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Immunomodulatory and Antitumor Effects of a Novel TLR7 Agonist Combined with Lapatinib.

ABSTRACT: As new treatment approaches, both immunotherapy and targeted treatments have been used in the clinical treatment of cancers. These therapies are different from traditional surgery, chemotherapy and radiotherapy. Use of a combination of immunotherapy and targeted treatments may improve tumor clearance. We investigated the feasibility of combining tyrosine kinase inhibitors (TKIs, targeted drugs) and SZU-101 (a novel TLR7 agonist synthesized by our laboratory). Thirteen different TKIs were combined with or without SZU-101 and studied to determine their effects on immunocytes. On the basis of the distinctive results, lapatinib and sunitinib were selected for further tumor-inhibition investigation and determination of the underlying mechanism. Interestingly, we found lapatinib to work better with SZU-101, enhancing tumor clearance in vivo, without affecting the TLR7-NF-?B pathway activated by the TLR7 agonist in mouse spleen lymphocytes and bone marrow dendritic cells (BMDCs).

SUBMITTER: Gao N

PROVIDER: S-EPMC5175151 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Immunomodulatory and Antitumor Effects of a Novel TLR7 Agonist Combined with Lapatinib.

Gao Ningning N Zhong Jingjing J Wang Xiaodong X Jin Zhenchao Z Li Wang W Liu Yu Y Diao Yuwen Y Wang Zhulin Z Jiang Wenqi W Jin Guangyi G

Scientific reports 20161221

As new treatment approaches, both immunotherapy and targeted treatments have been used in the clinical treatment of cancers. These therapies are different from traditional surgery, chemotherapy and radiotherapy. Use of a combination of immunotherapy and targeted treatments may improve tumor clearance. We investigated the feasibility of combining tyrosine kinase inhibitors (TKIs, targeted drugs) and SZU-101 (a novel TLR7 agonist synthesized by our laboratory). Thirteen different TKIs were combine ...[more]

PMID: 28000738

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Project description:BACKGROUND:Vaccines play increasingly important roles in cancer treatment due to their advantages of effective targeting and few side effects. Our laboratory has attempted to construct vaccines by conjugating TLR7 agonists with tumor-associated antigens. Furthermore, immunochemotherapy has recently become an appealing approach to cancer therapy. 5-fluorouracil (5-FU), a commonly used chemotherapeutic agent, can reportedly potently and selectively kill tumor-associated MDSCs in vivo. METHODS:Gastric cancer vaccines were synthesized by the covalent attachment of our TLR7 agonist with the gastric cancer antigen MG7-Ag tetra-epitope, leading to T7 - ML (linear tetra-epitope) and T7 - MB (branched tetra-epitope). Cytokines induced by the vaccines in vitro were assessed by ELISA. A tumor challenge model was created by treating BALB/c mice on either a prophylactic or therapeutic vaccination schedule. 5-FU was simultaneously applied to mice in the combination treatment group. CTL and ADCC activities were determined by the LDH method, while CD3+/CD8+, CD3+/CD4+ T cells and MDSCs were evaluated by flow cytometry. RESULTS:In vitro, rapid TNF-α and IL-12 inductions occurred in BMDCs treated with the vaccines. In vivo, among all the vaccines tested, T7 - MB most effectively reduced EAC tumor burdens and induced CTLs, antibodies and ADCC activity in BALB/c mice. Immunization with T7 - MB in combination with 5-FU chemotherapy reduced tumor sizes and extended long-term survival rates, mainly by improving T cell responses, including CTLs, CD3+/CD8+ and CD3+/CD4+ T cells. 5-FU also enhanced the T7 - MB efficiency by reversing immunosuppressive factors, i.e., MDSCs, which could not be validly inhibited by the vaccines alone. In addition, T7 - MB repressed tumor growth and immune tolerance when the therapeutic schedule was used, although the effects were weaker than those achieved with either T7 - MB alone or in combination with 5-FU on the prophylactic schedule. CONCLUSIONS:A novel effective gastric cancer vaccine was constructed, and the importance of branched multiple antigen peptides and chemical conjugation to vaccine design were confirmed. The synergistic effects and mechanisms of T7 - MB and 5-FU were also established, observing mainly T cell activation and MDSC inhibition.

Project description:Drug resistance presents serious difficulties for cancer treatment. A combination of paclitaxel (PTX) and lapatinib (LAPA) shows potentials in multiple drug resistant cancers in the clinic, but it is almost impossible to deliver these two drugs to the tumor at the same time with the best proportion by simple co-administration of the respective current formualtions for their different pharmacokinetic profiles. Here composite nanocrystals of PTX and LAPA (cNC) were designed with a ratio of 2:1 (w/w), which was their intracellular ratio at the best synergistic efficacy on a drug-resistant cancer cell line (MCF-7/ADR). Such cNC were prepared using a bottom-up method to achieve a nearly spherical appearance and a narrow size distribution of 95.1 ± 2.1 nm. For nanocrystal stabilization, Polyethylene glycol (PEG) coating was introduced into the cNC via polydopamine (PDA) coating in order to get a PEGylated composite nanocrystal (cNC@PDA-PEG) with nanoscale size (170.5 ± 1.4 nm), considerable drug loading (PTX: 21.33 ± 1.48%, LAPA: 10.95 ± 1.24%) and good stability for at least 4 days in plasma-containing buffers. Differential scanning calorimeter (DSC) and XRD data both indicated the different crystalline states of the cNC as well as the cNC@PDA-PEG in comparison with bulk drugs. In vitro release data showed that PTX and LAPA were gradually and completely released from cNC@PDA-PEG in 3 days, while drug release from bulk drugs or cNC was only 30%. cNC@PDA-PEG also showed negligible hemolysis in vitro. Cellular uptake experiments in the MCF-7/ADR cell line showed that the nanocrystals entered the cells in a complete form through endocytosis and then released the drug in the cell. cNC@PDA-PEG inhibits the growth of this drug-resistant cell more effectively than the unmodified version (cNC). In summary, PEGylated PTX and LAPA composite nanocrystals showed the potential for treament of drug-resistant tumors by simultaneously delivering two drugs to tumor cells with the best proportion.

Project description:BackgroundImmune checkpoint blockade (ICB) promotes adaptive immunity and tumor regression in some cancer patients. However, in patients with immunologically "cold" tumors, tumor-resident innate immune cell activation may be required to prime an adaptive immune response and so exploit the full potential of ICB. Whilst Toll-like receptor (TLR) agonists have been used topically to successfully treat some superficial skin tumors, systemic TLR agonists have not been well-tolerated.MethodsThe response of human immune cells to TLR7 and 8 agonism was measured in primary human immune cell assays. MEDI9197 (3M-052) was designed as a novel lipophilic TLR7/8 agonist that is retained at the injection site, limiting systemic exposure. Retention of the TLR7/8 agonist at the site of injection was demonstrated using quantitative whole-body autoradiography, HPLC-UV, and MALDI mass spectrometry imaging. Pharmacodynamic changes on T cells from TLR7/8 agonist treated B16-OVA tumors was assessed by histology, quantitative real time PCR, and flow cytometry. Combination activity of TLR7/8 agonism with immunotherapies was assessed in vitro by human DC-T cell MLR assay, and in vivo using multiple syngeneic mouse tumor models.ResultsTargeting both TLR7 and 8 triggers an innate and adaptive immune response in primary human immune cells, exemplified by secretion of IFNα, IL-12 and IFNγ. In contrast, a STING or a TLR9 agonist primarily induces release of IFNα. We demonstrate that the TLR7/8 agonist, MEDI9197, is retained at the sight of injection with limited systemic exposure. This localized TLR7/8 agonism leads to Th1 polarization, enrichment and activation of natural killer (NK) and CD8+ T cells, and inhibition of tumor growth in multiple syngeneic models. The anti-tumor activity of this TLR7/8 agonist is enhanced when combined with T cell-targeted immunotherapies in pre-clinical models.ConclusionLocalized TLR7/8 agonism can enhance recruitment and activation of immune cells in tumors and polarize anti-tumor immunity towards a Th1 response. Moreover, we demonstrate that the anti-tumor effects of this TLR7/8 agonist can be enhanced through combination with checkpoint inhibitors and co-stimulatory agonists.

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Immunomodulatory and Antitumor Effects of a Novel TLR7 Agonist Combined with Lapatinib.

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Immunomodulatory and Antitumor Effects of a Novel TLR7 Agonist Combined with Lapatinib.

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