Neil Senzer

Induction of Immune Responses and Clinical Efficacy in a Phase II Trial of IDM-2101, a 10-Epitope Cytotoxic T-Lymphocyte Vaccine, in Metastatic Non-Small-Cell Lung Cancer

PURPOSE Generation of broad cytotoxic T-lymphocyte responses against multiple epitopes and tumor-associated antigens (TAAs) may provide effective immunotherapy in patients with cancer. We evaluated a single-vial peptide vaccine consisting of nine HLA-A2 supertype-binding epitopes (two native and seven analog epitopes modified for optimal HLA binding or T-cell receptor stimulation) covering five TAAs and the universal helper pan-DR epitope, formulated as a stable emulsion with incomplete Freunds adjuvant (Montanide ISA 51; Seppic SA, Paris, France). The clinical efficacy, safety, and multiepitope immunogenicity of IDM-2101 was evaluated in patients with stage IIIB or IV non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS A total of 63 patients were enrolled who were positive for HLA-A2. End points included survival, safety, and immune response. IDM-2101 (previously EP-2101) was administered every 3 weeks for the first 15 weeks, then every 2 months through year 1, then quarterly through year 2, for a total of 13 doses. Epitope-specific cytotoxic and helper T-lymphocyte immunogenic responses were measured by the interferon gamma enzyme-linked immunosorbent spot assay. RESULTS No significant adverse events were noted. Low-grade erythema and pain at the injection site were the most common adverse effects. One-year survival in the treated patients was 60%, and median survival was 17.3 months. One complete and one partial response were identified. Survival was longer in patients demonstrating an immune response to epitope peptides (P < .001). CONCLUSION IDM-2101 was well tolerated, and evidence of efficacy was suggested.

Follow-up of bi-shRNA furin / GM-CSF Engineered Autologous Tumor Cell (EATC) Immunotherapy Vigil® in patients with advanced melanoma

Over the last decade, management of melanoma has dramatically evolved from chemotherapy through targeted molecular therapy (BRAF V600E signaling) and, currently, immunotherapy (checkpoint inhibitors, immunogenic oncolytic viruses). Response, time to progression and survival has improved for many melanoma patients undergoing targeted therapy, but insensitive population subsets, adaptive resistance and toxic side effectslimit therapeutic benefit. Previous studies have shown a correlation between Vigil engineered autologous tumor cell (EATC) immunotherapy induced circulating activated T-cells responsive against autologous tumor cells and survival prolongation. We now assess the safety and response to Vigil (1 x 107 cells/ intradermal injection monthly x 4-12) in 12 patients with advanced metastatic melanoma in comparison with 12 who underwent similar standard of careautologous tumor harvest but received other treatment regimens,not Vigil. None of the patients experienced≥ Grade 3 treatment-related toxicity. Two Grade 2 adverse events (AE) (fatigue, irritability) and local regionalGrade 1 AE (injection site erythema, induration, rash, skin hypopigmentation)in 19 of 63 injections were observed. IFN-γ ELISPOT analysis (PBMC) showed the induction of T-cell activation from 0-1 at baseline to 78 spots/106 cells post first cycle of Vigil. Median survival of Vigil treated patients was 20 months compared to 7 months (KaplanMeier analysis, log rank p=0.00009). In conclusion, preliminary evidence of safety and activity of Vigil supportsfurther clinical evaluation in advanced melanoma. Correspondence to: John Nemunaitis, M.D., Mary Crowley Cancer Research Centers, 12222 Merit Drive, Suite 1500, Dallas, Texas 75251, USA, Tel: 214-6581964, Fax: 214-658-1992, E-mail: jnemunaitis@marycrowley.org Received: September 15, 2016; Accepted: September 25, 2016; Published: September 29, 2016 Introduction MAGE-A3. MAGE-A1, NY-ESO-1 and SSX-2), a high tumor mutation burden (TMB) leading to an increased number of tumor-specific epitopes, and clinicallya reproducible response rate to immunotherapies [1-4] particularly to the recently FDA approved immune checkpoint inhibitors. One of these inhibitors is ipilimumab (Yervoy; a human monoclonal antibody (hMAb) CTLA-4 inhibitor), which was FDA approved in 2011 for patients with advanced, unresectable Stage III and IV melanoma [5]. Results show improvement in recurrence-free survival (RFS) as compared to placebo in the EORTC trial 18071 (HR 0.75, 95% CI 0.64 – 0.90), [6]. Pembrolizumab (Keytruda), ahMAbPD-1 inhibitor, subsequently demonstrated response rates of 36% [7] and has proven to be superior to chemotherapy and single agent ipilimumab in patients with advanced melanoma [8-10] as has nivolumab (Optivo) [11]. However, >60% of melanoma patients do not achieve an optimal response to a single agent checkpoint inhibitor and subsets of patients (i.e. PD-L1-; low TMB) predictively respond less favorably. Although the combination of mechanistically different immune checkpoint inhibitors elicits higher response rates, in a randomized trial of nivolumab alone,ipilimumab alone, or the combinationof the two in treatment-naïve patients with unresectable stage III or IV melanoma,the combination achieved an ORR of 57.6% (compared to 43.7% with nivolumaband 19% with ipilimumab) with a durable response of 11.5 months,but with 55% treatment-related Grade 3 or higher toxicities. Furthermore, in 36.4% of patients the combination leads to treatment-related discontinuation[9]. Although these data confirm the effectiveness of immunotherapy in advanced melanoma, they alsohighlight the need for further development of novel and/or combinatory immunotherapies with increased, predictable effectiveness at a lower risk of toxicity. Talimogenelaherparepvec(T-VEC), a genetically-modified, immuneenhanced H. simplex type I virus, is systemically effective in advanced melanoma [12] but the FDA indication is limited to Stages IIIb, IIIc or IVM1a disease that are unresectable based on regional efficacy shown in Phase III testing [13,14]. Vigil is a DNA engineered autologous tumor cell (EATC) immunotherapy. It contains a dual vector; a bi-shRNA targeting furinthe pro-protein convertase that activates the immunosuppressive TGF-beta 1 and 2 and the gene encoding hGM-CSF. A phase I clinical Barve M (2016) Follow-up of bi-shRNAfurin /GM-CSF Engineered Autologous Tumor Cell (EATC) Immunotherapy Vigil in patients with advanced melanoma Volume 1(3): 81-86 Biomed Genet Genomics, 2016 doi: 10.15761/BGG.1000116 trial of Vigil in patients with heavily pretreated advanced solid tumors showeda significant survival benefit which correlated with induction of an immune response measured by the interferon gamma (IFN-γ) ELISPOT assay. We now update the results of Vigil clinical activity in patients with advanced melanoma. Materials and methods The method and mechanism of construction and manufacturing of Vigil (formerly known as FANG) has previously been described [15,16]. The Vigil vector encodes for GM-CSF expressive cDNA and the bi-sh RNAfurin in autologous tumor cells. Following protocol-specific informed consent, tumor tissue is harvested, placed in sterile media and delivered to the Gradalis, Inc. manufacturing facility (Carrollton, TX, USA). Vigil is manufactured over 2 conservative days. Subsequent manufacturing, following FDA discussion, now utilizes Gentamicin in the sterile media in order to reduce contamination risk. First, autologous tumor cells are dissociated into a single-cell suspension, followed by electroporation(which allows cell transfection with the plasmid), and overnight incubation. Then the cells are irradiated, placed into the final vials, cryopreserved, and undergo release testing. Following product release by Quality Assurance compliance, patients are registered for treatment every 4 weeks with 1.0 x 107cells/injectionof Vigil.