Immunotherapy Study for Metastatic Renal Cell Cancer

Unfortunately, despite the best clinical efforts with surgical intervention and chemotherapy
many patients with high grade and advanced stage renal cell carcinoma (RCC) progress and die
of their disease. In United States approximately 13,000 individuals die from RCC each year.
The primary cause of failure is microscopic spread of the tumor prior to complete surgical
extirpation of detectable disease and the heterogenous nature of the metastatic cells. These
cells are resistant to all forms of therapy including chemotherapy, radiation, and escape
from immune surveillance by a variety of mechanism. This results in low 5-year survival
rates (approximately 10%) in patients with metastasis. Novel immunotherapeutic strategies
provide a hope in circumventing the drug resistant RCC and improve the survival of patients
undergoing surgery. RCC, like melanoma is one of the most immunogenic tumors and partial
successes have been achieved by a variety of immunotherapeutic strategies show partial
successes. Although vaccines have been highlighted in clinical trials since the mid-1970s
with subcutaneous autologous irradiated tumor cells most of these studies were in patients
with advanced disease. These approaches resulted in rare if any clinically relevant benefits
to patients. However, new vaccines in other cancers have shown responses equivalent to
chemotherapy with minimal toxicity [1]. The use of immune adjuvant strategies to increase
the therapeutic immune responses to tumor vaccines enhanced the proportion of patients with
therapeutic responses to vaccination to 10%-15% on average. Only during the last decade has
it become clear that failure of immune system to respond to the tumor vaccine is the main
obstacle that limits the efficacy of vaccine based immunotherapies. The precise reason for
failure of the immune system in cancers is very complex particularly as it relates to (1)
the escape of growing or metastasizing tumor from immune surveillance [2-4] and (2) low
immunogenicity of autoantigens associated with malignant neoplasms. This human clinical
trial will investigate the dose limiting toxicity of a polyvalent immune enhanced vaccine as
a first step towards developing a multipronged approach to triggering the immune system to
attack and destroy micrometastatic disease. Investigators hypothesize that the allogeneic
RCC cell genetically modified to express α (1,3)galactosyltransferase (enzyme responsible
for producing the strong xenoantigen on the cell surface of the cellular immunotherapy) will
augment the efficacy of cellular immunotherapy and thereby improve patient outcomes. In this
Phase 1 Trial investigators plan to establish the maximum tolerated dose (MTD) of
Hyperacute®-Renal (HAR) immunotherapy in subjects with clinically metastatic renal cell
carcinoma.

Inclusion Criteria:

- 18 years or older

- Signed written informed consent

- Diagnosis of RCC with clear-cell or predominant clear-cell histology (≤ 50% other
histologic features)

- Subjects with recurrent or refractory, metastatic disease (N1 or M1) fulfilling any
of the following combinations of pathologic staging based on American Joint Committee
on Cancer (AJCC) TNM staging version 2010 and Fuhrman nuclear grading

- pT3, G any, N1; or, pT4, G any, N1; or, pT any, G any, N1 or M1)

- Subjects have already undergone all standard of care surgery appropriate for stage of
disease.

- Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2.

- Serum albumin ≥3.0 gm/dL.

- Adequate organ function including:

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

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

3. Renal: Serum creatinine (sCr) ≤ 2.0 x upper limit of normal.

- 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.

- Patients who have received previous systemic therapies including TKI inhibitors are
eligible.

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 that 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 1 year (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.

- History of any one or more of the following cardiovascular conditions within the past
6 months:

- Cardiac angioplasty or stenting

- Myocardial infarction

- Unstable angina

- Coronary artery bypass graft surgery

- Symptomatic peripheral vascular disease

- History of Class III or IV congestive heart failure, as defined by the New York
Heart Association Classification of Congestive Heart Failure

- History of cerebrovascular accident including transient ischemic attack (TIA),
pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6
months.

- Any serious and/or unstable pre-existing medical, psychiatric, or other condition
that could interfere with subject's safety, provision of informed consent, or
compliance to study procedures

- Concurrent investigational therapy given to treat cancer or concurrent participation
in another clinical trial involving anti-cancer investigational drug.

- Administration of an investigational drug within 30 days or 5 half-lives, whichever
is longer, preceding the first dose of study treatment.