GP96 and SMP30 Protein Priming of Dendritic Cell Vaccination Induces a More Potent CTL Response against Hepatoma

Heat-shock protein (HSP) GP96 is a well-known adjuvant in immunotherapy. It belongs to the HSP90 family. Our previous study demonstrated that DC pulsed with recombinant senescence marker protein 30 (SMP30) could induce cytotoxic T lymphocytes (CTLs) against liver cancer cells in vitro. In this study, SMP30 and GP96 were subcloned into lentiviruses and transfected into DCs from healthy donors. We included six groups: the GP96-SMP30 group, GP96 group, SMP30 group, DC group, empty vector control group, and hepatoma extracted protein group. We used ELISA to detect cytokines and flow cytometry to assess CD80 and CD86 on DCs and the effect of CTLs. Our vector design was considered successful and further studied. In the SMP30 group, DC expresses more CCR7 and CD86 than the control group; in the SMP30+GP96 group, DC express more CCR7, CD86, and CD80 than the control group. Transfected DCs secreted more TNF-α and interferon-β and induced more CTLs than control DCs. SMP30 + GP96 effectively stimulated the proliferation of T cells compared with control treatment ( P < 0.01). We detected the cytokines TNF-α, TNF-β, IL-12, and IFN (α, β, and γ) via ELISA (Figure 5) and verified the killing effect via FCM. Four E : T ratios (0 : 1, 10 : 1, 20 : 1, and 40 : 1) were tested. The higher the ratio was, the better the effects were. We successfully constructed a liver cancer model and tested the CTL effect in each group. The GP96 + SMP30 group showed a better effect than the other groups. GP96 and SMP30 can stimulate DCs together and produce more potent antitumor effects. Our research may provide a new efficient way to improve the therapeutic effect of DC vaccines in liver cancer.

Evaluation of response in patients with hepatocellular carcinoma treated with intratumoral dendritic cell vaccination using intravoxel incoherent motion (IVIM) MRI and histogram analysis

Background Immunotherapy of hepatocellular carcinoma (HCC) is an emerging method with promising results. Immunotherapy can have an antitumor effect without affecting tumor size, calling for functional imaging methods for response evaluation. Purpose To evaluate the response to intratumoral injections with the immune primer ilixadencel in HCCs with diffusion-weighted magnetic resonance imaging (DW-MRI) using intravoxel incoherent motion (IVIM) and histogram analysis. Material and Methods A total of 17 patients with advanced HCC were treated with intratumoral injections with ilixadencel on three occasions 2–5 weeks apart. The patients were examined with IVIM before each injection as well as approximately three months after the first injection. Results The 10th percentile of perfusion-related parameter D* decreased significantly after the first and second intratumoral injections of ilixadencel compared to baseline ( P < 0.05). There was a non-significant trend of lower median region of interest f (perfusion fraction) before injection 2 compared to baseline ( P = 0.07). There were significant correlations between the 10th percentile and median of D at baseline and change in tumor size after three months ( r = 0.79, P < 0.01 and r = 0.72, P < 0.05, respectively). Conclusion DW-MRI with IVIM and histogram analysis revealed significant reductions of D* early after treatment as well as an association between D at baseline and smaller tumor growth at three months. The lower percentiles (10th and 50th) were found more important. Further research is needed to confirm our preliminary findings of reduced perfusion after ilixadencel vaccinations, suggesting a treatment effect on HCC.

Dendritic Cell Vaccination of Glioblastoma: Road to Success or Dead End

Glioblastomas (GBM) are the most frequent and aggressive malignant primary brain tumor and remains a therapeutic challenge: even after multimodal therapy, median survival of patients is only 15 months. Dendritic cell vaccination (DCV) is an active immunotherapy that aims at inducing an antitumoral immune response. Numerous DCV trials have been performed, vaccinating hundreds of GBM patients and confirming feasibility and safety. Many of these studies reported induction of an antitumoral immune response and indicated improved survival after DCV. However, two controlled randomized trials failed to detect a survival benefit. This raises the question of whether the promising concept of DCV may not hold true or whether we are not yet realizing the full potential of this therapeutic approach. Here, we discuss the results of recent vaccination trials, relevant parameters of the vaccines themselves and of their application, and possible synergies between DCV and other therapeutic approaches targeting the immunosuppressive microenvironment of GBM.

Prophylactic dendritic cell vaccination in antitumor immune response and tumor growth in a breast cancer mouse model

Dendritic cell vaccines have demonstrated promising results for poorly immunogenic tumors, which may promote the generation of better immune responses in the tumor microenvironment. However, the vaccine has little been evaluated as a prophylactic option. Therefore, this study evaluates the influence of prophylactic dendritic cell vaccination on the antitumor immune response in the tumor microenvironment and on tumor growth, in an experimental model with breast cancer induced by 4T1. Therefore, Balb/c mice were separated into a vaccinated group and an unvaccinated group. Dendritic cell vaccine was differentiated and matured ex vivo from bone marrow. During the experimental period, the tumor volumes were checked periodically. The tumors were evaluated for immune cells (helper T lymphocytes and cytotoxic T lymphocytes), helper T cells (Th1, Th2, Th17, and Treg), TNF-α, and IFN-γ synthesis by Th1 and cytotoxic T lymphocytes. The vaccinated group had decreased tumor volume (14.0, 0-131.7) compared to the unvaccinated group (89.59, 0.1250-459.6) (p=0.0421). The Th1, Th2, Th17, Treg, cytotoxic T subtypes, including TNF-α and IFN-γ produced by Th1 and T cytotoxic, showed a significant increase in the vaccinated group, as did the balance of Th1/Th2 and Th1/Treg. The results showed that prophylactic vaccination with dendritic cells showed a considerable antitumor effect in the studied model by promoting an increase in the activation of important cells in the immune response and a reduction in tumor volume. The data provide evidence for timely activation of immune surveillance in the absence of tumor burden.