Suicide Plus Immune Gene Therapy for Advanced Melanoma

This phase I clinical protocol is proposed to evaluate the safety of combined immunotherapy genetics in humans.

This treatment combines the high local cytotoxicity of the suicide gene system (HSV thymidine kinase: HSVt k) / prodrug (ganciclovir: GCV) with the immunostimulation of interleukin2 (hIL2) and immunoamplification of granulocyte and macrophage colony stimulating factor (hGMCSF) in the presence of tumor antigens.

The proposed scheme consists in the periodic intra / peritumoral application of plasmid DNA complexes: cationic lipid (lipoplexes) containing the HSVtk gene, co-administered with the prodrug GCV, and subcutaneous injections of a vaccine (LGvax) produced with formolized extracts of allogeneic melanoma combined with lipoplexes carrying the hIL2 and hGMCSF genes.

• Suicide plus immunogene therapy (Biological): 1. Intra and peritumoral infiltrates with multiple injections of 0.1 ml/cm2 or 0.2 ml/cm3 of lipoplexes bearing the HSVtk suicide gene (1: 1; 1 mg/ml, according to tumor size), co-administered with GCV (12.5 mg/ml). Patients start with a minimum of 0.5 ml and at the 3rd week, the maximum dose is scaled according to the tumor size up to 2 ml maximum. 2. Treated simultaneously with a subcutaneous vaccine produced with: * Formolized allogeneic tumor extracts and, * Lipoplexes carrying hIL-2 and hGM-CSF genes (0.5 mg each).

Primary outcomes

• Safety reported as the number of treatment-related adverse events as assessed by CTCAE v4.03 [1 year]: Number of participants with treatment-related adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf).

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Patients with histologically and / or cytologically confirmed melanoma.
* Patients progressed or are intolerant to conventional systemic treatments.
* Patients that are not candidates for surgery under oncologic criteria (complete resection).
* Performance status (ECOG) 0 or 1.
* Patients with life expectancy greater than 6 months.
* Patients with at least one accessible target lesion for gene inoculation (superficial localizations of the primary tumor, satelitosis, subcutaneous or accessible lymph node metastasis).
* Patients with measurable disease (according to RECIST 1.1 criteria, irrespective of the target lesion chosen for suicide gene inoculation)
* Patients with signed informed consent.

Exclusion Criteria:

* Patients with uncontrolled cardiovascular disease
* Patients with uncontrolled respiratory disease.
* Patients with uncontrolled immune disease.
* Patients with glucocorticoids or immunosuppressive drugs or agents with immunomodulatory activity (except non-steroidal anti-inflammatory agents) up to 2 weeks before treatment.
* Patients performing other experimental therapies.
* Patients who are pregnant or breastfeeding.
* Patients undergoing concurrent chemotherapy or radiation therapy.
* Uncontrolled diabetes.
* Patients with active diagnosis of other malignant neoplasms.
* HIV-positive patients.
* Uncontrolled thyroid abnormality.
* Patients with significant medical morbidity.
* Patients with a history of allergic reactions to chemicals or similar to those used in this study.
* Metastasis in the central nervous system.
* Laboratory eligibility criteria excluded:

  * Hemoglobin: <8 g / dL, leukocytes: <3,000 / mm3, platelets: <100,000 / mm3, neutrophils: <1000 / mm3, hematocrit: <25%. bilirubin> 2.0 mg / dL, GOT or GPT: 2.5 times> than normal upper institutional limit (ULN), alkaline phosphatase: 2 times> ULN, creatinine> 2.0 mg / dL, creatinine clearence : <60 ml / min / 1.73 m2.

• Ventura Simonovich, MD, Principal investigator, Hospital Italiano