Combining Vaccines with Checkpoint29 Jan 2019 17:06
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Combining Vaccines with Checkpoint Blockade
Many vaccine platforms are effective in generating detectable T cell responses against shared antigens or neoantigens. However, these T cells are often incapable of ablating established tumors. Many studies have revealed that tumor-infiltrating T cells are less functional than those found in circulation, both in vaccinated and unvaccinated patients (34–37). It is becoming increasingly clear that tumors utilize many strategies to evade antitumor T cells (38). Thus, tumor cell killing may be blunted by checkpoint receptor signaling, highly suppressive regulatory cells, or alterations in tissue oxygenation and nutrient availability.
Activated T cells express inhibitory receptors on their surface, limiting the magnitude of the T cell response and collateral tissue damage during normal immune responses. There are currently two T cell checkpoint pathways targeted by FDA-approved therapies: CTLA-4 and PD-1. CTLA-4 is a member of the immunoglobulin superfamily and limits T cell function when it binds CD28 on DCs during T cell priming (39). Ipilimumab, an antibody targeting CTLA-4, is an effective therapy for metastatic melanoma, receiving FDA approval in 2011 (40, 41). Nivolumab and atezolizumab are antibodies targeting PD-1 and PD-L1, respectively (42). When it binds the cognate ligand PD-L1, PD-1 limits antitumor T cell costimulation by disrupting CD28 signaling (43). The power of this inhibitory pathway in cancer is illustrated by the remarkable clinical responses seen in some patients treated with nivolumab (44, 45).
Importantly, PD-L1 expression is regulated by CD8+ and Th1 CD4+ T cell-produced IFN? (46–48). This upregulation of PD-L1 in response to T cell attack is a highly conserved pathway and can explain much of the PD-L1 expression seen in certain cancers (49). As a result of this pathway, vaccine-induced T cells can also enhance the expression of PD-L1, and this can limit vaccine efficacy (50, 51). However, vaccine-induced PD-L1 expression does not reliably predict responses to PD-1 blockade in all tumor models (52). Two recent preclinical studies showed that PD-L1 expression on DCs and macrophages is more predictive of response to PD-1 blockade than PD-L1 expression on tumor cells themselves (53, 54). PD-L1 expression on DCs is known to limit T cell activation (55). Thus, PD-1 blockade may also influence antitumor T cell priming. Whether PD-1 disrupts priming of naïve antitumor T cells or produces an exhausted state in previously activated cells is a point of future inquiry (56).
Regardless of the exact mechanism, tumor vaccination and checkpoint inhibition may be a potent combination in cancer therapy. In an early preclinical study, CTLA-4 blockade delayed B16 tumor growth when combined with a GM-CSF-secreting tumor vaccine, showing the value of combination immunotherapy (57). Similarly, PD-1 blockade can enhance T cell tumor infiltration, increase T cell activation, and improve
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