Safety Study on the Transfer of the CD40 Ligand Gene (AdcuCD40L) to Patients With Esophageal Carcinoma

Esophageal cancer is a deadly disease, with only slow advances in therapy over several
decades, despite a rapid increase in incidence. Esophageal cancer is estimated to be the
seventh most common malignancy worldwide, with incidence rates reaching epidemic proportions
in select regions in Asia and Africa. In the United States, it is estimated that 12,300 new
cases were diagnosed in 2000, however, the incidence of adenocarcinoma of the esophagus is
currently rising faster than that of any other human malignant tumor in this country.
Despite advances in surgical technique, chemotherapy, radiotherapy and early detection, only
12% of patients diagnosed with esophageal cancer will survive more than five years, a cure
rate more dismal than that seen with cancers of the breast, prostate, colon, and even lung.
Survival following treatment for esophageal cancer is stage dependent. This study is
directed towards augmenting host anti-tumor immunity by using gene transfer to activate
dendritic cells (DC; cells of our immune system that play a central role in initiating
immune responses) in tumors of patients with esophageal cancer. Based on extensive
pre-clinical data, two proposed clinical trial protocols will evaluate the concept that
transient modification of the genetic repertoire of esophageal tumors to express CD40 Ligand
(CD40L; a potent activator of DC) will induce the accumulation of activated DC within the
tumor, and the in vivo interaction of DC with the tumor cells/tumor antigens will induce
tumor-specific immunity. To assess this concept, an adenovirus (Ad) vector (AdcuCD40L) will
be used to transfer and transiently express the human CD40L cDNA in esophageal carcinoma by
direct injection into the tumor. Phase I represents a dose escalation study to determine the
maximum tolerated dose of the vector and will include 12 individuals with unresectable,
stage III or IV esophageal cancer. Phase II is a randomized, double-blinded assessment of
biologic efficacy and will include 24 individuals with resectable, stage I-III disease who
will be undergoing potentially curative resection. Together, both protocols are designed to
assess two hypotheses. First, that it is safe to administer the AdcuCD40L vector to
individuals with esophageal cancer. Second, that intratumoral administration of the
AdCUCD40L vector will induce both the accumulation, in the tumor and in regional lymph
nodes, of activated DC, and CD8+ T cells (and other inflammatory cells), including T cells
exhibiting tumor-specific responses, as well as systemic antitumor immunity.

Inclusion Criteria:

- Must be capable of providing informed consent

- Males and females, age 18 to 75 years

- Hematocrit > 30%

- WBC < 10,000

- Normal prothrombin, partial thromboplastin time; platelet count > 100,000

- Normal liver-related serum parameters

- Blood urea nitrogen < 60 mg/dL, creatinine < 2.5 mg/dl

- No evidence of active infection of any type, including with adenovirus, hepatitis
virus (A, B or C) or human immunodeficiency virus

- No evidence of central nervous system, major psychiatric, musculoskeletal or immune
disorder

- No allergy to the vehicle used to suspend the virus or contrast materials used in
radiographic procedures

- Fertile or infertile individuals; it will be recommended that fertile individuals
utilize barrier birth control measures to prevent pregnancy during and for 1 month
following the administration of the vector

- Biopsy proven esophageal cancer; stage IIIB or IV; no chemotherapy for 4 weeks prior
to vector dosing; and no chemotherapy or radiation for 4 weeks after vector dosing.
Patients must have viable tumor in the esophagus (or gastroesophageal junction). In
addition, patients must be (1) be untreated; or, (2) show endoscopic evidence of
persistence of disease after treatment with conventional chemotherapy, radiotherapy,
or both

- Individuals not receiving experimental medications or participating in another
experimental protocol for at least 4 weeks prior to entry to the study.

- The study individual must be able to undergo the procedures in the protocol

- Willingness to participate in the study

Exclusion Criteria:

- Individuals who do not meet the inclusion criteria will be unable to participate in
the protocol

- Individuals in whom participation in the study would compromise the normal care and
expected progression of their disease

- Individuals receiving corticosteroids or other immunosuppressive medications;
previous splenectomy or radiation to the spleen; autoimmune disease

- Recent (less than 6 wk) cerebral vascular accident

- Recent (less than 6 wk) transmural myocardial infarction

- Evidence of infection defined by elevated white blood cell count, temperature >
38.5oC or infiltrate on chest x-ray

- Cervical esophageal cancer

- Gastric cancer (tumor more than 50% in the stomach as determined by endoscopy)

- Lack of viable esophageal tumor (applies only to pretreated patients)

- Pathology other than squamous cell or adenocarcinoma

- Malignant ventricular arrhythmia

- Pregnancy

- Immunodeficiency disease, including evidence of HIV infection

- Current alcohol or drug abuse