Preliminary studies with a variety of vaccines suggest target accessibility (potential
immunogenicity) in a variety of solid tumors to immune directed approaches. However, four
primary factors limit the generation of effective immune mediated anticancer activity in
1. identifying and/or targeting cancer associated immunogen(s) in an individual patient
2. insufficient or inhibited level of antigen presenting cell priming and/or presentation
3. suboptimal T cell activation and proliferation
4. cancer-induced inhibition of the anticancer immune response in both afferent and
In an effort to overcome these limitations, we have designed a novel autologous vaccine to
address inability to fully identify cancer associated antigens, antigen recognition by the
immune system (i.e. antigen to immunogen), effector potency, and cancer-induced resistance.
We have completed clinical investigations using two different gene vaccine approaches to
induce enhancement of tumor antigen recognition which have demonstrated therapeutic
efficacy. Specifically, both the use of a GMCSF gene transduced vaccine and a TGFβ2
antisense gene vaccine, in separate trials, have demonstrated similar beneficial effects
without any evidence of significant toxicity in advanced cancer patients. The GMCSF
transgene directly stimulates increased expression of tumor antigen(s) and enhances
dendritic cell migration to the vaccination site. TGFβ2 blockade following intracellular
TGFβ2 antisense gene expression reduces production of immune inhibiting activity at the
vaccine site. These agents have never been used in combination but the rationale of
integrating enhancement of an anticancer immune response concurrently with a reduction in
cancer-induced immune suppression is conceptually sound. We will harvest autologous cancer
cells from patients with advanced refractory cancer. We have constructed a TGFβ2 antisense /
GMCSF expression vector plasmid and have successfully demonstrated preclinical activity of
the vector function following transfection by electroporation and irradiation of autologous
- Histologically confirmed advanced or metastatic non-curable solid tumor (if limited
to a single lesion and not a candidate for curative surgery or radiation therapy).
- Completed ≥1 conventional therapy.
- Clinically indicated surgery or procedure to collect available tumor in sufficient
quantity ("golf ball size," pleural or ascites fluid may also be collected) for
- Subjects that have completed all acceptable therapies that are the current standard
of care for their respective diseases.
- Recovered from all toxicities related to prior therapies.
- Subjects with brain metastases treated at least ≥2 months prior to enrollment,
without related clinical symptoms and must have a stable neurological exam on the
- ≥1 measurable or evaluable lesion.
- Age ≥18 years.
- ECOG performance status (PS) 0-1.
- Normal organ and marrow function:
- Absolute granulocyte count: ≥1,500/mm3
- Platelets: ≥100,000/mm3
- Total bilirubin: ≤2 mg/dL
- AST(SGOT)/ALT(SGPT): ≤2x institutional upper limit of normal
- Creatinine: <1.5 mg/dL
- Ability to understand and the willingness to sign a written informed consent
- Negative pregnancy test.
- Surgery involving general anesthesia, chemotherapy, radiotherapy, steroid therapy, or
immunotherapy within 4 weeks prior to entering the study.
- Patient must not have received any other investigational agents within 30 days prior
to study entry.
- Patients with known brain metastases unless treated and stable for ≥2 months.
- Patients with mucinous adenocarcinoma.
- Short term (<30 days) concurrent systemic steroids ≤ 0.125 mg/kg prednisone per day
(maximum 10 mg/day) and bronchodilators (inhaled steroids) are permitted; other
steroid regimens and/or immunosuppressives are excluded. Patients requiring steroids
following previous CNS radiation for metastatic disease are excluded.
- Prior splenectomy.
- Prior malignancy (excluding nonmelanoma carcinomas of the skin) unless in remission
for ≥2 years.
- Kaposi's Sarcoma.
- Uncontrolled intercurrent illness including, but not limited to ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
- Patients who are pregnant or nursing.
- Patients who are HIV positive.
- Patients with chronic Hepatitis B and C infection.
- Patients with a history of autoimmune diseases.