The goal of this clinical trial is to learn if DOC1021 + pIFN will be safe and will lead to tumor responses in patients with refractory melanoma. DOC1021 is a dendritic cell immunotherapy derived from a patient's own blood cells and loaded with antigens from the patient's tumor in the form of tumor lysate and mRNA. The goal is to stimulate a T cell immune response that eliminates tumor cells.

The study consists of two components: an initial phase I safety study to confirm safety/tolerability of the treatment regimen, and, subsequently, a single-arm phase II cohort to assess efficacy of the treatment regimen.

All participants will:

• Take filgrastim subcutaneously x 5 doses and subsequently undergo a leukapheresis collection
• Receive two doses of DOC1021 under image guidance 2 weeks apart
• Receive subcutaneous pIFN injections weekly for a total of 4 doses in parallel with the DOC1021 injections
• Undergo an optional image-guided perinodal DOC1021 booster injection approximately 6 months after the first DOC1021 dose along with additional subcutaneous pIFN injections at time of the booster and the subsequent week for a total of 2 pIFN doses
• Visit the clinic regularly to assess quality of life, symptoms, medication use, imaging, bloodwork, and to receive optional treatment with anti-PD1 agents

Inclusion Criteria:

1. Provision of signed and dated informed consent form

2. Stated willingness to comply with all study procedures and avail-ability for the duration of the study

3. Age 18 years or older

4. Patients diagnosed with unresectable or metastatic melanoma and progressed following ≥1 prior systemic therapy including anti-PD-1 (i.e., refractory to anti-PD-1). Refractory defined as primary or secondary resistance as per SITC guidelines, except that confirmatory scan not required if clinical progression requiring surgery or radiation to relieve symptoms

5. Willing and able to withhold anti-PD-1 treatment from the time of enrollment through ~6 weeks after the first DOC1021 administration

6. One or more lesions available for biopsy or resection to yield at least 50 mg (e.g., 5 core biopsies) and preferably 100 mg of tumor for generating DOC1021 and at least 1 measurable target tumor lesion evaluable after DOC1021 by RECIST version 1.1.

7. Brain metastases allowed if stable after prior treatment

8. Ability to receive filgrastim (e.g. Neupogen), leukapheresis and perinodal injections of DOC1021 near regional nodes + weekly pIFN x 4 weeks.

9. Females of reproductive potential must have a negative serum pregnancy test and agree to use effective contraception (as deter-mined appropriate for the patient by the investigator) during study treatment.

10. Adequate kidney, liver, bone marrow function, and immune function, as follows:

    1. Hemoglobin ≥ 8.0 gm/dL (use of transfusion or other intervention to achieve is acceptable)
    2. Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3
    3. Platelet count ≥ 75,000/mm3
    4. Calculated creatinine clearance (CrCl) > 30 mL/min using Cockcroft and Gault formula:

    i. For males = (140 - age[years]) x (body weight [kg]) / (72 x serum creatinine [mg/dL]) ii. For females = 0.85 x value from male formula e. Total bilirubin ≤ 1.5 times upper limit of normal (ULN) except in patients with Gilbert's disease for which total bilirubin must be ≤ 3 times ULN f. Aspartate transaminase AST (SGOT) and alanine aminotransferase ALT (SGPT) ≤ 3 times the ULN (or ≤ 5.0 × ULN if liver metastases)

11. Eastern Cooperative Group (ECOG) Performance Score 0 or 1

Exclusion Criteria:

1. Patients who are pregnant or breastfeeding.
2. Known active HIV or hepatitis infection. Patients with HIV that is well-controlled and have undetectable viral titers remain eligible. Patients with history of HCV adequately treated such that RNA viral load is negative also remain eligible.
3. Any severe or uncontrolled medical condition or other condition that could affect participation in this study as determined by the investigator, including but not limited to uncontrolled or severe cardiac dis-ease, systemic autoimmune disorders requiring immunosuppression*, autoimmune hyper/hypothyroidism, untreated viral hepatitis, autoimmune hepatitis (*autoimmune disorders include but are not limited to rheumatoid arthritis, psoriasis and inflammatory bowel disease and immunosuppressive medications include DMARDs like methotrexate, TNF inhibitors, IL-6 receptor blockers, CD80/86 inhibitors, anti-CD20 and JAK inhibitors)
4. Residual immune-related toxicities from prior immunotherapy > Grade 1 severity. However, patients who experienced prior endocrine toxicity are eligible if well-controlled on replacement therapy.
5. Treatment with another investigational drug or other experimental intervention within the last 30 days.