Amir Ghaemi

Boosting immune response against cervical cancer: A combined approach using oncolytic virus and targeted therapies

Background Cervical cancer remains a primary reason for cancer malignancy among women worldwide, primarily due to human papillomavirus (HPV) strains HPV16 and HPV18. Despite having access to vaccines, there are few treatment options for advanced or recurring cases. This research investigates the possibility of using Newcastle disease virus (NDV) along with Everolimus (EVE) and Beclin-1 (BEC) to improve immune reactions and decrease tumor development in an experimental model of HPV-related cervical cancer. Methods A mouse model for cervical cancer was created by utilizing HPV16 E6/E7-expressing TC-1 cells in C57BL/6 mice. The mice underwent treatment with NDV, EVE, BEC, or various combinations of these therapies. Tumor progression was monitored, evaluated immune responses by measuring cytokine levels (including IL-4, IFN-γ, and IL-12), and investigated the presence of CD8 + T cells within the tumors. Additionally, survival rates were monitored throughout the study. Results The synergy of NDV, EVE, and BEC led to a remarkable decrease in tumor growth, achieving reductions of as much as 70% when compared to monotherapies. Additionally, our combination therapy elicited strong immune reactions, evidenced by increased concentrations of IL-4, IFN-γ, and IL-12, along with enhanced infiltration of CD8 + T cells into the tumors. Mice that were subjected to this Triple therapy exhibited better survival rates than those in other treatment categories. Conclusions Our findings highlight the potential to improve outcomes in cervical cancer associated with HPV through a multi-faceted approach incorporating NDV, Everolimus, and Beclin-1. This therapeutic strategy not only hinders tumor growth but also strengthens the immune system’s ability to fight against cancer. These results prompt further exploration of this combination in clinical trials, with the goal of offering new treatment avenues for patients who have limited choices.

Oncolytic effects of Hitchner B1 strain of newcastle disease virus against cervical cancer cell proliferation is mediated by the increased expression of cytochrome C, autophagy and apoptotic pathways

Newcastle disease virus (NDV) is a potential oncolytic virus for the cancer treatment due to its ability to replicate in tumor cells. The aim of this study was to evaluate the in vitro anticancer properties of Hitchner B1 (HB1) strain of NDV on TC-1 cell line and underlying molecular mechanisms. The cytolytic effects of oncolytic HB1 strain of NDV was determined by lactate dehydrogenase (LDH) release assay. Apoptosis, intracellular reactive oxygen species (ROS) levels, cleaved caspase-3 and autophagy were evaluated by flow cytometry. Cytochrome-C and survivin protein levels were distinguished by Enzyme-Linked Immunosorbent Assay (ELISA). Our results from LDH method showed that the viability of the TC-1 cell line following HB1 NDV infection was dose-dependent and decreased significantly with increasing the dose of HB1 NDV infection (MOIs: 5, 10, and 15). Other evaluations also revealed that HB1 strain of NDV potentially led to the ROS production, and apoptosis and autophagy induction in TC-1 cell line in a dose-dependent manner. The in vitro experiments also presented that NDV treatment significantly up-regulated the expression of cytochrome-C and down-regulated the expression of survivin, as detected by ELISA assay. Our results confirmed that the HB1 NDV could be introduced as a powerful candidate for the therapy of cervical cancer. However, further examinations are needed to explain the underlying mechanisms of the HB1 NDV against TC-1 cell line and cervical cancer.

Enhanced synergistic antitumor effect of a DNA vaccine with anticancer cytokine, MDA-7/IL-24, and immune checkpoint blockade

Abstract Background MDA-7/IL-24 cytokine has shown potent antitumor properties in various types of cancer without exerting any significant toxicity on healthy cells. It has also been proved to encompass pro-immune Th1 cytokine-like behavior. Several E7 DNA vaccines have developed against human papillomavirus (HPV)-related cervical cancer. However, the restricted immunogenicity has limited their clinical applications individually. To address this deficiency, we investigated whether combining the E7 DNA vaccine with MDA-7/IL-24 as an adjuvant would elicit efficient antitumor responses in tumor-bearing mouse models. Next, we evaluated how suppression of immunosuppressive IL-10 cytokine would enhance the outcome of our candidate adjuvant vaccine. Methods For this purpose, tumor-bearing mice received either E7 DNA vaccine, MDA-7/IL-24 cytokine or combination of E7 vaccine with MDA-7/IL-24 adjuvant one week after tumor challenge and boosted two times with one-week interval. IL-10 blockade was performed by injection of anti-IL-10 mAb before each immunization. One week after the last immunization, mice were sacrificed and the treatment efficacy was evaluated through immunological and immunohistochemical analysis. Moreover, the condition of tumors was monitored every two days for six weeks intervals from week 2 on, and the tumor volume was measured and compared within different groups. Results A highly significant synergistic relationship was observed between the E7 DNA vaccine and the MDA-7/IL-24 cytokine against HPV-16+ cervical cancer models. An increase in proliferation of lymphocytes, cytotoxicity of CD8+ T cells, the level of Th1 cytokines (IFN-γ, TNF-α) and IL-4, the level of apoptotic markers (TRAIL and caspase-9), and a decrease in the level of immunosuppressive IL-10 cytokine, together with the control of tumor growth and the induction of tumor regression, all prove the efficacy of adjuvant E7&IL-24 vaccine when compared to their individual administration. Surprisingly, vaccination with the DNA E7&IL-24 significantly reduced the population of Regulatory T cells (Treg) in the spleen of immunized mice compared to sole administration and control groups. Moreover, IL-10 blockade enhanced the effect of the co-administration by eliciting higher levels of IFN-γ and caspase-9, reducing Il-10 secretion and provoking the regression of tumor size. Conclusion The synergy between the E7 DNA vaccine and MDA-7/IL-24 suggests that DNA vaccines’ low immunogenicity can be effectively addressed by coupling them with an immunoregulatory agent. Moreover, IL-10 blockade can be considered a complementary treatment to improve the outcome of conventional or novel cancer therapies.