Inclusion Criteria:  Histologically confirmed advanced metastatic melanoma Male or female participants who are at least 18 years of age on the day of signing informed consent Participants must be planned or scheduled by their treating physician to receive PD-1 therapy or PD-1 plus anti CTLA-4 therapy as standard of care Participant (or legally acceptable representative if applicable) provides written informed consent for the trial Participant must have at least 1 lesion that is at least 8 mm in size and is cutaneous, subcutaneous, palpable, or amenable to ultrasound guided core biopsy. The lesion chosen for biopsy can also be a target lesion but does not have to be a target lesion  Adequate organ function as defined below. Standard of care labs drawn within 45 days prior to consent may be used for the purposes of determining eligibility  ANC >/= 1500/uL platelets >/=100,000/uL Hemoglobin >/= 9.0 g/dL  Exclusion Criteria:  Uveal or mucosal melanoma Any women known to be pregnant or breastfeeding Any prior systemic therapy for metastatic melanoma (prior surgery is allowed) Known diagnosis of immunodeficiency or receiving chronic systemic steroid therapy (in doses exceeding 10 mg daily of prednisone or equivalent), or any other form of immunosuppressive therapy within 7 days prior to first research biopsy  Patients with symptomatic CNS metastases and/or carcinomatous meningitis  a) Patients with asymptomatic, stable CNS metastases are allowed provided that they are not on >10mg prednisone daily  History of or active (non-infectious) pneumonitis that required steroids Active infection requiring systemic therapy Known history of Human Immunodeficiency Virus (HIV) infection Known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. NOTE: no testing for Hepatitis B or Hepatitis C is required Known history of active TB (Bacillus Tuberculosis) History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with subject's participation for the full duration of the study, or make it not in the best interest of the subject to participate, in the opinion of the treating physician Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial History of allogenic tissue or solid organ transplant History of allergic reaction to IPOL or Td vaccine Receipt of Td vaccine within 30 days prior to starting IO therapy