Multi-center Phase I/IIa Trial of an Autologous Tumor Lysate (TL) + Yeast Cell Wall Particles (YCWP) + Dendritic Cells (DC) Vaccine in Addition to Standard of Care Checkpoint Inhibitor of Choice in Metastatic Melanoma Patients With Measurable Disease.

Metastatic melanoma patients eligible for (or currently on) CPI therapy per SoC will be
identified and screened for inclusion/exclusion criteria. Eligible patients will be counseled
and consented for tissue procurement. They will undergo excisional or core needle biopsy as
clinically indicated and this tissue will be shipped in liquid nitrogen shippers through
FedEx to our central facility in Greenville, SC.The tumor will be stored frozen until vaccine
preparation. Vaccine development requires 48 hours for preparation. Upon verification that
adequate tissue was obtained, these patients will then be counseled and consented for
participation in the trial.

The patients who qualify for participation in this trial will continue their treatment of
CPI. Once consented, patients will receive a single injection of Neupogen (G-CSF) 300 μg SQ
24-48 hrs prior to having 70 mL of blood collected and sent to our central facility for DC
isolation and preparation. Those who cannot tolerate Neupogen or refuse it will have 120 mL
of blood drawn and sent. Additional blood may be drawn if additional vaccine doses need to be
made or re-made for any reason. Vaccines will be prepared by producing TL through freeze/thaw
cycling and then loaded into pre-prepared YCWP. The TL-loaded YCWP will be introduced to the
DC for phagocytosis thus creating the TLPLDC vaccine, which will be frozen in single dose
vials. Each vial will contain 1 x 106 TLPLDC and will be labeled with the patient's unique
study number.

The frozen autologous TLPLDC will be sent back to the site with a total of 6 single dose
vials after the vaccine has completed QA/QC testing and lot-release (usually 3 weeks). The
primary vaccination series will include monthly inoculations at 0, 1, 2, 3 months followed by
boosters at 6 and 9 months in the same lymph node draining area (preferably the anterior
thigh). Once received, the first inoculation should occur within 4 weeks.

Safety data will be collected on local and systemic toxicities and graded and reported per
the Common Terminology Criteria for Adverse Events (CTCAE) v4.03.

Patients will follow-up at their respective sites for evaluation of metastatic disease per
SoC. They will under imaging, CT/PET-CT, to meet Response Evaluation Criteria in Solid Tumors
(RECIST) criteria version 1.1 and iRECIST to monitor disease.

Blood (50 mL) will be collected from all patients prior to each inoculation and at 12 months
from enrollment for a total of 7 time points or a total of 350 mL of blood over 1 year. The
collected blood will be sent to our central facility for immunologic testing of T-cell
responses.

Inclusion Criteria:

- 18 years or older

- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Appendix A)

- Metastatic melanoma eligible for {or currently on} standard of care CPI therapy
(treating physician's choice) with measurable disease.

- Approximately 1 cm3 preferred but 1 mg minimum of accessible and dispensable tumor
(minimum of 3 passes with a core needle)

- Able to tolerate CPI treatment regimen {if already started}

- Adequate organ function as determined by the following laboratory values:

- ANC ≥ 1,000/μL

- Platelets ≥ 75,000/μL

- Hgb ≥ 9 g/dL

- Creatinine ≤ 1.5 x upper limit of normal (ULN) or Creatinine clearance ≥ 50% of lower
limit of normal (LLN)

- Total bilirubin ≤ 1.5 ULN

- ALT and AST ≤ 1.5 ULN

- For women of child-bearing potential, agreement to use adequate birth control
(abstinence, hysterectomy, bilateral oophorectomy, bilateral tubal ligation, oral
contraception, IUD, or use of condoms or diaphragms)

Exclusion Criteria:

- Inability to tolerate CPI therapy {if already started}

- Rapidly progressing multi-focal metastatic melanoma

- Insufficient tumor available to produce vaccine

- ECOG >2 performance status (Appendix A)

- Immune deficiency disease or known history of HIV, HBV, HCV

- Receiving immunosuppressive therapy including chronic steroids (except physiologic
maintenance doses), methotrexate, or other known immunosuppressive agents

- Pregnancy (assessed by urine HCG)

- Breast feeding

- Active pulmonary disease requiring medication to include multiple inhalers (>2
inhalers and one containing steroids)

- Involved in other experimental protocols (except with permission of the other study
PI)