Phase I Trial of TGFB2-Antisense-GMCSF Gene Modified Autologous Tumor Cell (TAG) Vaccine for Advanced Cancer
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 4/17/2018 |
| Start Date: | May 27, 2008 |
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
therapeutic application:
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
efferent limbs.
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 cancer tissue.
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
therapeutic application:
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
efferent limbs.
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 cancer tissue.
Inclusion Criteria:
- 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
vaccine processing.
- 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 screening
evaluation.
- ≥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 document.
- Negative pregnancy test.
Exclusion Criteria:
- 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
study requirements.
- 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.
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