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T-cell agonists in cancer immunotherapy.

ABSTRACT: Cancer cells can evade immune surveillance in the body. However, immune checkpoint inhibitors can interrupt this evasion and enhance the antitumor activity of T cells. Other mechanisms for promoting antitumor T-cell function are the targeting of costimulatory molecules expressed on the surface of T cells, such as 4-1BB, OX40, inducible T-cell costimulator and glucocorticoid-induced tumor necrosis factor receptor. In addition, CD40 targets the modulation of the activation of antigen-presenting cells, which ultimately leads to T-cell activation. Agonists of these costimulatory molecules have demonstrated promising results in preclinical and early-phase trials and are now being tested in ongoing clinical trials. In addition, researchers are conducting trials of combinations of such immune modulators with checkpoint blockade, radiotherapy and cytotoxic chemotherapeutic drugs in patients with advanced tumors. This review gives a comprehensive picture of the current knowledge of T-cell agonists based on their use in recent and ongoing clinical trials.

SUBMITTER: Choi Y

PROVIDER: S-EPMC7537335 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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T-cell agonists in cancer immunotherapy.

Choi Yeonjoo Y Shi Yaoyao Y Haymaker Cara L CL Naing Aung A Ciliberto Gennaro G Hajjar Joud J

Journal for immunotherapy of cancer 20201001 2

Cancer cells can evade immune surveillance in the body. However, immune checkpoint inhibitors can interrupt this evasion and enhance the antitumor activity of T cells. Other mechanisms for promoting antitumor T-cell function are the targeting of costimulatory molecules expressed on the surface of T cells, such as 4-1BB, OX40, inducible T-cell costimulator and glucocorticoid-induced tumor necrosis factor receptor. In addition, CD40 targets the modulation of the activation of antigen-presenting ce ...[more]

PMID: 33020242

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Project description:BackgroundToll-like receptor 9 agonists are potent activators of the immune system. Their clinical potential in immunotherapy against metastatic cancers is being evaluated across a number of clinical trials. TLR9 agonists are DNA-based molecules that contain several non-methylated CG-motifs for TLR9 recognition. Chemical modifications of DNA backbones are usually employed to prevent degradation by nucleases. These, however, can promote undesirable off-target effects and therapeutic restrictions.MethodsWithin the EnanDIM® family members of TLR9 agonists described here, D-deoxyribose nucleotides at the nuclease-accessible 3'-ends are replaced by nuclease-resistant L-deoxyribose nucleotides. EnanDIM® molecules with varying sequences were screened for their activation of human peripheral blood mononuclear cells based on secretion of IFN-alpha and IP-10 as well as activation of immune cells. Selected molecules were evaluated in mice in a maximum feasible dose study and for analysis of immune activation. The ability to modulate the tumor-microenvironment and anti-tumor responses after EnanDIM® administration was analyzed in syngeneic murine tumor models.ResultsThe presence of L-deoxyribose containing nucleotides at their 3'-ends is sufficient to prevent EnanDIM® molecules from nucleolytic degradation. EnanDIM® molecules show broad immune activation targeting specific components of both the innate and adaptive immune systems. Activation was strictly dependent on the presence of CG-motifs, known to be recognized by TLR9. The absence of off-target effects may enable a wide therapeutic window. This advantageous anti-tumoral immune profile also promotes increased T cell infiltration into CT26 colon carcinoma tumors, which translates into reduced tumor growth. EnanDIM® molecules also drove regression of multiple other murine syngeneic tumors including MC38 colon carcinoma, B16 melanoma, A20 lymphoma, and EMT-6 breast cancer. In A20 and EMT-6, EnanDIM® immunotherapy cured a majority of mice and established persistent anti-tumor immune memory as evidenced by the complete immunity of these mice to subsequent tumor re-challenge.ConclusionsIn summary, EnanDIM® comprise a novel family of TLR9 agonists that facilitate an efficacious activation of both innate and adaptive immunity. Their proven potential in onco-immunotherapy, as shown by cytotoxic activity, beneficial modulation of the tumor microenvironment, inhibition of tumor growth, and induction of long-lasting, tumor-specific memory, supports EnanDIM® molecules for further preclinical and clinical development.

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T-cell agonists in cancer immunotherapy.

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T-cell agonists in cancer immunotherapy.

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