have opened new avenues to modulate the TME. Progress in the current nanocomposite technology can overcome immunosuppression and trigger robust immunotherapeutic responses by integrating synergistic functions of different molecules. We will review recent advancements in nanomedical applications and discuss specifically designed nanocomposites modulating the TME for cancer immunotherapy. In addition, we provide information on the current landscape of clinical-stage nanocomposites for cancer immunotherapy.

SUBMITTER: Sharma P

PROVIDER: S-EPMC10494322 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Multifunctional nanocomposites modulating the tumor microenvironment for enhanced cancer immunotherapy.

Sharma Prashant P Otto Mario M

Bioactive materials 20230906

Cancer immunotherapy has gained momentum for treating malignant tumors over the past decade. Checkpoint blockade and chimeric antigen receptor cell therapy (CAR-T) have shown considerable potency against liquid and solid cancers. However, the tumor microenvironment (TME) is highly immunosuppressive and hampers the effect of currently available cancer immunotherapies on overall treatment outcomes. Advancements in the design and engineering of nanomaterials have opened new avenues to modulate the ...[more]

PMID: 37701452

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Project description:Colorectal cancer (CRC), mostly categorized as a low immunogenic microsatellite-stable phenotype bearing complex immunosuppressive tumor microenvironment (TME), is highly resistant to immunotherapy. Seeking safe and efficient alternatives aimed at modulating tumor immunosuppressive TME to improve outcome of CRC is highly anticipated yet remains challenging. Methods: Enlightened from the drug complementary art in traditional Chinese medicine, we designed a self-assembled nanomedicine (termed LNT-UA) by the natural active ingredients of ursolic acid (UA) and lentinan (LNT) through a simple nano-precipitation method, without any extra carriers, for CRC immunotherapy. Results: UA induces immunogenic cell death (ICD), while LNT further promotes dendritic cell (DC) maturation and repolarizes tumor-associated macrophage (TAM) from a protumorigenic M2 to an antitumor M1 phenotype. Co-delivery of UA and LNT by LNT-UA effectively reshapes the immunosuppressive TME and mobilizes innate and adaptive immunity to inhibit tumor progression in the CT26 CRC tumor model. Following the principle of integrative theoretical system of traditional Chinese medicine (TCM) on overall regulation, the further combination of LNT-UA and anti-CD47 antibody (αCD47) would reinforce the antitumor immunity by promoting phagocytosis of dying tumor cells and tumor-associated antigens (TAAs), leading to effective suppression of both primary and distant tumor growth with 2.2-fold longer of median survival time in the bilateral tumor model. Most notably, this combination effect is also observed in the spontaneous CRC model induced by chemical carcinogens, with much less and smaller size of tumor nodules after sequential administration of LNT-UA and αCD47 through gavage and intraperitoneal injection, respectively. Conclusions: This study provides a promising self-assembled traditional Chinese nanomedicine to improve immunotherapy for CRC, which might be applicable for future clinical translation.

Project description:BackgroundThe efficacy of PD-(L)1 blockade depends on the composition of the tumor immune microenvironment (TIME) and is generally higher in tumors with pre-existing cytotoxic T cells (CTL) than in those with low CTL numbers. Nonetheless, a significant proportion of patients with pre-existing immunity fail to respond, indicating a therapeutic potential for combining PD-(L)1 blockade with additional immunomodulatory agents in both CTL-high and -low immune phenotypes. Here, we evaluated domatinostat (4SC-202), a class I-selective histone deacetylase (HDAC) inhibitor, for its effect on the TIME and its antitumoral efficacy using syngeneic mouse models with CTL-high or CTL-low tumors.MethodsDomatinostat was evaluated in PD-1 blockade-insensitive CTL-low (CT26) and CTL-high (C38) syngeneic models alone and in combination with different immune-inhibitory and -stimulatory approaches. Effects on the immunophenotype were assessed via flow cytometry and RNA-seq analyses. The changes in RNA-seq-based immune signatures determined in a murine setting were investigated in patient samples from the first-dose cohort of the SENSITIZE trial (NCT03278665) evaluating domatinostat combined with pembrolizumab in advanced-stage melanoma patients refractory/nonresponding to PD-1 blockade.ResultsDomatinostat increased the expression of antigen-presenting machinery (APM) genes and MHC class I and II molecules, along with CTL infiltration, in tumors of both immune phenotypes. In combination with PD-(L)1 blockade, domatinostat augmented antitumor effects substantially above the effects of single-agent therapies, displaying greater benefit in tumors with pre-existing CTLs. In this setting, the combination of domatinostat with agonistic anti-4-1BB or both PD-1 and LAG3 blockade further increased the antitumor efficacy. In CTL-low tumors, domatinostat enhanced the expression of genes known to reinforce immune responses against tumors. Specifically, domatinostat increased the expression of Ifng and genes associated with responses to pembrolizumab and nivolumab. Clinically, these findings were confirmed in patients with advanced melanoma treated with domatinostat for 14 days, who demonstrated elevated expression of APM and MHC genes, the IFNG gene, and the IFN-γ and pembrolizumab response signatures in individual tumor samples.ConclusionIn summary, these data suggest a promising potential of domatinostat in combination with immunotherapy to improve the outcome of refractory cancer patients.

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Multifunctional nanocomposites modulating the tumor microenvironment for enhanced cancer immunotherapy.

Publications

Multifunctional nanocomposites modulating the tumor microenvironment for enhanced cancer immunotherapy.

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