Preclinical Evidence That PD1 Blockade Cooperates with Cancer Vaccine TEGVAX to Elicit Regression of Established Tumors

Abstract

Biomarker studies have shown that expression of the T cell co-regulatory ligand PD-L1 on tumor cells correlates with clinical responsiveness to the PD-1 antibody nivolumab. Here we report the findings of a preclinical cancer vaccine study demonstrating a similiar correlate where PD-L1 is upregulated in the tumor microenvironment. We formulated an IFNγ-inducing cancer vaccine called TEGVAX that combined GM-CSF and multiple toll-like receptor agonists to increase the number of activated dendritic cells. Treatment of established tumors with TEGVAX retarded tumor growth in a manner associated with enhanced systemic anti-tumor immunity. Unexpectedly, TEGVAX also upregulated PD-L1 expression in the tumor microenvironment, possibly explaining why tumors were not eliminated completely. In support of this likelihood, PD-L1 upregulation in this setting relied upon IFNγ-expressing tumor-infiltrating CD4+ and CD8+ T cells and administration of a PD-1 blocking antibody with TEGVAX elicited complete regression of established tumors. Taken together, our findings provide a mechanistic rationale to combine IFNγ inducing cancer vaccines with immune checkpoint blockade.

IMA901: A multi-peptide cancer vaccine for treatment of renal cell cancer

“…Preclinical findings [74][75][76][77] as well as early clinical data in pancreatic, melanoma and prostate cancer [78][79][80] suggest synergistic effects between cancer vaccines and immune checkpoint blockade. Nivolumab, a programmed death-1 (PD-1) inhibitor blocking the PD-1 co-inhibitory receptor on activated T-cells is a promising and in RCC well advanced checkpoint inhibitor, currently being investigated in a phase III trial to assess whether it prolongs survival of second-or third-line RCC patients compared with everolimus.…”

The importance of correctly timing cancer immunotherapy

“…Furthermore, immunological activity, such as increased antigen-specific CD8 + T-cells but also increased frequencies of CD25 + or CTLA-4 + CD4 + T-cells, was associated with promising survival results [82]. Preclinical evidence has shown that TEGVAX vaccine, which is an IFNγ-inducing cancer vaccine combined with GM-CSF and TLR agonists, is associated with DC activation and an increase in the number of tumor-specific IFNγ-producing tumor-infiltrating T-cells [83]. However, as a consequence of this influx, cells in the tumor microenvironment upregulate PD-L1 resulting in incomplete tumor cell elimination.…”

Talimogene Laherparepvec for the Treatment of Advanced Melanoma

“…Although traditional peptide vaccines targeting native antigens such as gp100 and MART-1, given with incomplete Freund's adjuvant, have not provided synergy with CTLA-4 or PD-1 inhibition in advanced melanoma (13,24), T-VEC (and other novel vaccines) may provide the necessary stimulation to broaden the repertoire of T cells engaged in the antitumor response. In support of this hypothesis, synergy of CTLA-4 and PD-1 inhibition with the whole tumor cell vaccines GVAX (autologous tumor þ GM-CSF), FVAX (autologous tumor þ Flt3 ligand), and TEGVAX (autologous tumor þ GM-CSF þ TLR4 and TLR 7/8 agonists) was demonstrated in the mouse B16 melanoma model (25,26). Both CTLA-4 and PD-1 inhibition also showed synergy with a novel material-engineered scaffold vaccine that codelivers autologous tumor lysate, GM-CSF, and the TLR-9 agonist CPG with precise spatial and temporal control (27).…”