Intratumoral OX40/CpG Potentiates Immunologic Tumor Elimination of Breast Cancer–Origin Diffuse Liver Metastases

Purpose: Depending on the origin of the primary lesion, patients with distant metastases of aggressive solid tumors have traditionally been deemed incurable. A complete abscopal effect, or cure, is a rare exception rather than the rule. This is secondary to cancer stem cells providing resilience to treatment and the propensity to recur after remission. Harnessing the potential of the immune system to recognize and destroy malignant cells harboring tumor antigens may allow stage 4 cancer to be completely eliminated from the body. This report describes a case of diffuse liver metastases from advanced breast cancer that was eliminated immunologically by intratumoral injection of immunostimulatory pharmacotherapy. -OX40 is a stimulatory monoclonal antibody with a dual mechanism of action on T cells designed to potentiate longterm immunity. Activating the OX40 protein triggers a sustained immune response in effector T cells while also potentiating the demise of regulatory T cells. Intratumoral -OX40 was shown to work synergistically with intratumoral CpG, a Toll-like receptor 9 agonist, in a mouse model of breast cancer. To our knowledge, this is the first report of an -OX40 antibody administered intratumorally, in vivo, in a human patient.

Materials and Methods: Two liver metastases were treated with combination immunotherapy suspended in Montanide, an oil adjuvant. A combination of -OX40, CpG, ipilimumab, and ketorolac was injected into two accessible, dominant hepatic lesions under computed tomography (CT) guidance with general anesthesia. A CT scan was performed 6 weeks postprocedure, and positron emission tomography (PET)/CT was performed 12 weeks postprocedure. Tumor markers CA125, CA27.29, and CA15.3 were monitored weekly for 12 weeks posttreatment. Results: No suspicious uptake was noted anywhere in the body on the 12-week postprocedure PET/CT. Complete abrogation of all diffuse liver metastases was documented at that time. At 12 weeks posttreatment, tumor marker CA125 decreased by 98% to 35 U/mL from a baseline of 1767 U/mL, CA27.29 decreased 93% to 112 U/ mL from a baseline of 1511 U/mL, and CA15.3 decreased 93% to 56 U/mL from a baseline of 821 U/mL.

Conclusions: Intratumoral injection allows a much higher proportion of immunotherapy to directly interact with the tumor microenvironment compared with intravenous injection. With intratumoral dosing of multimodal immunotherapy an order of magnitude less than intravenous dosing, a patient with stage 4 breast cancer was able to achieve complete immunologic tumor elimination at 12 weeks’ follow-up. This durable abscopal effect remains complete at 20 weeks posttreatment.