Adenovirus (Ad) vector vaccines have been frequently reported in recent years as the main force against COVID-19. In fact, Ad vaccines have a wide range of applications, and also play an important role in tumor treatment.
Previous studies have confirmed that the combination of Ad vector vaccine encoding tumor neoantigen and PD-1 inhibitor has a good inhibitory effect on tumors in mouse models. However, the mechanism of this combination therapy has not been elucidated.
Recently, some researchers have found that the combination of Great Ape adenovirus (GAd) and PD-1 inhibitor can enhance the stem of neoantigen-specific CD8+ T cells, increase the amount, improve immunogenicity, and then enhance anti-tumor efficacy.
After chronic antigen exposure, CD8+ T cells are depleted and dysfunctional, reducing the ability to control infection or tumor progression. In contrast, Tcf1+ stem cell-like CD8+ T (TSTEM) progenitor cells still promote and maintain effective immunity against tumors.
Studies have shown that in immune checkpoint inhibitor (ICI) therapy, the increase in the proportion of Tcf1+CD8+ T cells is positively correlated with the prolongation of ICI treatment response. Therefore, maintaining the differentiation of Tcf1+CD8+ T cells plays an important role in improving the efficacy of immunotherapy. Increasing the number of Tcf1+CD8+ T cells and maintaining their self-renewal ability are expected to overcome the problem of drug resistance encountered by ICI.
At the same time, a number of studies have shown that the clinical efficacy of PD-1 inhibitors depends on the quantity and quality of CD8+T cells targeting mutation-related tumor neoantigen and the characteristics of tumor invasion. Therefore, tumor neoantigen has become the target of cancer vaccines.
In this project, seven tumor antigen-related genes were cloned into GAd vectors to prepare GAd vaccines, and GAd vaccine and PD-1 inhibitor were used to treat and evaluate MC38 tumor-bearing mouse model. The results showed that the combination of GAd vaccines and PD-1 inhibitors significantly prolonged the survival time of mice, mainly because the enhanced responsiveness of of CD8+ T cells to two new epitopes of Adpgk and Reps1, which improved the immunogenicity of new epitopes.
Next, the researchers measured the number of CD8+ memory precursors and effector T cells in mice after administration. The results showed that compared with the PD-1 inhibitor group, the number of Db-Adpgk+CD8+ memory progenitor cells and specific CD8+ effector T cells in the spleen, tumor tissue, and lymph nodes of the mice treated with GAd vaccines were significantly increased, and only some depleted T cells appeared in the CD127-KLRG1-CD8+ T cell population.
These results suggest that GAd vaccines can improve immunogenicity, and the combination of GAd vaccines and PD-1 inhibitor can promote the differentiation and expansion of tumor neoantigen-specific CD8+ T cells by regulating memory precursors and effector T cells.
Does the combination of GAd vaccines and PD-1 inhibitor also have an effect on the dryness of T cells?
The researchers used single-cell sequencing and principal component analysis to detect that the Db-Adpgk+CD8+ T cells in the lymph nodes of the GAd vaccines combined with the PD-1 inhibitor group were mainly in the TSTEM precursor cell group (69%), while the Db-Adpgk+CD8+ T cells in the tumor tissue were mainly distributed in the depleted T cell group (44%) and the effector T cell group (19%). It is suggested that GAd vaccines combined with PD-1 inhibitors can promote the differentiation of Db-Adpgk+CD8+ T cells into TSTEM precursor cells in lymph nodes and into effector T cells in tumor tissues.
So, what is the relationship between this increase in TSTEM precursors and effector T cells? The researchers identified 330 unique and 34 expanded T cell receptor (TCR) clones and found that GAd vaccines combined with PD-1 inhibitors significantly promoted the expansion and diversity of TCR clones in tumor tissues and lymph nodes of mice. It is suggested that the increase of TSTEM precursor cells and effector T cells is closely related to the clonal expansion of T cells.
Subsequently, the researchers conducted a clinical trial in which 12 cancer patients were vaccinated once against GAd, and then were vaccinated with modified vaccinia virus Ankara (MVA) to enhance anti-tumor immunity three times according to the design of the corresponding cancer vaccine, and were treated with PD-1 inhibitors every three weeks. The subjects were divided into two groups and given 1 (low) and 2 (high) doses respectively.
The median follow-up period of subjects given dose 1 was 20.5 months (range: 18.1-22.5 months), and that of subjects given dose 2 was 9.4 months (range: 1.7-15.2 months). At the secondary end of the study, the immunogenicity of the vaccine was evaluated by testing for interferon (IFN).
The results showed that 67% of the subjects who were given the 1-dose vaccines were detected to have immunogenicity, and all the subjects who were given 2 doses of the vaccines were detected to have immunogenicity. The average baseline response after administration of the first dose of PD-1 inhibitor was ~ 200 SFCs/ million human peripheral blood mononuclear cells (PBMCs), while the average response after vaccination was ~ 1500 SFCs/ million PBMCs.
In addition, the researchers selected one subject from each dose group to evaluate the breadth and kinetics of the response, and the immunogenic response time in both subjects lasted for nearly 26 weeks. At the same time, a large number of IFN- γ + frameshift peptide (FSP) specific CD8+ T cells were detected in both subjects.
It is suggested that GAd vaccines combined with PD-1 inhibitors can produce persistent tumor neoantigen-specific T cell immune response in human bodies.
Finally, the researchers tested the variability of TCR during treatment. The increase in the number of TCR copies in the three subjects indicated that the GAd vaccine promoted the amplification and diversification of TCR clones.
Further studies have shown that the expansion of TCR clones is related to the increase of RNA relative abundance of effector memory T cells. In addition, the researchers also found that tumor neoantigen -specific CD8+ T cells gradually expanded and migrated from peripheral blood to tumor sites induced by GAd vaccines.
In summary, the researchers found that the combination of Ad vector vaccine and PD-1 inhibitors can improve the dryness of tumor antigen-specific CD8+ T cells, maintain and promote their ability to proliferate, expand and transport to tumor sites, as well as promote and induce memory T cells to produce anti-tumor immune responses.