Are immune checkpoints and CAR-T all the tumor immunotherapy? It's way more than that. Vaccines are one of the possibilities. Vaccines are not only recognized as the most contributory technology to human health in immunoprevention but also highly expected in immunotherapy. Nowadays, vaccines are in vigorous development, especially with the advent of high-throughput low-cost antigen screening technology. The era of personalized vaccine is coming out soon.

However, a vaccine is a duet of antigen and adjuvant. Without adjuvant, the antigen alone could not do much single-handed. More than 90 years ago, it was the discovery of aluminum hydroxide adjuvant that laid a technical foundation for the development of preventive vaccines. The antigen repository effect of aluminum hydroxide adjuvant helped the vaccine to achieve great success in epidemic prevention.

The success of the aluminum hydroxide adjuvant could hardly be replicated when the subject turns to cancer, which is more dependent on cellular immunity. nanocarriers have both the characteristics of traditional adjuvants and the size of viroids, and thus acclaimed as the hope of a new generation of adjuvants. However, it is difficult for traditional nanocarriers to give full play to the advantages of “viroid” immunity in vaccine design owing to the difficulty of antigen surface exposure (being encapsulated) and low antigen density (low loading rate), which greatly limits the improvement of cellular immune effect.

In view of this, Yongyong Li’s research group of Tongji University recently reported a new concept of minimalist nanovaccine on ACS Nano, that is, to build a “self adjuvant” nano vaccine by excavating the packaging potential of antigen, in which the antigen undertakes the dual functions of both antigen and adjuvant, so as to overcome the two unavoidable problems of traditional nano vaccine: difficulty of antigen surface exposure and low antigen loading rate.

In this study, ovalbumin (OVA) was selected as the model antigen. Through taking advantage of the unique chemical structure of proteins, the researchers innovatively developed a new strategy of “regulating sulfhydryl exposure + disulfide bond cross-link”. Without using any traditional nanocarriers, more than 500 antigen molecules go “hand in hand” on the nanoscale to form a stable disulfide bond spatial network structure, and thus construct a new type of nano vaccine with “the most simplified” composition (nearly 100% antigen). The whole method is fast, green, highly controllable in size, and has good universality for other proteins.

Figure 1. Scheme for the structure and assembly of OVA@CpG nanoparticles with 100% immune compositions.

It is encouraging that the new vaccine shows excellent tumor prevention ability in the B16-OVA melanoma mice model. After three times of preventive inoculation, no tumor was found in 7 of 10 mice attacked by B16-OVA, and the tumor-free state lasted for the whole experimental period (18 weeks), while all 10 mice in the control group developed tumor genesis and rapid growth. In addition, this new vaccine can significantly prolong the survival period and improve the survival rate of B16-OVA tumor-bearing mice. The mechanism study revealed that the new vaccine could mediate a higher level of T cell immune effect and T cell infiltration in the tumor area.

Figure 2.The tetramer assay of OVA-specific CD8+ T cells, and tumor-infiltrating condition of T cells elicited by mNVs in prophylactic test.

This work was recently published in ACS Nano (2018, 12, 6398-6409, DOI: 10.1021/acsno.8b00558, IF=13.7), titled as Minimalist Nanovaccine Constituted from Near Whole Antigen for Cancer Immunotherapy. Wang Kun, postgraduate of Tongji University, is the first author, and Prof。Li Yongyong is the corresponding author, while Tongji University is the first signature unit. It is worth mentioning that the ACS Nano editor introduced this work with the title of Less is More for Cancer Nanovaccine (ACS Nano 2018, 12, 6347).

In addition, in 2018, Prof. Li Yongyong’s group also developed a new physical regulation method for the important proposition “tumor immunosuppression microenvironment”. Relevant results are published in the famous journal Advanced Science (2018, 1700805, DOI: 10.1002 / advs. 2017008053, IF=12.4) under the title of Fever-Inspired Immunotherapy Based on Photothermal CpG Nanotherapeutics: The Critical Role of Mild Heat in Regulating Tumor Microenvironment. Based on the self-assembly of disulfide bond in macromolecules, this work constructs a CPG photothermal protein nanoparticles, which can form a “fever-like” microenvironment at the tumor site as well as significantly improve the local immunosuppressive microenvironment and immune effector cell infiltration of 4T1 tumor, and thus dramatically improve the immunotherapeutic effect of CpG on in situ 4T1 tumor. The study discovered that the induced immune memory effect caused by the CpG nanotherapeutics can better control the tumor distant metastasis. Dr. Li Yan from Tongji University is the first author, and Prof.Li Yongyong is the corresponding author, while Tongji University is the first signature unit. Shortly after the publication, the international journal Immunotherapy invited Prof. Xiaojun Xia from Zhongshan University to make a special comment on this study (a CPG never for cancer Nanovaccine, Immunotherapy 2018, 10, 631–633).

Reference：Mamo T, Poland GA. Nanovaccinology: the next generation of vaccines meets 21st century materials science and engineering. Vaccine 2012; 30: 6609–11.