a Polyphenol Whole Tumor Cell Vaccine in Patients With Advanced Malignant Solid Tumors

Malignant solid tumors are malignant tumors that originate in epithelial tissue (carcinoma), mesenchymal tissue (sarcoma), or the nervous system (glioma, etc.). According to Global Cancer Statistics 2022, there will be 19.96 million new cancer cases and 9.74 million new deaths globally in 2022, with solid tumors accounting for the majority of these cases. Overall, the annual global cancer incidence rate continues to trend upward, and the number of new cancers in 2050 is expected to increase to 35.3 million cases. Cancer remains a major health challenge globally, with serious implications for human life safety and quality of life.

Tumor vaccines are a promising immunotherapeutic modality to achieve inhibition of tumor growth and metastasis by utilizing the body's immune system to trigger a specific anti-tumor immune response. In recent years, impressive progress has been made in the development of tumor vaccines, and hundreds of such vaccines are currently under development and in clinical trials. These vaccine types are mainly tumor cell vaccines, dendritic cell vaccines, peptide vaccines, oncolytic viral or bacterial vector vaccines, and nucleic acid vaccines. Typically, the effectiveness of tumor vaccines relies on the availability of a sufficiently large number of tumor antigens to stimulate the innate immune system, and the ability to achieve antigen cross-presentation and T-cell immune activation. However, most tumor vaccines developed at this stage do not contain complete antigenic information, which affects the clinical efficacy of the vaccine and hinders application expansion. In order to avoid the problem of immune escape caused by insufficient immune stimulation due to the lack of a sufficient number of tumor antigens, the development of autologous tumor cells and the retention of complete specific tumor-associated antigens have become the key to the development of personalized vaccines.

Whole tumor cell vaccine (TCV) is a classic individualized tumor immunotherapy, and its advantage lies in the inclusion of the patient's own full series of tumor-associated antigens, which can simultaneously target multiple unknown and known tumor antigens optimally, thus avoiding immune escape caused by the loss of tumor antigens, and has an important application prospect for the inhibition of tumor development, progression and recurrence. It has important application prospects for inhibiting tumor occurrence, development and recurrence. Its mechanism of action is to introduce tumor antigens into the patient's body in order to overcome tumor-induced immunosuppression, enhance immunogenicity, activate the patient's own immune system, induce the body's cellular and humoral immune responses, and achieve the goal of controlling or clearing the tumor. Although these strategies are promising, it is still difficult to retain intact tumor antigens and effectively trigger anti-tumor immune responses during vaccine preparation. In addition, since vaccines made from intact tumor cells usually fail to elicit an effective immune response, in order to improve their immunogenicity as vaccines, scientists have been exploring adjuvant-related approaches to introduce various interventions to enhance their immune potential. However, these methods are usually complex and time-consuming, and therefore, there is an urgent need to develop new concepts and technologies through interdisciplinary intersections to achieve on-demand immunopotentiation of TCVs.

Recently, the team of investigators developed a novel strategy of encapsulating tumor cells by metallic polyphenol nanocoatings and further constructed a whole-cell vaccine (referred to as LMP vaccine) using bacterial lipopolysaccharide (LPS) with surface modification as a vaccine adjuvant. In this study, by constructing a single-cell coating of plant polyphenols, all neoplastic antigens of the encapsulated tumor cells were preserved, and upon uptake by dendritic cells, the LMP vaccine released manganese ions and tumor antigen components inside the dendritic cells to stimulate the innate immune pathway STING, which synergistically with the tumor antigens facilitated the maturation of the dendritic cells and further presented the tumor antigen signals to the T cells, resulting in an enhanced The research results of LMP vaccine were published in Angewandte Chemie International Edition in 2024 and selected as "Hot Paper", which gained wide attention. The study used C57BL/6 mice to establish a B16F10 melanoma model, and after inoculation with tumor cells on day 0, the mice were injected subcutaneously with the LMP vaccine on days 3, 6, 9, and 15. The results showed that tumor growth was significantly inhibited in the LMP vaccine group compared with the PBS control group, and the average tumor volume was only 350 mm³ on day 20, while the average tumor volume of the PBS group was more than 1,200 mm³. The mean tumor volume of the PBS group exceeded 1200 mm³. In addition, when the LMP vaccine was combined with anti-programmed cell death ligand 1 (anti-PD-L1), the therapeutic effect was even more pronounced, and the tumor volume of all mice receiving the combined treatment was significantly reduced, with the mean tumor volume reduced to less than 100 mm³, demonstrating a synergistic tumor-suppressive effect. In addition, the investigators paid special attention to the safety of the LMP vaccine, especially the inactivation of tumor cells and the risk of secondary tumorigenesis. The results showed that the LMP vaccine was successfully inactivated by encapsulation of metal polyphenol nanocoatings during the preparation of tumor cells, which lost their proliferation ability after injection. Through in vivo observations in mice for up to 27 days, the investigators found that mice receiving the LMP vaccine did not show any signs of tumor growth, whereas mice in the control group rapidly developed significant tumors, with tumor volumes exceeding 1,400 mm³ within 27 days. In addition, by histopathological analysis of major organs (heart, liver, spleen, and kidneys), H\&E staining showed no significant differences in organ histology between the different treatment groups of mice, suggesting that the LMP vaccine did not cause significant tissue damage. Key blood biochemical analyses, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin (ALB), creatine kinase (CK), creatinine (CREA), and urea (UREA), were all within the normal reference ranges, which further confirmed the systemic safety of the LMP vaccine. Together, these data indicate that the LMP vaccine provides an effective anti-tumor immune response as well as good biocompatibility and safety, does not cause secondary tumorigenesis, and provides a solid safety foundation for clinical application. In summary, the results show that LMP vaccine is biosafe and can inhibit primary tumor growth and metastasis. In combination with anti-programmed cell death ligand 1 (anti-PD-L1), it showed synergistic tumor inhibition effects, which is important for achieving superior anti-tumor therapeutic effects in the clinic.

This project intends to carry out phase I clinical studies on the basis of the previous work, initially exploring the possible effective dose, evaluating its safety and tolerability, with a view to achieving long-term control of the disease, which is expected to provide more options for the treatment of patients with advanced malignant solid tumors. The development of this project will provide new ideas, strategies and theoretical basis for the research and development of whole tumor cell vaccines; at the same time, it is expected to obtain original new drugs with independent intellectual property rights.