Summary

The majority of melanoma vaccines tested to date have been antigen-specific vaccines
targeting melanoma-specific or associated antigens and utilizing a variety of delivery
systems and immune-adjuvants. As opposed to testing an "off the shelf" vaccine that might
be able to treat a subset of patients, our approach has been personalized to the patient
and applicable to all patients. Our vaccine approach consists of harnessing the most
potent antigen presenting cell in the body - the dendritic cell (DC) - together with the
full repertoire of tumor antigens from an individual's cancer. We have conducted phase I
and II studies using an autologous DC-tumor cell fusion technique that has now been
simplified into a DC-tumor cell lysate vaccine. The autologous tumor lysate (TL) is
loaded into yeast cell wall particles (YCWP) that are naturally and efficiently taken up
into the patient's DC. These autologous tumor lysate, particle-loaded, DC (TLPLDC) are
injected intradermally (ID) monthly x 3 followed by boosters at 6, 12, and 18 months.

Objectives

Stage III and Stage IV (resected) melanoma patients will be identified prior to
definitive surgery and screened for inclusion/exclusion criteria. Eligible patients will
be counseled and consented for tissue procurement. Enrolled patients will have their
disease surgically resected and a portion 1mg minimum of their melanoma sterilely frozen
in provided freezing vials and storage tubes. This tissue will be shipped in liquid
nitrogen shippers through FedEx to our central facility in Greenville SC and stored
frozen until vaccine preparation. If patients cannot be rendered disease-free, they will
be considered screen failures for this study. If melanoma is being resected from multiple
locations primary and nodes two different metastatic sites then samples of each would be
preferred but not mandatory.

As indicated by SoC per the National Comprehensive Cancer Network (NCCN) guidelines and
determined by the treating team, if a patient is to receive systemic therapy
(chemotherapy or IFN-aguidelines) and determined by the treating team, if a patient is to
receive systemic therapy (chemotherapy or IFN-central facility in Greenville, SC) and
stored frozen until vaccine preparation. If patients cannot be rendered disease-free,
they will receive a single injection of Neupogen (G-CSF) 300 mod (or its equivalent) SQ
24-48 hrs. prior to having 70 mL of blood collected and sent to our central facility for
DC isolation and preparation. Patients who cannot tolerate Neupogen, or its equivalent 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 1-1.5 x
106 TLPLDC and will be labeled with the patient's unique study number.

Based on their randomization, autologous TLPLDC (active vaccine) or unloaded YCWP +
autologous DC (control) will be sent back to the site in a blinded fashion. Regardless of
assigned group, the site will receive 6 single dose vials to be injected intradermal
monthly x 3 followed by boosters at 6, 12, and 18 months in the same lymph node draining
area (preferably the anterior thigh). Patients must begin vaccinations between 3 weeks
and 3 months from completion of (SoC). Frozen tumor will be maintained for active
vaccines for all patients to include the control patients. The latter will be offered
their active vaccine at time of recurrence in a crossover fashion. Additionally, control
patients who do not recur will be offered active vaccine at the completion of the trial.

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.

Disease-free status will be monitored per SoC as outlined by NCCN. Suspected recurrences
will be documented with biopsy and pathologic confirmation. Time to recurrence will be
based on date of randomization to time of confirmed recurrence.

Recurrent patients will be offered participation in the open label portion of the study.
New active vaccine will be made for all patients, and they will be inoculated at 0, 1, 2,
3, 6, and 9 mos. Patients will be treated per SoC for their recurrence. Safety and tumor
response will be assessed per RECIST and irRC on their SoC follow-up scans.

Blood (50 mL) will be collected from all patients prior to each inoculation and at 24
months from enrollment for a total of 7 time points or a total of 350 mL of blood over 2
years. The collected blood will be sent to our central facility for immunologic testing
of the T-cell response.

Eligibility

1. 18 years or older
2. Eastern Cooperative Oncology Group (ECOG) performance status 0,1 (Appendix D)
3. AJCC stage III or IV completely resectable melanoma identified before surgery
4. Approximately 1 mg (1 cm3) of accessible and dispensable tumor that will not interfere with pathologic staging
5. Clinically disease-free after surgery
6. Completing SoC adjuvant therapy per NCCN guidelines to include chemotherapy, radiation therapy, and/or biologic therapy as clinically indicated. (Consent #2 should be signed as close to completion of SoC as possible but may overlap completion by up to one month.)
7. Vaccinations initiated between 3 weeks and 3 months from completion of SoC multi-modality cancer care
8. Adequate organ function as determined by the following laboratory values:
9. ANC = 1,000/µL
10. Platelets = 75,000/µL
11. Hgb = 9 g/dL
12. Creatinine = 1.5 x upper limit of normal (ULN) or Creatinine clearance = 50%
13. Total bilirubin = 1.5 ULN
14. ALT and AST = 1.5 ULN
15. 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)
16. Signed informed consent