Immunotherapy Study for Patients With Stage IV Melanoma

According to statistics of the American Cancer Society, an estimated 73,800 individuals will
be diagnosed with melanoma and 9,900 will die of the disease in 2015 in the Unites States
despite current therapy. This protocol attempts to exploit an approach to melanoma
immunotherapy using a naturally occurring barrier to xenotransplantation in humans to
increase the effectiveness of immunizing patients against their melanoma. The expression of
the murine (1,3)galactosyltransferase [alpha(1,3)GT] gene results in the cell surface
expression of (1,3)galactosyl-epitopes (alpha-gal) on membrane glycoproteins and
glycolipids. These epitopes are the major target of the hyperacute rejection response that
occurs when organs are transplanted from non-primate donor species into man. Human hosts
often have pre-existing anti-alpha-gal antibodies that bind alpha-gal epitopes and lead to
rapid activation of complement and cell lysis. The pre-existing anti-alpha-gal antibodies
found in most individuals are thought to be due to exposure to alpha-gal epitopes that are
naturally expressed on normal gut flora leading to chronic immunological stimulation.

These antibodies may comprise up to 1% of serum IgG. In this phase 2b study, patients with
advanced stage melanoma will receive immune checkpoint inhibition consisting of ipilimumab,
nivolumab, or pembrolizumab per the treating physician's standard of care. In addition to
the immune checkpoint therapy, half of the patients will also receive dorgenmeltucel-L.
Dorgenmeltucel-L is composed of irradiated allogeneic melanoma cell lines (HAM-1, HAM-2 and
HAM-3). These cell lines have been transduced with a recombinant Moloney murine leukemia
virus (MoMLV)-based retroviral vector expressing the murine (1,3)GT gene. Endpoints of the
study include safety assessments, efficacy, and immunological responses.

Inclusion Criteria:

- Histological/cytological diagnosis of melanoma. AJCC stage IV (any T, any N, M1),
metastatic, progressive, refractory, melanoma.

- Patients may have advanced unresectable stage IV disease, resectable stave IV disease
or recently resected stage IV disease (<10 weeks prior) with no apparent disease.

- Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1.

- Serum albumin ≥3.0 gm/dL.

- Adequate organ function including:

- A. Marrow: Hemoglobin ≥10.0 gm/dL, absolute granulocyte count (AGC) ≥1,000/mm3,
platelets ≥75,000/mm3, absolute lymphocyte count ≥475/mm3.

- B. Hepatic: Serum total bilirubin ≤2.5 x upper limit of normal (ULN), ALT (SGPT)
and AST (SGOT) ≤2.5 x ULN.

- C. Renal: Serum creatinine (sCr) ≤ 1.5 x upper limit of normal.

- Prior therapy for melanoma that may include surgery, radiation therapy, immunotherapy
including interleukins and interferon, and/or ≤2 different regiments of systemic
chemotherapy, targeted therapy, or other experimental systemic therapies. Prior
treatment with immune checkpoint inhibitors is not allowed.

- Patients must be ≥4 weeks since major surgery, radiotherapy, chemotherapy (6 weeks if
they were treated with nitrosureas) or biotherapy/targeted therapies.

- Patients must have the ability to understand the study, its risks, side effects,
potential benefits and be able to give written informed consent to participate.
Patients may not be consented by a durable power of attorney (DPA).

- Male and female subjects of child producing potential must agree to use contraception
or avoidance of pregnancy measures while enrolled on study and receiving the
experimental drug, and for one month after the last immunization.

Exclusion Criteria:

- Age <18-years-old.

- Active CNS metastases or carcinomatous meningitis. Patients with CNS lesions that
have been treated and who have no evidence of progression in the brain on CT/MRI for

≥1 month are eligible. Pregnant or nursing women due to the unknown effects of
immunization on the developing fetus or newborn infant.

- Other malignancy within five years, except the following may be eligible:

- patients curatively treated for localized squamous or basal cell carcinoma of
the skin or for carcinoma in situ of the uterine cervix (CIN) or breast,

- patients with a history of malignant tumor who have been disease free for at
least five years and are not currently being treated.

- History of an allogeneic solid organ transplant or bone marrow transplant, or current
active immunosuppressive therapy such as cyclosporine, tacrolimus, etc.

- Subjects taking systemic (parentally or orally) corticosteroid therapy for any
reason, including replacement therapy for hypoadrenalism, are not eligible. Topical
steroids are acceptable as are intranasal steroids.

- Active infection or antibiotics within 48 hours prior to study enrollment, including
unexplained fever (temp > 38.1°C), if deemed clinically significant by the treating
physician.

- Evidence of active autoimmune disease (e.g., systemic lupus erythematosis, rheumatoid
arthritis, with the exception of vitiligo. Patients with a remote history of asthma
or mild asthma are eligible.

- Other serious medical conditions that may be expected to limit life expectancy to
less than 2 years (e.g., liver cirrhosis).

- Any condition, psychiatric or otherwise, that would preclude informed consent,
consistent follow-up or compliance with any aspect of the study (e.g., untreated
schizophrenia or other significant cognitive impairment, etc).

- Patients having previously undergone splenectomy.

- Patients with known hepatitis or unstable liver disease, and/or positive serologies
for Hepatitis B or C and HIV.

- Patients with sickle-cell anemia or thalassemia major.

- Subjects who received prior treatment with immune checkpoint inhibition, consisting
of ipilimumab, tremelimumab, nivolumab, pembrolizumab or other antibody to CTLA4 or
PD-1.