Background: RP2 is a selective replication-competent herpes simplex virus 1 (HSV-1) that contains a codon-optimized sequence for human granulocyte-macrophage colony-stimulating factor (GM-CSF), the gibbon ape leukemia virus surface glycoprotein (GALV-GP) with the R- sequence deleted (R-), GM-CSF, and an anti–cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody-like molecule. These modifications are intended to increase oncolytic potency, cell-to-cell spread, tumor antigen release, and systemic anti-tumor immune activation. RP2 has demonstrated antitumor activity in preclinical models using viruses similar to RP2 expressing murine versions of anti-CTLA-4 and GM-CSF, both alone and in combination with PD1-1 blockade. Methods: This is a Phase 1 multicenter, open-label, study evaluating RP2 ± nivolumab (NCT04336241). Part 1 evaluated escalating doses of monotherapy RP2 with a modified 3 + 3 design. Patients (pts) received intratumoral (IT) injections of up to 10 mL of RP2 into superficial or visceral tumors Q2W x5 across two dose levels (DL1: 10⁵ plaque-forming units (PFU)/mL once, then followed by 10⁶ PFU/mL x4; DL 2: 10⁶ PFU/mL once, then followed by 10⁷ PFU/mL x4). The recommended Phase 2 dose of RP2 was identified as 10⁶ PFU/mL once, followed by subsequent doses of 1 × 10⁷ PFU/mL. In Part 2, up to 60 evaluable pts will be enrolled, including 30 pts in Cohort 2a and 30 in Cohort 2b. Cohort 2a was designed to evaluate the safety and antitumor activity of the combination in pts with solid tumors, and is fully enrolled. Cohort 2b is open for enrollment of pts with advanced or metastatic uveal melanoma, NSCLC, breast cancer, head and neck cancer or GI cancers (NSCLC, breast or GI cancers must have at least one liver tumor suitable for injection). Pts in Part 2 receive intra-tumoral RP2 at the RP2D Q2W for up to 8 doses in combination with 240 mg nivolumab IV Q2W or 480 mg nivolumab IV Q4W for up to two years from the first RP2 dose. In Part 3 (not yet open for enrollment), up to 15 evaluable pts are able to be enrolled to evaluate RP2 monotherapy including at least 10 pts with NSCLC, breast or GI cancers with at least one liver tumor suitable for injection. Reinitiation of up to 8 additional RP2 doses is permitted if prespecified criteria are met. Pts are dosed with RP2 by direct visualization or ultrasound-guided injection into superficial, subcutaneous, or nodal tumors and by image-guided injection into deeper lesions, including visceral lesions. Key inclusion criteria include histologically confirmed advanced or metastatic non-neurological solid tumors, at least one measurable and injectable tumor of diameter ≥1 cm, ECOG ≤1, and adequate hematologic, hepatic, and renal function. Exclusion criteria include prior treatment with oncolytic viruses, acute or chronic hepatitis B or C infection, and HIV infections. Clinical trial information: NCT04336241.