Evaluate The Toxicity And Feasibility Of Intra-Tumoral Injection

This is a Phase I pilot study to evaluate the toxicity and feasibility of intratumoral injection GSL alpha-GAL in patients with advanced, refractory solid tumors who have failed standard therapies or are not eligible for standard treatment.

Intratumoral injection of alpha gal glycolipid in experimental knockout mouse model systems incorporates into tumor cell membranes and presents these xeno-transplantation epitopes to antigen presenting cells with that particular tumor's tumor associated antigens (TAA). Thus this maneuver converts any individual tumor into an in situ tumor vaccine without the need to isolate, purify or supply TAA exogenously. The effects in these model systems demonstrate both the upregulation of cytotoxic T cells which react against the particular tumor's TAA, as well as resolution of injected primary tumor and eradication and prevention of metastatic disease at distant sites. This current study was undertaken to investigate the safety and feasibility of such an approach in humans. The major toxicity concerns are acute allergic or complement activation reactions or development of autoimmunity. The primary treatment is a single intratumoral injection of alpha gal glycolipid. The study design is a standard dose escalation design and the primary endpoint is Dose limiting toxicity at one month after injection (grade 3 or 4. Subjects are followed until death utilizing standard clinical imaging and evaluation to judge overall tumor response.

• Lugade AA, Moran JP, Gerber SA, Rose RC, Frelinger JG, Lord EM. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor. J Immunol. 2005 Jun 15;174(12):7516-23.
• Malmberg KJ. Effective immunotherapy against cancer: a question of overcoming immune suppression and immune escape? Cancer Immunol Immunother. 2004 Oct;53(10):879-92. Epub 2004 Jul 28. Review.
• DiGiacomo A, North RJ. T cell suppressors of antitumor immunity. The production of Ly-1-,2+ suppressors of delayed sensitivity precedes the production of suppressors of protective immunity. J Exp Med. 1986 Oct 1;164(4):1179-92. Erratum in: J Exp Med 1986 Dec 1;164(6):2131.
• Shimizu J, Yamazaki S, Sakaguchi S. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol. 1999 Nov 15;163(10):5211-8.

Inclusion Criteria:

1. Patients with solid tumors who have failed standard therapies, or are not candidates for standard therapies.
2. Patients must have at least one measurable lesion that is accessible and suitable for injection of the GSL alpha-GAL.
3. Patients should not be undergoing any active treatment with chemotherapy, radiotherapy, or steroids (either because the patient or the treating physician have decided not to employ these therapies at this time, or because they had already been tried and failed). If they have been treated with these modalities, the treatments should have been completed at least two weeks prior to date of injection of GSL alpha-GAL.
4. Patients should be judged by the investigator to be able to undergo safely the procedure needed to inject the tumor with GSL alpha-GAL.
5. Age equal or over 18 years old.
6. ECOG performance of less than 2. INR less than 1.5 and a PTT no greater than normal limits within 1 week prior to intra-tumoral injection (For patients who requires invasive procedure for intra-tumoral injection).

7. Laboratory Criteria (completed equal or less 2 weeks before enrollment) Hematologic: WBC equal or above 3500/millimeter-cubed or ANC equal or above 1500/millimeter-cubed and platelet count equal or above 100,000/ millimeter-cubed.

   Hepatic: Total bilirubin equal or less 4.0 milligrams/deciliter. Renal: Creatinine equal or less 2.2 milligrams/deciliter.

8. Patients must be negative for HIV (circulating antibody), Hepatitis B (circulating antigen), and Hepatitis C (circulating antibody).
9. Patients should have an expected survival of more than 6 weeks and should not have other systemic anti-tumor treatments planned during this time frame.

Exclusion Criteria:

1. Patients who are pregnant (as determined by a positive serum HCG in patients of childbearing potential) or nursing.
2. Patients under the age of 18.
3. Patients with severe infections or septicemia.
4. Patients with a history of autoimmune disease.
5. Patients in, or about to be in, active treatment with chemotherapy or steroids.
6. Patients who refuse HIV/hepatitis testing and patients who do not sign an approved consent form.
7. Patient has received other investigational drugs within 14 days before enrollment or is expected to participate in an experimental drug study during this study treatment.
8. Serious medical or psychiatric illness likely to interfere with participation in this clinical study.