The purpose of this arm of the study is to find the best way to give patients this investigational product and determine if it can treat advanced melanoma by stimulating the immune system. PV-001-DV is an attenuated (weakened) strain of dengue virus developed as a potential preventative vaccine for dengue fever by the US Army as Dengue Virus-1 #45AZ5. This is the first time PV-001-DV will be given to patients with melanoma. Up to 4 dose levels of PV-001-DV will tested in this arm. PV-001-DV (at the lowest dose) will be given to a group of 3 people. As each dose level is found to be safe, it will be given to another other 3 people at the next higher dose level, for a total of up to 10 people in this study. Investigators will monitor patients carefully for any harmful side effects. The side effects in people cannot be completely known ahead of time.

Patients must be progressing after having completed prior therapy with a PD-1 / PD-L1 antagonist alone or in combination with anti-CTLA-4. If the patient is positive for BRAF, the patient must have progressed on at least one BRAF inhibitor in addition to a PD-1 / PD-L1 inhibitor alone or in combination with CTLA-4 for metastatic melanoma.

Patients will have a prescribed amount of PV-001-DV injected into one of their melanoma tumors. Scans will be performed during the study at different times to see if their tumors have changed in size. Patients will also have their blood and small samples of tumors tested for changes to the immune system. After 365 days, the trial will be completed for that patient.

Inclusion Criteria:

1. Biopsy confirmed patients with un-resectable American Joint Committee on Cancer Stage III or IV melanoma who have measurable disease. Measurable disease is required, and is defined as tumor can be measured in one dimension along the longest diameter
2. Patients must have tumors that are not responsive having completed prior therapy with a Progressive Death-1/Progressive Death Ligand-1 (PD-1 / PD-L1), antagonist alone or in combination with anti-Cytotoxic T Lymphocyte Antigen-4 (CTLA-4). If the patient is positive for BRAF mutation, the patient must have progressed on at least one BRAF inhibitor in addition to a PD-1 / PD-L1 inhibitor alone or in combination with CTLA-4 for metastatic melanoma
3. Patients must be progressing after having completed one standard of care therapy for metastatic melanoma
4. Tumor specimens must be available for tumor lysates and immunological studies.
5. Tumors must be available for intratumoral injection of dengue virus. This includes cutaneous and subcutaneous lesions with ultrasound-guided injection.
6. Eastern Cooperative Oncology Group Performance Status of ≤ 2 (corresponds to a Karnofsky Performance Status (KPS) of ≥ 70).
7. Patients must be 18 years or older and able to give informed consent.
8. Adequate bone marrow function of White Blood Cell (WBC) count to ≥ 1,500/microliter (uL); platelet count ≥ 100,000/mm3; absolute neutrophil count (ANC) > 1,500/mm3
9. Patients must have adequate renal function by serum creatinine of ≤ 2.0 milligrams/decaliter (mg/dL).
10. Adequate hepatic function of bilirubin ≤ 2.5 mg/dL; Serum Glutamic Oxaloacetate Transaminase/Serum Glutamic Pyruvate Transaminase (SGOT/SGPT < 3× upper limit of normal (ULN).
11. Patients must have the required wash out periods from prior therapy:
12. Topical therapy: 2 weeks.
13. Chemotherapy and radiotherapy: 4 weeks.
14. Other investigational therapy: 4 weeks
15. Patients of reproductive potential and their partners must agree to use an effective (>95% reliability) form of contraception during the study and for 4 weeks following the last study drug. Patients who become pregnant during the course of the study will be withdrawn from the trial.
16. Women of reproductive potential must have a negative urine pregnancy test.
17. Patients should have a life expectancy of > 4 months.
18. Patient should be able to comply with the treatment schedule and have the ability to understand and the willingness to sign the informed consent document.
19. Patients with manageable central nervous system metastases may be selected to this trial. Central Nervous System (CNS) metastasis patients are eligible if the CNS metastases have had no progression for at least 4 weeks (as defined by Magnetic Resonance Imaging/Computerized Tomography (MRI /CT).

Exclusion Criteria:

1. Patients with positive antibody (Ab), to any Dengue Virus serotype by tetravalent Enzyme Linked Immunosorbent Assay (ELISA).
2. Patients with prior vaccinations or positive Ab detected by ELISA to: West Nile, St. Louis Encephalitis, or Yellow Fever
3. Pre-existing autoimmune or antibody mediated disease including systemic lupus erythematous, rheumatoid arthritis, multiple sclerosis, Sjogren's syndrome, autoimmune thrombocytopenia, but excluding controlled thyroid disease, or the presence of autoantibodies without clinical autoimmune disease.
4. Known history of human immunodeficiency virus (HIV) or any active immunosuppressive systemic infection or a suppressed immune system, including acquired immuno-deficiency syndrome (AIDS) or HIV positivity and known hepatitis infections C or B (HCV or HBC), as assessed by serology.
5. Patients on immunosuppressive therapy. Concurrent steroid use of not more than an equivalent of 10 mg of prednisone is allowed.
6. Any other open wounds.
7. Previous organ transplantation.
8. Patients with clinically significant dermatological disorders, as judged by the clinical investigator (e.g., eczema or psoriasis), any skin lesions or ulcers, any history of atopic dermatitis, or any history of Darier's disease (Keratosis Follicularis).
9. Patients with White Blood Cell count <1,500/uL; platelet count <100,000/mm3; absolute neutrophil count (ANC) 1,500/mm3 (Grade 2)
10. Patients with inadequate renal function by serum creatinine of >1.5 x ULN (Grade 2)
11. Patients with inadequate liver function by SGPT/SGOT > 3x ULN, and bilirubin >2.5 mg/dl (Grade 2)
12. Patients with active infection or with a fever >101°F (38.5°C) within 3 days prior to the first scheduled treatment.
13. Concurrent participation in other treatment related clinical studies. Non-treatment studies (e.g. observation or tumor cell analysis studies) are allowed.
14. Prior malignancy (active within 3 years of screening) except basal cell or completely excised non-invasive squamous cell carcinoma of the skin, or in situ squamous cell carcinoma of the cervix.
15. Significant cardiovascular disease (i.e., New York Heart Association (NYHA) class 3 congestive heart failure; myocardial infarction within the past 6 months; unstable angina; coronary angioplasty within the past 6 months; uncontrolled atrial or ventricular cardiac arrhythmias).
16. Female patients who are pregnant or lactating.
17. Patients taken off Checkpoint Blockade agents: Ipilimumab, Nivolumab, Pembrolizumab, for Grade 3 or greater autoimmune toxicity.
18. Patients who are positive for B-RafV600 mutation and are responding to targeted therapy.
19. Any other medical history, including laboratory results, deemed by the investigator to be likely to interfere with his/her participation in the study, or to interfere with the interpretation of the results.
20. Patients with endocrinopathy greater than grade III.
21. Patients who have undergone a splenectomy in their previous medical history will be excluded from this trial. Evidence of a splenectomy will be from history or records.
22. Prior history or serologic evidence of other flavivirus infections (yellow fever, St. Louis encephalitis, West Nile virus)
23. Prior history of having received a flavivirus vaccine
24. Patients who are actively taking Non-steroidal anti-inflammatory drugs (NSAIDs including aspirin