Phase II Study of RP2 as Immunoprevention in High-Risk Oral Precancerous Disease

Inclusion Criteria: * Patients with a diagnosis of high-risk OPD defined by any of the following: * Proliferative leukoplakia (PL) * Localized leukoplakia showing at least moderate dysplasia not treated with surgery * Erythroplakia (regardless of dysplasia) * High-risk LOH profile: 9p21 or CDKN2A or MTAP loss; regardless of personal oral cancer history * Any degree of dysplasia with a known TP53 mutation * A history of treated stage 1 or 2 (AJCC 2017 8th edition) HNSCC with at least moderate dysplasia at the resection margins or known 9p21 loss or a known TP53 mutation * No evidence of head and neck cancer recurrence within the last 3 months (if applicable). * Willing to provide blood and tissue for diagnostic biopsies. * At least one target injectable measurable lesion ≥1 cm in longest diameter that can be followed. * Any smoking history is permitted. While discouraged, patients are permitted to continue tobacco use while on the study. * Age 18 years or older at the time of consent. * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2. * Participant must have normal marrow function and coagulation profile as defined within 21 days prior to study registration: * absolute neutrophil count ≥1,000/mcL * hemoglobin ≥9 g/dL * platelets ≥75,000/mcL, and (d) PT/INR \<2.5, and (e) aPTT \<1.5x ULN. * Women of childbearing potential (WOCBP) must agree to use appropriate method(s) of contraception. WOCBP and men should plan to use an adequate method to avoid pregnancy for 90 days after the last dose of RP2. WOCBP and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Serum or urine BhCG testing is required within 24 hours of initial RP2 dosing. Exclusion Criteria: * Prior treatment with an oncolytic virus therapy. * Systemic infection requiring intravenous (IV) antibiotics. * Requires chronic use of systemic (oral or IV) antivirals with known antiherpetic activity (e.g. acyclovir or valacyclovir). * Active significant herpetic infections or prior complications of HSV-1 infection (e.g., herpetic keratitis or encephalitis). Patients with sporadic cold sores may be enrolled provided they are asymptomatic at the time of starting RP2. * Known acute or chronic hepatitis B (defined as hepatitis B surface antigen \[HBsAg\] reactive) or acute or chronic hepatitis C virus (defined as HCV RNA \[qualitative\] is detected). Note: Patients who have been effectively treated are eligible for enrollment. Patients must be negative for HBsAg and HCV RNA. * Known human immunodeficiency virus (HIV) infection. Note: Testing for HIV is not required unless mandated by local health authority or clinically indicated. * A history of a prior stage III (T1-2N1, T3N0) or IV (T1-3N2, T4N0) invasive head \& neck squamous cell carcinoma treated with surgery and/or radiation with or without chemotherapy. * Patients cannot be on long-term (\>4 weeks) corticosteroids at doses exceeding prednisone 20 mg daily (or its equivalent) at the time of enrollment. * A personal history of hematopoietic stem cell (bone marrow) or solid organ transplant. * A personal history of other active malignancies, with exceptions including (but not limited to): non-melanomatous skin cancers, low-risk prostate adenocarcinoma on active surveillance, or treated cancers in remission for the last 2 years. * Significant bleeding event within the last 6 months that places the patient at risk for bleeding due to the injection procedure based on Investigator assessment.