ABSTRACT
Chemoimmunotherapy has attracted much attention as an emerging therapy pattern for the treatment of cancers. Exploring effective drug combination schemes and reasonable delivery methods remained the key issue in current research. Herein, we designed sorafenib (SF) and anti-Tim-3 monoclonal antibody (Tim-3 mAb) co-loaded MMP2-responsive mesoporous silica nanoparticles (ST-MSNs) for combined chemoimmunotherapy of hepatocellular carcinoma (HCC). The shell of ST-MSNs was fabricated by Tim-3 mAb through matrix metalloproteinase 2 (MMP2) sensitive peptides as "gatekeepers" to prevent drug release during the blood circulation. In tumor microenvironment, the high levels of MMP2 caused the responsive shedding of Tim-3 mAb, leading to the triggerred release of SF and Tim-3 mAb. Then, SF could be delivered to tumor cells and Tim-3 mAb could be delivered to T cells, respectively. In vivo tumor inhibition study results demonstrated that ST-MSNs can significantly enhance synergistic antitumor activity compared with sequential administration of free SF solution and Tim-3 mAb solution. Meanwhile, the expression of antitumor cytokines IFN-γ, IL-12 and the percentage of CD3+CD4+ cells, CD3+CD8+ cells in tumors were upregulated after the administration of ST-MSNs, demonstrating good immunomodulatory ability. In addition, within the dosage range, the ST-MSNs had low cytotoxicity and hemolysis, and no obvious tissue toxicity was observed. All animal experiments were performed in line with national regulations and approved by the Animal Experiments Ethical Committee of Shandong University. In conclusion, this study provided a promising drug combination of chemoimmunotherapy with good application prospects for clinical HCC treatment, and exhibited a potential drug carrier for clinical chemoimmunotherapy.
ABSTRACT
In the development of chemo-immunotherapy, many efforts have been focusing on designing suitable carriers to realize the co-delivery of chemotherapeutic and immunotherapeutic with different physicochemical properties and mechanisms of action. Besides, rapid drug release at the tumor site with minimal drug degradation is also essential to facilitate the antitumor effect in a short time. Here, we reported a cancer cell membrane-coated pH-responsive nanogel (NG@M) to co-deliver chemotherapeutic paclitaxel (PTX) and immunotherapeutic agent interleukin-2 (IL-2) under mild conditions for combinational treatment of triple-negative breast cancer. In the designed nanogels, the synthetic copolymer PDEA-co-HP-β-cyclodextrin-co-Pluronic F127 and charge reversible polymer dimethylmaleic anhydride-modified polyethyleneimine endowed nanogels with excellent drug-loading capacity and rapid responsive drug-releasing behavior under acidic tumor microenvironment. Benefited from tumor homologous targeting capacity, NG@M exhibited 4.59-fold higher accumulation at the homologous tumor site than heterologous cancer cell membrane-coated NG. Rapidly released PTX and IL-2 enhanced the maturation of dendritic cells and quickly activated the antitumor immune response in situ, followed by prompted infiltration of immune effector cells. By the combined chemo-immunotherapy, enhanced antitumor effect and efficient pulmonary metastasis inhibition were achieved with a prolonged median survival rate (39 days).
ABSTRACT
Immune checkpoint inhibitors (ICIs) have become an important treatment strategy for advanced esophageal cancer in the first and second line. Currently, the use of ICIs in neoadjuvant therapy is very limited. However, neoadjuvant immunotherapy may bring better survival benefits for patients with early esophageal cancer or with resectable locally advanced esophageal cancer. The authors review relevant studies to discuss the current status and future of neoadjuvant immunotherapy for esophageal cancer.
ABSTRACT
Co-delivery of chemotherapeutics and immunostimulant or chemoimmunotherapy is an emerging strategy in cancer therapy. The precise control of the targeting and release of agents is critical in this methodology. This article proposes the asynchronous release of the chemotherapeutic agents and immunostimulants to realize the synergistic effect between chemotherapy and immunotherapy. To obtain a proof-of-concept, a co-delivery system was prepared
ABSTRACT
More efficient drug delivery system and formulation with less adverse effects are needed for the clinical application of broad-spectrum antineoplastic agent doxorubicin (DOX). Here we obtained outer-membrane vesicles (OMVs), a nano-sized proteoliposomes naturally released by Gram-negative bacteria, from attenuated and prepared doxorubicin-loaded O0MVs (DOX-OMV). Confocal microscopy and distribution study observed that DOX encapsulated in OMVs was efficiently transported into NSCLC A549 cells. DOX-OMV resulted in intensive cytotoxic effects and cell apoptosis as evident from MTT assay, Western blotting and flow cytometry due to the rapid cellular uptake of DOX. In A549 tumor-bearing BALB/c nude mice, DOX-OMV presented a substantial tumor growth inhibition with favorable tolerability and pharmacokinetic profile, and TUNEL assay and H&E staining displayed extensive apoptotic cells and necrosis in tumor tissues. More importantly, OMVs' appropriate immunogenicity enabled the recruitment of macrophages in tumor microenvironment which might synergize with their cargo DOX . Our results suggest that OMVs can not only function as biological nanocarriers for chemotherapeutic agents but also elicit suitable immune responses, thus having a great potential for the tumor chemoimmunotherapy.
ABSTRACT
Cancer‐induced immunosuppressive cells play an important immunosuppressive role during the tumor develop‐ment process ,and the development and progression of tumors are always accompanied with abnormal accumulation of cancer‐in‐duced immunosuppressive cells .Regulatory T lymphocytes (Treg) and myeloid‐derived suppressor cells (MDSC) are major components of these inhibitory cellular networks ,and they can inhibit antitumor immune response through multiple mecha‐nisms .Recent studies have provided evidence that beyond their direct cytotoxic or cytostatic effects on cancer cells ,some con‐ventional chemotherapeutic drugs and agents used in targeted therapies can promote the elimination or inactivation of suppres‐sive Tregs or MDSCs ,resulting in enhanced anti‐tumor immunity .Hence ,chemotherapeutics ,used as a preconditioning regi‐men and combined with subsequent immunotherapy ,can promote anti‐tumor immune response .Anticancer chemoimmunothera‐py strategy will change the recognization of the role for conventional chemotherapy in anticancer treatment ,and it will be help‐ful to optimize the chemotherapy strategies more reasonably .
ABSTRACT
We present a new mathematical model of colorectal cancer growth and its response to monoclonalantibody (mAb) therapy. Although promising, most mAb drugs are still in trial phases, and the possible variations in the dosing schedules of those currently approved for use have not yet been thoroughly explored. To investigate the effectiveness of current mAb treatment schedules, and to test hypothetical treatment strategies, we have created a system of nonlinear ordinary differential equations (ODEs) to model colorectal cancer growth and treatment. The model includes tumor cells, elements of the host’s immune response, and treatments. Model treatments include the chemotherapy agent irinotecan and one of two monoclonal antibodies - cetuximab, which is FDAapproved for colorectal cancer, and panitumumab, which is still being evaluated in clinical trials. The model incorporates patient-specific parameters to account for individual variations in immune system strength and in medication efficacy against the tumor. We have simulated outcomes for groups of virtual patients on treatment protocols for which clinical trial data are available, using a range of biologically reasonable patient-specific parameter values. Our results closely match clinical trial results for these protocols. We also simulated experimental dosing schedules, and have found new schedules which, in our simulations, reduce tumor size more effectively than current treatment schedules. Additionally, we examined the system’s equilibria and sensitivity to parameter values. In the absence of treatment, tumor evolution is most affected by the intrinsic tumor growth rate and carrying capacity. When treatment is introduced, tumor growth is most affected by drugspecific PK/PD parameters.
ABSTRACT
A comparison of effectiveness of chemo-immunotherapy (CIT) using LAK/CD3AK 1-2 weeks after TACE in 74 patients with no surgical indication and TACE alone in 41 patients with moderately advanced HCC was carried out. The rates of remission between CIT group and TACE alone group were 72.4% and 40.4%(P
ABSTRACT
We report a case of malignant melanorna, which showed dramatic effect by combination therapy of DTIC and BCG immunotherpy. The case was s 56-year-old female patient who had an asymptomatic dark brown colored walunt sized protruding tumor with ulceration of the medial aspect of lower one third of right leg for 1 year and palpable masses over the right popliteal fossa and inguinal area. Histologic fingings showed cellular mass composed of epithelioid cells with atypical nucleus, occasionally mitotic figure and numerous melanin granules scattered in the epidermo-dermal junction and papillary or reticular dermis. The mass was diagnosed nodular malignant melanoma which showed Clark level W with metastasis in 4th thoracic vertebra and lymph node. After surgical remove of the primary lesion, chemo-immunotherapy with combined DTIC and BCG was tried, and all the lesion were completely dissppeared. No evidence of recurrence either in primsry focus or other sites was observed up to one year and eight months.