Tumor and Vaccine Site With a Toll Like Receptor (TLR) Agonist

The Study Drug/Vaccines:

Resiquimod (R848) is designed to increase the production of antigen-specific T-cells, to
activate immune cells, and to increase T-cells going into the tumor, which may cause the
tumor cells to die.

gp100(g209-2M) and MAGE-3 are vaccines designed to stimulate immune cells, also called
T-cells, which may help the immune system to recognize and kill melanoma cells.

Study Groups:

If you are found to be eligible to take part in this study, and you have metastatic melanoma,
you will be assigned to Group 3. If you have had the melanoma removed and want to be treated
to try to keep it from coming back, you will be randomly assigned (as in the flip of a coin)
to Group 1 or 2.

- If you are in Group 1, you will receive the vaccines gp100(g209-2M) and MAGE-3 and R848
for 8 weeks. After 8 weeks, if you have melanoma lesions, you will apply R848 to half of
the lesions on your body for 16 weeks.

- If you are in Group 2, you will receive only the vaccines (gp100(g209-2M) and MAGE-3)
only for 8 weeks. After 8 weeks, if you have melanoma lesions, you will apply R848 to
half of the lesions on your body for 16 weeks.

- If you are in Group 3, you will receive the vaccines gp100(g209-2M) and MAGE-3 and R848
for 8 weeks. After 8 weeks, if you have melanoma lesions, you will apply R848 to half of
the lesions on your body for 16 weeks.

After 8 weeks, if you no longer have melanoma lesions, you will have completed the study
treatment.

Study Drug/Vaccine Administration:

Once a week for 8 weeks, you will receive the vaccines, gp100(g209-2M) and MAGE-3,
intradermally (through a needle into your skin) and subcutaneously (through a needle under
your skin) at 2 separate sites in separate extremities. Half of each dose will be given one
way, and half given the other way. These vaccines will also be given on the same day. You
will receive a total of 4 injections each week.

If you are in Group 1, every time you have the vaccine injection, R848 will be applied as a
gel over the gp100(g209-2M) injection site. The R848 gel will be allowed to air dry for 30
minutes and then covered with a gauze dressing which remain on overnight.

After 8 weeks, for participants with melanoma lesions, 2 times a week for 16 weeks, you will
apply the R848 gel to half of the lesions on your body. You will be given written
instructions and a "hands-on" demonstration on how to apply the gel. You will also be given a
worksheet to help you with applying the gel.

Study Visits:

One day after your first dose of vaccine (Day 2), you will have a punch biopsy of the vaccine
injection site to check your immune system. A punch biopsy is when a hollow instrument that
is used to remove a small coin-shaped sample of tissue.

At Week 2, the following tests and procedures will be performed:

- You will have a physical exam, including measurement of your vital signs and weight.

- Your performance status will be recorded.

- Blood (about 1 teaspoon) will be drawn for routine tests.

- Blood (about 4 tablespoons) will be drawn to study your immune response to the vaccine
combinations.

- You will have a punch biopsy of the injection site to check your immune system the day
after the vaccine is given.

Every 4 weeks, the following tests and procedures will be performed:

- You will have a physical exam, including measurement of your vital signs and weight.

- Your performance status will be recorded.

- Blood (about 1 teaspoon) will be drawn for routine tests.

- Blood (about 4 tablespoons) will be drawn to study your immune response to the vaccine
combinations.

Every 8 weeks, for participants with metastatic disease, the following tests and procedures
will be performed:

- You will have CT or PET/CT scans of the chest, abdomen, and pelvis to check the status
of the disease.

- The tumors will be measured and photographed. Your private areas will be covered (as
much as possible), and a picture of your face will not be taken unless there are tumors
on your face.

- If the doctor thinks it is necessary, the tumors will be measured by CT scan.

- If the doctor thinks it is needed, you will have an MRI/CT of the brain to check the
status of the disease.

The day after you first start the gel (Week 8), you will have 2 punch tumor biopsies to check
your immune system. One biopsy will be of a lesion with the R848 and one without, if it is
available. For participants without disease, the study will be completed and your follow-up
will be decided by your doctor.

At Week 0 (before vaccine is started), after treatment at Week 8 (+/- 1 week)., and Week 16
(+/- 1 week), white blood cells will be collected by leukapheresis to test for antibodies. If
you have the leukapheresis, blood (about 2 teaspoons) will be drawn as well. If you do not
have leukapheresis, blood (about 4 tablespoons) will be drawn instead.

The leukapheresis procedure is research-related and would not be performed as standard of
care if you were not on study. Blood for the leukapheresis will be taken through a needle in
a vein in one of your arms. A solution will be added to keep your blood from clotting while
it goes through the machine that collects and removes white blood cells from your blood. The
remaining blood is returned to you through a needle in a vein of your other arm. This is may
take up to 3-4 hours. Although several pints of blood will go through the machine, only about
1/2 a pint (1 cup) will be in the machine at any time. If you cannot have a needle in your
vein, this blood will be removed thorough a central venous catheter (CVC). A CVC is a sterile
flexible tube that will be placed into a large vein while you are under local anesthesia. You
will be given another informed consent document to sign, which describes the risks of the CVC
and the care involved.

Length of Study:

You will continue to receive treatment for up to 4 6 months, as long as you may benefit from
the study and are responding to the gel. You will be taken off study if the disease gets
worse or you experience any intolerable side effects. If you are in the group without
disease, you will not receive the study treatment.

Follow-Up:

All three groups will be called 1 time a month for 12 months after coming off the study drugs
to check on the status of the disease.

This is an investigational study. The study drugs/vaccines gp100(g209-2M), MAGE-3, and R848
are not FDA approved or commercially available. At this time, they are only being used in
research.

Up to 71 participants will take part in this study. All will be enrolled at MD Anderson.

Inclusion Criteria:

1. HLA-A*0201 positive (to enable immunization with the HLA class I restricted
gp100(g209-2M) peptide). Stage IIB or IIC patients will be enrolled after review and
approval by the PI. (a tool to determine the projected survival at 5 years, like, but
not limited to, the nomogram at www.melanomaprognosis.org. If the projected survival
is less than 50% at 5 years, then the patient is considered for enrollment. This is
with the recognition that the adjuvant, if effective offers a significant impact in
that group of stage II patients.)

2. Patients >/= 18 years old with histologically documented metastatic melanoma with a.
(Metastatic disease cohort) Measurable disease, stage IIIB, IIIC (in transit lesions
with or without nodal metastases) that includes lesions accessible for biopsies or IV
M1B b. (Adjuvant cohort) subjects who are NED and stage III or IV. This includes
patients with stage IV disease resected to NED. Stage IIB or IIC patients will be
enrolled after review and approval by the PI.

3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

4. At least 2 biopsiable easily accessible cutaneous and subcutaneous lesions in patients
in the metastatic disease cohort

5. White Blood Count (WBC) >/= 3000/mm^3 (part 1 & 2)

6. Platelet count >/= 90,000/mm^3 (part 1 & 2)

7. Serum alanine aminotransferase (ALT) and Aspartate Aminotransferase (AST) upper limit of normal (ULN) (part 1 & 2)

8. Total bilirubin a total bilirubin less than 3.0 mg/dl Total bilirubin with Gilbert's syndrome who must have a total bilirubin less than 3.0 mg/dl (part 1 &
2)

9. Seronegative for human immunodeficiency virus (HIV) antibody. (The experimental
treatment being evaluated in this protocol depends on an intact immune system.
Patients who are HIV seropositive can have decreased immune competence and thus may be
less responsive to the experimental treatment and more susceptible to its toxicities.)

10. Negative pregnancy test for women of childbearing potential (WOCBP) A WOCBP has not
undergone a hysterectomy or who has not been naturally postmenopausal for at least 12
consecutive months (i.e., who has had menses at any time in the preceding 12
consecutive months)

11. Patients of both gender must practice a barrier method of birth control while
participating in this trial.

Exclusion Criteria:

1. Active autoimmune disease requiring active therapy with any form of steroid or
immunosuppressive therapy or a documented history of any of the following:
inflammatory bowel disease; regional enteritis; systemic lupus erythematosis;
Sjogren's syndrome; inflammatory neurologic disorder such as multiple sclerosis; or
any immune mediated disease that can cause life-threatening symptoms or severe
organ/tissue damage in the opinion of the principle investigator.

2. Concurrent systemic or inhaled steroid therapy

3. Any form of active primary or secondary immunodeficiency

4. Prior malignancy except for the following: adequately treated basal cell or squamous
cell skin cancer, in-situ cervical cancer, thyroid cancer (except anaplastic) or any
cancer from which the patient has been disease-free for 2 years

5. History of immunization with gp100(g209-2M)

6. Active systemic infections requiring intravenous antibiotics

7. Women who are breastfeeding

8. Prior systemic therapy, radiation therapy or intracavitary surgery (intra-thoracic,
intra-abdominal or intracranial) within 28 days of starting study treatment.

9. Patients on chronic anticoagulation such as Aspirin, Plavix, or Coumadin who cannot
have anticoagulation held for procedures are not eligible due to the need for
leukapheresis