Bo-112 As A Modifier Of The Tumor Microenvironment For Liver Metastases.

Abstract Introduction: BO-112 is an analogue of double-stranded viral RNA which is an agonist of TLR3, RIG-1 and MDA5. It is currently in phase II clinical development, being administered intratumorally (IT), in combination with checkpoint inhibitors. It has been administered through different tumor locations, including liver metastases. Liver metastases constitute a challenging setting, with a proven negative impact on prognosis in those patients treated with immunotherapy independently of the tumor type but especially in those tumors considered as cold. Liver has a particular microenvironment, due to its continuous exposure to nonself-antigens. In order to deal with those antigens arising from the gut via the portal circulation, the liver must strike a balance between tolerating them and exhibiting some degree of antimicrobial effect. This microenvironment shows low level expression of antigen presenting cells, impaired to prime T cells. As a result, it is challenging to respond to exposed antigens, what may eventually prevent protective immune responses. A viral infection mimic induced by BO-112 results in upregulation of genes involved in T-cell homing and migration. This rationale provide support for the potential of IT BO-112 administration into liver metastases. Besides, PD-L1 induced upregulation in response to BO-112, suggests the need to combine treatment with an anti-PD-1/PD-L1 agent. Methods: BO-112 has been injected intratumorally into the liver in 16 patients so far at two different studies: a phase I trial (NCT02828098, which included initially patients with solid tumors being treated with BO-112 monotherapy and, through subsequent amendment, in combination with anti PD-1 drugs in patients having developed progressive disease on these therapies, being treated with BO-112 plus the same checkpoint inhibitor) and a phase II study (NCT04508140), which is including patients with liver metastases from colorectal (CRC) or gastroesophageal (GE) origin, receiving IT BO-112 plus pembrolizumab. A new phase II in patients with metastatic melanoma will start enrollment shortly and will also allow injection of liver metastases (NCT04570332). New unpublished data: Tumor biopsy results from phase 1 study (NCT02828098) showed increased expression of gene signatures for IFN, CD8 T-cell activation, CTL effector function and tumor inflammation. Changes in CD8 lymphocytes infiltration of the tumor microenvironment (TME) and PD-L1 expression in the injected liver metastases from CRC and GE tumors will be presented as part of an independent abstract sharing NCT04508140 preliminary results. Conclusions: Liver is a challenging organ to achieve clinical benefit in terms of response; however, with IT BO-112 being administered in liver metastases from different tumors, there is a change in the TME with an increase in key biomarkers, which may overcome primary or secondary resistance to systemic immunotherapy. Citation Format: Marisol Quintero, Vanesa Pons, Sonia Maciá, María Rojas, Javier Sánchez López, Desiree Kanters, Helena Escuin-Ordinas, Mark Branum, Juan M. Funes, Mercedes Pozuelo, Mike Doherty. BO-112 as a modifier of the tumor microenvironment for liver metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1790.