Immunotherapy has dramatically improved outcomes for some cancer patients; however, novel treatments are needed for more patients to achieve a long-lasting response. FAP-targeted molecular radiotherapy has shown efficacy in both preclinical and clinical models and has immunomodulatory effects. Here, we studied if combined immunotherapy and radiotherapy could increase antitumor efficacy in murine models of lung cancer and melanoma and interrogated the mechanisms by which these treatments attenuate tumor growth. Using LLC1 and B16F10 murine models of lung cancer and melanoma, respectively, we tested the efficacy of 177Lu-FAPI-04 alone and in combination with immunotherapy. Alone, 177Lu-FAPI-04 significantly reduced tumor growth in both models. In animals with melanoma, combined therapy resulted in tumor regression while lung tumor growth was attenuated, but tumors did not regress. Combined therapy significantly increased caspase-3 and decreased Ki67 compared with immunotherapy alone. Flow cytometry demonstrated that tumor-associated macrophages responded in a tumor-dependent manner which was distinct in animals treated with both therapies compared with either therapy alone. These data demonstrate that 177Lu-FAPI-04 is an effective anticancer therapy for melanoma and lung cancer which mediates effects at least partially through induction of apoptosis and modulation of the immune response. Translational studies with immunotherapy and 177Lu-FAPI-04 are needed to demonstrate the clinical efficacy of this combined regimen.

The Columbia University image-guided therapeutics development pipeline is supported by the National Center for Advancing Translational Sciences (NCATS) UL1TR001873 (Reilly) through the ACCELERATE Resource.

Purpose: Bladder cancer represents 3% of all new cancer diagnoses per year. We propose intravesical radionuclide therapy using the β-emitter 90 Y linked to DOTA-biotin-avidin ([ 90 Y]DBA) to deliver short-range radiation against non-muscle invasive bladder cancer (NMIBC). Material and methods: Image-guided biodistribution of intravesical DBA was investigated in an animal model by radiolabeling DBA with the 68 Ga and dynamic microPET imaging following intravesical infusion of [ 68 Ga]DBA for up to 4 hours and post-necropsy γ-counting of organs. The antitumor activity of [ 90 Y]DBA was investigated using an orthotopic MB49 murine bladder cancer model. Mice were injected with luciferase-expressing MB49 cells and treated via intravesical administration with 9.2 MBq of [ 90 Y]DBA or unlabeled DBA 3 days after the tumor implantation. Bioluminescence imaging was conducted after tumor implantation to monitor the bladder tumor growth. In addition, we investigated the effects of [ 90 Y]DBA radiation on urothelial histology with immunohistochemistry analysis of bladder morphology. Results: Our results demonstrated that DBA is contained in the bladder for up to 4 hours after intravesical infusion. A single dose of [ 90 Y]DBA radiation treatment significantly reduced growth of MB49 bladder carcinoma. Attaching 90 Y to the DOTA-avidin prevents its re-absorption into the blood and distribution throughout the rest of the body. Furthermore, immunohistochemistry demonstrated that [ 90 Y]DBA radiation treatment did not irreversibly damage the bladder urothelium, which appeared similar to the normal urothelium of healthy mice. Conclusion: Our data demonstrates the potential of intravesical [ 90 Y]DBA as a treatment for non-muscle invasive bladder cancer.