Intratumor delivery of TLR4 agonist monophosphoryl lipid A and agonistic anti-CD40 in combination with anti-PD-1 (CMP) regressed treated and distant matched tumors in multiple bilateral murine tumor models. CMP activated CD11chi cells in tumors, which were later found in the draining lymph nodes (LNs). CMP boosted proliferation of both endogenous and adoptively transferred tumor antigen-specific CD8+ T cells and reduced exhausted CD8+ T cells in treated and distant tumors, but not in the spleen and LNs. Melanoma patients with pre-treatment tumor gene sets matching the CMP-induced signature had improved progression-free survival on nivolumab.
Contributed by Alex Najibi
Irreversible T cell exhaustion limits the efficacy of programmed cell death 1 (PD-1) blockade. We observed that dual CD40-TLR4 stimulation within a single tumor restored PD-1 sensitivity and that this regimen triggered a systemic tumor-specific CD8+ T cell response. This approach effectively treated established tumors in diverse syngeneic cancer models, and the systemic effect was dependent on the injected tumor, indicating that treated tumors were converted into necessary components of this therapy. Strikingly, this approach was associated with the absence of exhausted PD-1hi T cells in treated and distant tumors, while sparing the intervening draining lymph node and spleen. Furthermore, patients with transcription changes like those induced by this therapy experienced improved progression-free survival with anti-PD-1 treatment. Dual CD40-TLR4 activation within a single tumor is thus an approach for overcoming resistance to PD-1 blockade that is unique in its ability to cause the loss of exhausted T cells within tumors while sparing nonmalignant tissues.