• The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.

• Be \> or equal to 18 years of age on day of signing informed consent.

• Participant with histologically or cytologically confirmed diagnosis of unresectable metastatic melanoma at stage III B, C, D or IV M1a (AJCC 8th ed.). Patients with Stage IVM1b, M1c and M1d oligometastatic disease \[up to 10 lesions in aggregate including lung, liver, bone or brain, with or without lymph node involvement\], are eligible. However, patients with symptomatic or rapidly enlarging/bleeding brain lesions are excluded. Patients with acral lentiginous melanoma are eligible as well. Detailed information about prior therapies and burden of disease at study entry must be available.

• Patients must have confirmed primary resistance to or acquired resistance on treatment with an anti-PD1/L1 monoclonal antibody (mAb) administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies. PD-1 treatment progression is defined by meeting all of the following criteria: a.) Has received at least 2 doses of an approved anti-PD-1/L1 mAb.

• b.) Has demonstrated disease progression (PD) after PD-1/L1 as defined by RECIST v1.1. The initial evidence of PD is to be confirmed by a second assessment no less than four weeks from the date of the first documented PD, in the absence of rapid clinical progression. c.) Progressive disease has been documented within 12 weeks from the last dose of anti- PD-1/L1 mAb.

• i. Progressive disease is determined according to iRECIST. ii. This determination is made by the investigator. Once PD is confirmed, the initial date of PD documentation will be considered the date of disease progression.

• Patients harboring the BRAF mutation who received BRAF/MEK inhibition (or declined BRAF/MEK inhibitors) and received thereafter anti-PD1 therapy showing resistance to such immunotherapy are eligible to the study. Anti-PD1 immunotherapy must be the last therapy received by the patient prior to randomization.

• Eligible subjects must have measurable disease (according to RECIST v1.1) as assessed by the local site investigator/radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. Eligible subjects must be a candidate for intralesional therapy with at least one injectable cutaneous, subcutaneous, or nodal metastatic melanoma lesion (≥ 5 mm in longest diameter) or with multiple injectable lesions that in aggregate have a diameter of ≥ 5 mm.

• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: a.) Not a woman of childbearing potential (WOCBP) b.) A WOCBP who agrees to follow contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment. WOCBP must be using for the time period indicated highly effective contraception methods. WOCBP and effective contraception methods are defined by the Recommendations for contraception and pregnancy testing in clinical trials issued by the Head of Medicine Agencies' Clinical Trial Facilitation Group and which include, for instance, progesterone-only or combined (estrogen- and progesterone-containing) hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion, vasectomized partner or sexual abstinence. Pregnancy test will be repeated at the safety visit (only WOCBP).

• Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.

• Note: If submitting unstained cut slides, newly cut slides should be submitted to the testing laboratory within 14 days from the date slides are cut (details pertaining to tumor tissue submission can be found in the Procedures Manual).

• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

⁃ Have adequate organ function as defined in the following table. Specimens must be collected within 14 days prior to the start of study treatment.

⁃ Be able to provide a core or excisional lymph node biopsy for biomarker analysis from an archival or newly obtained biopsy at Screening. In addition, participants may provide additional biopsy at Week 18 and at the time of discontinuation due to progression

⁃ Documented negative test for HIV, HBV and HCV. For HBV serology, the determination of HBsAg and anti-HBcAg Ab is required. In patients with serology documenting previous exposure to HBV (e.g. anti-HBsAg and/or anti-HBc Ab) a negative serum HBV-DNA test is also required.

⁃ All acute toxic effects (excluding alopecia and vitiligo) of any prior therapy must have resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v. 5.0) Grade ≤ 1 or baseline unless otherwise specified above. Note: Participants with ≤Grade β neuropathy may be eligible. Participants with endocrinerelated AEs Grade ≤β requiring treatment or hormone replacement may be eligible. Note: If the participant had major surgery, the participant must have recovered adequately from the procedure and/or any complications from the surgery prior to starting study intervention.

⁃ Full resolution of checkpoint blockade therapy-related adverse effects (including immunerelated adverse effects) and no treatment for these AEs for at least 4 weeks prior to the time of enrollment.

⁃ No history of severe immune related adverse effects from prior given immune checkpoint blockade therapy (CTCAE Grade 4; CTCAE Grade 3 requiring treatment \>4 weeks).

⁃ Male patients with WOCBP partners must agree to use simultaneously two acceptable methods of contraception (i.e. spermicidal gel plus condom) from the screening to three months following the last study drug administration. In addition, male participant must refrain from sperm donation during the treatment period.

⁃ Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.