Enhancing immunotherapy of STING agonist for lymphoma in preclinical models

Adrienne Sallets, Sophie Robinson, Adel Kardosh, Ronald Levy

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Direct activation of tumor infiltrating antigen-presenting cells (APCs) by intratumoral injection of STING agonists (STINGa) leads to regression of the treated lymphoma tumor. Because STING activation induces apoptosis in lymphoma cells in vitro, we distinguished between the direct therapeutic vs the indirect immunotherapeutic properties of STINGa in vivo. Employing wild-type or STING knockout hosts bearing either wild-type or STING knockout tumor cells, we demonstrated that local tumor regression is totally dependent on STING expression by the host and is therefore immune mediated. However, distant untreated tumors are weakly affected after injection of STINGa to a single tumor site. Therefore, using the STINGa currently being tested in clinical trials, wescreened for immunomodulatory agents that could synergize with the STING pathway to induce a systemic antitumor immune response and regression of distant tumors. We combined the STINGa with agents that improve APC or T-cell function. We found that modulation of both APCs and T cells can enhance control of distant lymphoma tumors by STINGa. In particular, adding an anti-GITR antibody induced lymphocyte expansion in the lymph node draining the treated site followed by increased T-cell infiltration in the distant tumor. Furthermore, more of these CD8 T cells at the distant site expressed PD-1. Therefore, blockade of PD-1 further enhanced tumor control at the distant site, leading to cure in 50% of the mice. These preclinical data provide the rationale for testing local injection of STINGa followed by agonistic anti-GITR and anti-PD-1 antibodies as immunotherapy for human lymphoma.

Original languageEnglish (US)
Pages (from-to)2230-2241
Number of pages12
JournalBlood Advances
Volume2
Issue number17
DOIs
StatePublished - Sep 11 2018

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Immunotherapy
Lymphoma
Neoplasms
Antigen-Presenting Cells
T-Lymphocytes
Injections
Neoplasm Antigens
Anti-Idiotypic Antibodies
Lymph Nodes
Clinical Trials
Lymphocytes
Apoptosis
Antibodies

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Enhancing immunotherapy of STING agonist for lymphoma in preclinical models. / Sallets, Adrienne; Robinson, Sophie; Kardosh, Adel; Levy, Ronald.

In: Blood Advances, Vol. 2, No. 17, 11.09.2018, p. 2230-2241.

Research output: Contribution to journalArticle

Sallets, Adrienne ; Robinson, Sophie ; Kardosh, Adel ; Levy, Ronald. / Enhancing immunotherapy of STING agonist for lymphoma in preclinical models. In: Blood Advances. 2018 ; Vol. 2, No. 17. pp. 2230-2241.
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