A novel cancer vaccine with the ability to simultaneously produce anti-PD-1 antibody and GM-CSF in cancer cells and enhance Th1-biased antitumor immunity

Abstract

Tumor escape from immune-mediated destruction has been associated with immunosuppressive mechanisms that inhibit T-cell activation. A promising strategy for cancer immunotherapy is to disrupt key pathways regulating immune tolerance, such as program death-1 (PD-1/PD-L1) pathway in the tumor environment. However, the determinants of response to anti-PD-1 monoclonal antibodies (mAbs) treatment remain incompletely understood. In murine models, PD-1 blockade alone fails to induce effective immune responses to poorly immunogenic tumors, but is successful when combined with additional interventions, such as cancer vaccines. Novel cancer vaccines combined with antibody may offer promising control of cancer development and progression. In this investigation, we generated a novel tumor cell vaccine simultaneously expressing anti-PD-1 mAbs and granulocyte-macrophage colony stimulating factor (GM-CSF) in CT26 colon cancer and B16-F10 melanoma. The antitumor effect of the vaccine was verified by therapeutic and adoptive animal experiments in vivo. The antitumor mechanism was analyzed using Flow cytometry, Elispot and in vivo intervention approaches. The results showed that tumor cell vaccine secreting PD-1 neutralizing antibodies and GM-CSF induced remarkable antitumor immune effects and prolonged the survival of tumor-bearing animals compared with animals treated with either PD-1 mAbs or GM-CSF alone. Antitumor effects and prolonged survival correlated with strong antigen-specific T-cell responses by analyzing CD11c+CD86+ DC, CD11b+F4/80+ MΦ cells, increased ratio of Teff/Treg in the tumor microenvironment, and higher secretion levels of Th1 proinflammatory cytokines in serum. Furthermore, the results of ELISPOT and in vivo blocking strategies further confirmed that the antitumor immune response is acquired by CD4 and CD8 T immune responses, primarily dependent on CD4 Th1 immune response, not NK innate immune response. The combination of PD-1 blockade with GM-CSF secretion potency creates a novel tumor cell vaccine immunotherapy, affording significantly improved antitumor responses by releasing the state of immunosuppressive microenvironment and augmenting the tumor-reactive T-cell responses.

The Effect of Different Immunization Cycles of a Recombinant Mucin1-Maltose-Binding Protein Vaccine on T Cell Responses to B16-MUC1 Melanoma in Mice

“…Furthermore, the results of flow cytometry showed that the vaccine increased the proportion of CD4+ T and CD8+ T cells in the spleen and TME, suggesting the important role of CD4+ T and CD8+ T cells in antitumor immunity. Consistent with our results, Tondini et al and Tian et al evaluated CD4+ T and CD8+ T cells in vivo by injecting anti-CD4 and anti-CD8 antibodies in mice, and found that tumor regression was dependent on CD4+ T and CD8+ T cells [ 25 , 26 , 27 ]. Other experiments have also shown that increases in the numbers of CD4+ T and CD8+ T cells in the TME are closely related to tumor prognosis [ 28 , 29 , 30 , 31 ].…”

Inducible IFN-γ Expression for MHC-I Upregulation in Devil Facial Tumor Cells

“…Alternatively, given the success of PD-1/PD-L1 blocking antibodies in human cancer, incorporating existing devil PD-1/PD-L1 blocking antibodies in immunotherapies and vaccines could be an effective means to amplify anti-DFT responses. Another potential approach that can be explored with the system developed here is to modify the tumor cells to produce the blocking antibodies (39). This would actually be more cost-effective than using purified antibodies.…”

Polyphenols as Immunomodulatory Compounds in the Tumor Microenvironment: Friends or Foes?

“…Unlike the proteins/peptides approach, genetic vaccines (either DNA- or RNA-based) can deliver large chunks of antigenic information into target cells, making it possible to induce the expression of multiple TAAs with a single immunization [38,55,57,58,59]. Furthermore, with a suitable choice of a genetic vaccine and a vector, it is possible to induce ectopic TAAs expression not only on cancer cells, but also, and possibly concomitantly, on the DCs which are needed to elicit complete T cell activation [55,60,61], thus resulting in cross-priming and/or direct antigen presentation and large benefits in terms of response magnitude.…”