An Open-Label Study of the Safety and Efficacy of Tag-7 Gene-Modified Tumor Cells-Based Vaccine in Patients with Locally Advanced or Metastatic Malignant Melanoma or Renal Cell Cancer
Authors: Novik Aleksei Viktorovich , Danilova Anna Borisovna , Sluzhev Maksim Ivanovich , Nehaeva Tatiana Leonidovna , Larin Sergei Sergeevich , Girdyuk Dmitry Viktorovich , Protsenko Svetlana Anatolevna , Semenova Anna Igorevna , Danilov Aleksei Olegovich , Moiseyenko Vladimir Mikhailovich , Georgiev Georgii Pavlovich , Baldueva Irina Aleksandrovna 
Published: April 2020

Abstract

Lessons Learned
This study showed that carefully selected patients with locally advanced and metastatic forms of malignant melanoma and renal cell carcinoma could potentially have long-term disease control with a tag-7 gene-modified tumor cells-based vaccine. Randomized clinical trials in patients whose tumors produce low amounts of immunosuppressive factors are needed to confirm this hypothesis in both the adjuvant and metastatic settings.

Background
Immunotherapy may produce long-lasting effects on survival and toxicity. The magnitude of efficacy may be dependent on immune factors. We analyzed the results of a phase I/II study of a tag-7 gene-modified tumor cells-based vaccine (GMV) in patients with malignant melanoma (MM) or renal cell carcinoma (RCC) with biomarker analysis of immunosuppressive factors (ISFs) production by their tumor cells.

Methods
From 2001 to 2014, 80 patients received GMV: 68 with MM and 12 with RCC. Treatment in the metastatic setting included 61 patients (MM, 51; RCC, 10), and treatment in the adjuvant setting (after complete cytoreduction) included 19 patients (MM, 17; RCC, 2). Twenty-six patients were stage III (33%), and 54 (67%) were stage IV. The patients’ tumor samples were transferred to culture, transfected with tag-7 gene, and inactivated by radiation. The produced product was injected subcutaneously every 3 weeks until progression or 2 years of therapy. ISFs were measured in the supernatants of the tumor cell cultures and used as predictive factors.

Results
No major safety issues or grade 5 adverse events (AEs) were seen. One grade 4 and two grade 3 AEs were registered. No AEs were registered in 89.4% of treatment cycles. No delayed AE was found. The 5-year overall survival (OS) in the intention-to-treat population was 25.1%. There were no differences between MM OS and RCC OS (log rank, p = .44). Median OS in the metastatic setting was 0.7 years and in the adjuvant setting was 3.1 years. Classification trees were built on the basis of ISF production (Fig. 1). The median OS was 6.6 years in the favorable prognosis (FP) group (major histocompatibility complex class I polypeptide-related sequence A [MICA] level ≤582 pg/mL, n = 15) and 4.6 months in the unfavorable (UF) group (MICA level &gt;582 pg/mL, n = 12; p &lt; .0001). No significant differences were found between classification trees based on ISFs (transforming growth factor β1 [TGF-β1], interleukin-10 [IL-10], and vascular endothelial growth factor [VEGF]). In patients with stage III–IV MM with FP, median OS was 2.3 years, with 31% patients alive at 10 years (Fig. 2) in the UF group (0.4 years; log rank, p = 1.94E−5). No FP patients received modern immunotherapy.

Conclusion
GMV showed high results in carefully selected patients with low ISF (TGF-β1, IL-10, and VEGF) production. The method should be further investigated in patients with FP.