In-Situ Vaccination Using Sting Agonists Combined with Immune-Modulating Antibodies to Treat Lymphoma

We have developed a therapeutic "in situ vaccination" strategy against lymphomas involving the intratumoral injection of a STING agonist. The advantage of this approach is that it does not require the isolation of tumor specific antigens since the STING agonist will prim the immune system at the tumor site, where it can utilize endogenous tumor antigens.

The Stimulator of Interferon Gene (STING) is part of the innate immunity involved in the intracellular pathogen recognition and it was shown to be a player in the spontaneous immune response against immunogenic tumors. Modified cyclic dinucleotides (CDNs), work as agonists for both mouse and human STING variants. These CDNs are able to induce an immune response by activating dendritic cells that then produce cytokines and chemokines including type 1 IFN. Moreover, when injected intratumorally, these CDNs were able to induce a tumor-specific CD8 T cell response in various tumor models. A Phase 1 clinical trial is evaluating the safety and the efficacy of intratumoral injection of CDNs in patients with advanced/metastatic solid tumors or lymphomas [NCT02675439].

We studied the efficacy of this STING agonist for in situ vaccination using a lymphoma tumor model. In this model, A20 lymphoma is injected into two different bilateral subcutaneous sites. The STING agonist is then injected in one tumor site, and then both tumor sites are monitored to assess the local and the systemic effects of the treatment. As a single agent, the STING agonist induced clearance of the treated tumor, and retarded growth of the distant tumor. We assumed that the failure to cure the second tumor was due to the dampening of the immune response by local immunosuppressive mechanisms. Therefore, we investigated the combination of the STING agonist with different immune-modulating agents.

Among the molecules that were screened, agonistic antibodies for GITR or CD40 showed the best efficacy when combined with STING in situ vaccination. GITR and CD40 are both part of the Tumor Necrosis Factor (TNF) receptor superfamily. Although, GITR is expressed on T cells while CD40 is expressed broadly on antigen-presenting cells (APC) including; macrophages, dendritic cells, and B cells. We studied the mechanisms of therapeutic effects of both combinations. Interestingly, we found that the therapeutic activities of both are dependent on the presence of CD8 T cells. Also, in both cases, CD8 T cells from treated animals were able to respond specifically to tumor cells in vitro. Furthermore, we demonstrated that activated T cells were present in the distant non-treated tumor sites.

Our results indicate that in situ stimulation of the immune system using STING combined with CD40 or GITR agonistic antibodies is a promising approach for the therapy of lymphoma.