In situ vaccination with defined factors overcomes T cell exhaustion in distant tumors

Abstract

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-1 hi 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.

CD40 and CD80/86 signaling in cDC1s mediate effective neoantigen vaccination and generation of antigen-specific CX3CR1+ CD8+ T cells in mice

“…To examine the relationship between antitumor efficacy of neoantigen vaccination and the generation of neoantigen-specific CX3CR1+CD8+ T cells, we sought to validate a preclinical model of neoantigen vaccination using MC38 colon adenocarcinoma cells that harbor a singleepitope mutation within the Adpgk protein (Supplemental Figure 1) (18). In this model, to maximize the therapeutic efficacy of neoantigen vaccination with mutant Adpgk peptide (AdpgkMut), dual TLR/CD40 stimulation was used as vaccine adjuvants ( Figure 1A), which has been known to synergistically activate DCs, augment CD8+ T cell expansion, and mediate potent antitumor immunity in multiple preclinical models (19)(20)(21)(22). Vaccination of AdpgkMut, but not irrelevant AH1 peptide with agonistic anti-CD40 antibody (Ab), and TLR3 agonist, poly(I:C) (referred to as AdpgkMut/TLR3/CD40 hereafter) markedly delayed the growth of established MC38 tumors and improved survival ( Figure 1B).…”

Mechanisms of T-Cell Exhaustion in Pancreatic Cancer

“…Due to the exhaustion of antitumor T cells, the number of T cells interacting with tumor antigens is diminished, limiting the efficacy of PD-1 blockade [ 195 ]. In order to overcome T-cell exhaustion, intratumoral in situ injection using dual CD40-TLR4 stimulation was applied and exhausted Tc cells were eliminated in murine models with bilateral tumor approach to assess its efficacy both on the treated tumor and on the distant tumor which improved tumor control with the addition of PD-1 inhibitor [ 196 ]. Activation of the CD40 receptors by tumor cells is an important step for T-cell immunity.…”

Overcoming primary and acquired resistance to anti-PD-L1 therapy by induction and activation of tumor-residing cDC1s

“…A growing body of evidence shows that engagement of CD40 on DCs provides potent maturation and anti-apoptotic signals to DCs, augments priming of antigen-specific cytotoxic T lymphocytes (CTLs), induces interleukin 12 (IL-12) production for the development of T helper 1 (Th1) cells, and overcomes peripheral T cell tolerance 19 , 20 . Combined TLR/CD40 stimulation synergistically enhances CD8 + T cell expansion 21 , and mediates potent antitumor immunity in multiple syngeneic mouse models 22 – 24 .…”