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.

Human papillomavirus associated cervical lesion: pathogenesis and therapeutic interventions

“…However, nucleic acid‐based vaccines have limited immunoprototypes, which curtails their utility. Nonetheless, preclinical studies have demonstrated that the incorporation of adjuvants such as MDA‐7/IL‐24/IL‐7/GM‐CSF, immune checkpoint blockers, and chitosan nanoparticles enhances the functionality of DNA vaccines 319–322 . A noteworthy example of therapeutic DNA‐based vaccines is VGX3100, which comprises two DNA plasmids encoding HPV16/18 E6/E7 proteins.…”

“…Nonetheless, preclinical studies have demonstrated that the incorporation of adjuvants such as MDA‐7/IL‐24/IL‐7/GM‐CSF, immune checkpoint blockers, and chitosan nanoparticles enhances the functionality of DNA vaccines. 319 , 320 , 321 , 322 A noteworthy example of therapeutic DNA‐based vaccines is VGX3100, which comprises two DNA plasmids encoding HPV16/18 E6/E7 proteins. Phase III clinical trials of VGX3100 in CIN II‐III have been completed (NCT03185013 and NCT03721978), although the results have not been published yet.…”

Inhibitory effect of human interleukin-24 on the proliferation, migration, and invasion of cervical cancer cells

“… 15 – 17 Although research has shown the ability of hIL-24 to inhibit tumor cell growth and promote apoptosis, its use in treating cervical cancer is not well explored. 18 – 20 …”

“…[15][16][17] Although research has shown the ability of hIL-24 to inhibit tumor cell growth and promote apoptosis, its use in treating cervical cancer is not well explored. [18][19][20] To address this gap, our study investigates the specific impact of hIL-24 on SiHa and HeLa cervical cancer cells. We created a pcDNA3.1 (þ)-hIL-24 recombinant plasmid and introduced it into SiHa and HeLa cells through lipofection.…”

Interleukin-24-mediated antitumor effects against human glioblastoma via upregulation of P38 MAPK and endogenous TRAIL-induced apoptosis and LC3-II activation-dependent autophagy

“…Interleukin-24 (IL-24)/Melanoma differentiation-associated gene-7(Mda-7) is a special member of the IL-10 family of cytokines that can specifically cause apoptosis in cancer cells without affecting healthy cells. The multi-functional tumor suppressing properties of Mda-7/IL-24 include: inducing apoptosis, inhibition of migration, invasion, and eventually metastasis; induction of differentiation and/or killing of cancer stem cells; sensitization of cancer cells to radiation, chemotherapy, and induction of an anti-tumor immune modulating effect [ 5 , 6 ]. Also, based on the positive results from pre-clinical and Phase I clinical trials, IL-24 has been transitioned into a phase II clinical trial, indicating that it has the potential to be safe and effective for cancer gene therapy.…”