Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small-cell lung cancer: a controlled phase 2B trial.

BACKGROUND: Chemotherapy is the standard of care for advanced stages of non-small-cell lung cancer (NSCLC). TG4010 is a targeted immunotherapy based on a poxvirus (modified vaccinia virus Ankara) that codes for MUC1 tumour-associated antigen and interleukin 2. This study assessed TG4010 in combination with first-line chemotherapy in advanced NSCLC. METHODS: 148 patients with advanced (stage IIIB [wet] or IV) NSCLC expressing MUC1 by immunohistochemistry, and with performance status 0 or 1, were enrolled in parallel groups in this open-label, phase 2B study. 74 patients were allocated to the combination therapy group, and received TG4010 (10(8) plaque forming units) plus cisplatin (75 mg/m(2) on day 1) and gemcitabine (1250 mg/m(2) on days 1 and 8) repeated every 3 weeks for up to six cycles. 74 patients allocated to the control group received the same chemotherapy alone. Patients were allocated using a dynamic minimisation procedure stratified by centre, performance status, and disease stage. The primary endpoint was 6-month progression-free survival (PFS), with a target rate of 40% or higher in the experimental group. Analyses were done on an intention-to-treat basis. This study is completed and is registered with ClinicalTrials.gov, number NCT00415818. FINDINGS: 6-month PFS was 43·2% (32 of 74; 95% CI 33·4-53·5) in the TG4010 plus chemotherapy group, and 35·1% (26 of 74; 25·9-45·3) in the chemotherapy alone group. Fever, abdominal pain, and injection-site pain of any grade according to National Cancer Institute Common Toxicity Criteria were more common in the TG4010 group than in the chemotherapy alone group: 17 of 73 patients (23·3%) versus six of 72 (8·3%), 12 (16·4%) versus two (2·8%), and four (5·5%) versus zero (0%), respectively. The most common grade 3-4 adverse events were neutropenia (33 [45·2%] of patients in the TG4010 plus chemotherapy group vs 31 [43·1%] in the chemotherapy alone group) and fatigue (18 [24·7%] vs 13 [18·1%]); the only grade 3-4 events that differed significantly between groups were anorexia (three [4·1%] vs 10 [13·9%]) and pleural effusion (none vs four [5·6%]). 38 of 73 patients (52·1%) in the TG4010 plus chemotherapy group and 34 of 72 (47·2%) in the chemotherapy alone group had at least one serious adverse event. INTERPRETATION: This phase 2B study suggests that TG4010 enhances the effect of chemotherapy in advanced NSCLC. A confirmatory phase 2B-3 trial has been initiated. FUNDING: Transgene SA, Advanced Diagnostics for New Therapeutic Approaches (ADNA)/OSEO.

Metastatic Breast Tumour Regression Following Treatment by a Gene-Modified Vaccinia Virus Expressing MUC1 and IL-2.

MUC1 is expressed by glandular epithelial cells. It is overexpressed in the majority of breast tumours, making it a potential target for immune therapy. The objectives of the present study were to evaluate the anti-tumour activity and tolerance of repeated administration of TG1031 (an attenuated recombinant vaccinia virus containing sequences coding for human MUC1 and the immune stimulatory cytokine IL-2) in patients with MUC1-positive metastatic breast cancer. This was an open-label, randomised study comparing two dose levels, 5 x 10E6 and 5 x 10E7, with 14 patients in each arm. The treatment was administered intramuscularly every 3 weeks for the first 4 doses and every 6 weeks thereafter, until progression. Two patients had a partial tumour regression ( > 50%), and 15 patients had stable disease as their best overall response until at least the 5th injection. Partial regression lasted for 11 months in one patient and for 12 months in the second patient who then underwent surgical resection of her hepatic metastases. The most frequent adverse events included inflammation at injection site: 7 patients, itching or pain at injection site: 5 patients, and moderate fever: 6 patients. One responding patient developed antinuclear, anti-DNA, and increased anti-TPO antibodies after the fifth injection, and which resolved at the end of treatment. The treatment regimes were well tolerated with a low toxicity profile. Although clinical efficacy remains limited, this study demonstrates the potential use of MUC1-based immune therapy in breast cancer.

A phase II study of Tg4010 (Mva-Muc1-Il2) in association with chemotherapy in patients with stage III/IV Non-small cell lung cancer.

BACKGROUND: TG4010 is a recombinant viral vector expressing both the tumor-associated antigen MUC1 and Interleukine-2. This vector is based on the modified virus of Ankara, a significantly attenuated strain of vaccinia virus. TG4010 has been designed to induce or amplify a cellular immune response directed against tumor cells expressing MUC1. METHODS: A multicenter, randomized phase II study has explored two schedules of the combination of TG4010 with first line chemotherapy in patients with stage IIIB/IV non-small cell lung cancer. In Arm 1, TG4010 was combined upfront with cisplatin (100 mg/m day 1) and vinorelbine (25 mg/m day 1 and day 8). In Arm 2, patients were treated with TG4010 monotherapy until disease progression, followed by TG4010 plus the same chemotherapy as in Arm1. Response rate was evaluated according to RECIST. Median time to progression and median overall survival were calculated according to the Kaplan-Meier method. RESULTS: Sixty-five patients were enrolled, 44 in Arm 1 and 21 in Arm 2, in accordance with the two stage Simon design of the statistical plan. In Arm 1, partial response was observed in 13 patients out of 37 evaluable patients (29.5% of the intent to treat population, 35.1% of the evaluable patients). In Arm 2, two patients experienced stable disease for more than 6 months with TG4010 alone (up to 211 days), in the subsequent combination with chemotherapy, one complete and one partial response were observed out of 14 evaluable patients. Arm 2 did not meet the criteria for moving forward to second stage. The median time to progression was 4.8 months for Arm 1. The median overall survival was 12.7 months for Arm 1 and 14.9 for Arm 2. One year survival rate was 53% for Arm 1 and 60% for Arm 2. TG4010 was well tolerated, mild to moderate injection site reactions, flu-like symptoms, and fatigue being the most frequent adverse reactions. A MUC1-specific cellular immune response was observed in lymphocyte samples from all responding patients evaluable for immunology. CONCLUSIONS: The combination of TG4010 with standard chemotherapy in advanced non-small cell lung cancer is feasible and shows encouraging results. A randomized study evaluating the addition of TG4010 to first line chemotherapy in this population is in progress.

Gene-based vaccines and immunotherapeutics.

DNA vaccines, comprised of plasmid DNA encoding proteins from pathogens, allergens, and tumors, are being evaluated as prophylactic vaccines and therapeutic treatments for infectious diseases, allergies, and cancer; plasmids encoding normal human proteins are likewise being tested as vaccines and treatments for autoimmune diseases. Examples of in vivo prophylaxis and immunotherapy, based on different types of immune responses (humoral and cellular), in a variety of disease models and under evaluation in early phase human clinical trials are presented. Viral vectors continue to show better levels of expression than those achieved by DNA plasmid vectors. We have focused our clinical efforts, at this time, on the use of recombinant viral vectors for both vaccine as well as cytokine gene transfer studies. We currently have four clinical programs in cancer immunotherapy. Two nonspecific immunotherapy programs are underway that apply adenoviral vectors for the transfer of cytokine genes into tumors in situ. An adenovirus-IFN gamma construct (TG1042) is currently being tested in phase II clinical trials in cutaneous lymphoma. A similar construct, adenovirus-IL2 (TG1024), also injected directly into solid tumors, is currently being tested in patients with solid tumors (about one-half of which are melanoma). Encouraging results are seen in both programs. Two cancer vaccine immunotherapy programs focus on two cancer-associated antigens: human papilloma virus E6 and E7 proteins and the epithelial cancer-associated antigen MUC1. Both are encoded by a highly attenuated vaccinia virus vector [modified vaccinia Ankara (MVA)] and both are coexpressed with IL-2. Encouraging results seen in both of these programs are described.

Phase I immunotherapy with a modified vaccinia virus (MVA) expressing human MUC1 as antigen-specific immunotherapy in patients with MUC1-positive advanced cancer.

BACKGROUND: The MUC1 protein is a highly glycosylated mucin normally found at the apical surface of mucin-secreting epithelial cells in many types of tissues. MUC1 is expressed, but heavily underglycosylated, in different human tumors. TG4010 is a viral suspension of a recombinant vaccinia vector (MVA) containing DNA sequences coding for the human MUC1 antigen and interleukin-2 (IL-2). This product was developed for use as a vaccine in cancer patients whose tumors express the MUC1 antigen. The objective of the present study was to determine the safety of the product and to define the dose of TG4010 to be used in further clinical trials. MATERIALS AND METHODS: Thirteen patients with different solid tumors were treated by repeated intramuscular injection with increasing doses of TG4010 in two separate phase I studies, one in Europe (Basel-CR) and one in the United States (UCLA-RF): a total of 6 patients were treated at a dose of 5 x 10(6) pfu, 3 patients at 5 x 10(7) pfu, and 4 patients at 10(8) pfu. Safety, efficacy, and different immunological tests were the endpoints of the study. RESULTS: Tolerance of TG4010 was excellent, and side effects mainly consisted of injection site pain and influenza-like symptoms. There was no apparent detrimental effect of repeated injections of the vaccinia virus. Four of thirteen evaluable patients showed stabilization of their disease for 6 to 9 months. One lung cancer patient who was initially progressing after the first injections later showed a marked decrease in the size of his metastases that lasted for 14 months. Some T cell proliferative immune responses were seen in five patients. CONCLUSIONS: The administration of TG4010 was generally well tolerated in patients with metastatic tumors, and transient disease stabilization was observed in several patients, warranting further clinical studies with the product.