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

doi:10.1016/S1470-2045(11)70259-5

The Lancet Oncology

Volume 12, Issue 12, November 2011, Pages 1125-1133

, , , , , , , , , , , , , , , , , , , …

https://doi.org/10.1016/S1470-2045(11)70259-5 Get rights and content

Summary

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 (10⁸ plaque forming units) plus cisplatin (75 mg/m² on day 1) and gemcitabine (1250 mg/m² 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.

Introduction

Lung cancer is the most common malignancy worldwide in terms of incidence and mortality.1, 2 Chemotherapy improves the survival and quality of life of patients with advanced non-small-cell lung cancer (NSCLC). The current recommendation is to use a platinum-based two-drug regimen as first-line therapy.³ Despite progressive improvement in the standard of care for NSCLC, there remains much unmet medical need, and new approaches aimed at significantly improving patient outcomes are necessary. By modifying the host–tumour relationship, immunotherapy might be key in achieving this goal. Several targeted immunotherapy drugs for NSCLC are in different stages of development.4, 5, 6, 7

TG4010 (Transgene SA, Illkirch, France) consists of a suspension of a recombinant modified vaccinia virus strain Ankara (MVA) that codes for the MUC1 tumour-associated antigen and interleukin 2.⁸ A previous phase 2 study of TG4010 in combination with cisplatin and vinorelbine as first-line chemotherapy in advanced NSCLC showed the feasibility of such a combination with an overall response rate of 37%; a MUC1-specific cellular immune response was observed in lymphocyte samples from all responding patients evaluable for immunology.⁹

We report here the results of a phase 2B study in which chemotherapy-naive patients with advanced stage NSCLC were allocated to receive either chemotherapy in combination with TG4010 or chemotherapy alone. The chemotherapy regimen selected for this study was gemcitabine plus cisplatin, in accordance with standard practice in Europe at the time of study initiation. The main objective of this study was to assess whether TG4010 improves the outcome of NSCLC patients receiving first-line chemotherapy.

Section snippets

Patients

This study was a multicentre, open-label, controlled phase 2B trial with two parallel groups, assessing TG4010 as an adjunct to chemotherapy in patients with advanced NSCLC. Eligibility criteria were the following: male or female patients aged 18 years or older with histologically confirmed stage IIIB wet (pleural or pericardic effusion) or stage IV NSCLC,¹⁰ chemotherapy-naive for this stage of the disease, at least one lesion measurable by CT according to WHO criteria,¹¹ Eastern Collaborative

Results

148 patients with stage IIIB (wet) or stage IV NSCLC were enrolled from Dec 14, 2005, to July 3, 2007, from 23 centres in France, Poland, Germany, and Hungary. 74 patients were allocated to each treatment group; a total of 145 patients received treatment (figure 1). Patient characteristics were well balanced between groups. During monitoring, it became apparent that one patient in the TG4010 group had a performance status of 2 at inclusion, which was a violation of inclusion criteria; he was

Discussion

Addition of TG4010 to first-line chemotherapy in patients with advanced NSCLC resulted in 6-month PFS of 43·2%, exceeding the target of 40%. Moreover, other parameters of clinical outcome seemed to be improved by the addition of the therapeutic vaccine. Lung cancer and several other malignancies are often accompanied by an overexpression of MUC1 by tumour cells.18, 19, 20 The reduced and aberrant glycosylation of MUC1 associated with overexpression contributes to its immunogenicity and makes it

References (28)

R Digumarti et al.
A randomized, double-blind, placebo-controlled, phase II study of oral talactoferrin in combination with carboplatin and paclitaxel in previously untreated locally advanced or metastatic non-small cell lung cancer
J Thorac Oncol
(2011)
R Ramlau et al.
A phase II study of TG4010 (Mva-Muc1-Il2) in association with chemotherapy in patients with stage III/IV non-small cell lung cancer
J Thorac Oncol
(2008)
E Vivier et al.
Regulatory natural killer cells: new players in the IL-10 anti-inflammatory response
Cell Host Microbe
(2009)
J Ferlay et al.
Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008
Int J Cancer
(2010)
S Ramalingam et al.
Systemic chemotherapy for advanced NSCLC: recent advances and future directions
Oncologist
(2008)
CG Azzoli et al.
American Society of Clinical Oncology. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer
J Clin Oncol
(2009)
J Vansteenkiste et al.
Final results of a multi-center, double-blind, randomized, placebo-controlled phase II study to assess the efficacy of MAGE-A3 immunotherapeutic as adjuvant therapy in stage IB/II non-small cell lung cancer (NSCLC)
Proc Am Soc Clin Oncol
(2007)
C Butts et al.
A multi-centre phase IIB randomized controlled study of BLP25 liposome vaccine (L-BLP25 or Stimuvax) for active specific immunotherapy of non-small cell lung cancer (NSCLC): updated survival analysis [abstract B1–01]
J Thorac Oncol
(2007)
J Nemunaitis et al.
Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small-cell lung cancer
J Clin Oncol
(2006)
S Cohen et al.
TG-4010 Transgene
Curr Opin Investig Drugs
(2004)

LH Sobin et al.

International Union Against Cancer (UICC) TNM classification of malignant tumors

(2002)

AB Miller et al.

Reporting results of cancer treatment

Cancer

(1981)

E6 (R1). Good clinical practice: consolidated guideline

SJ Pocock et al.

Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trials

Biometrics

(1975)

Cited by (229)

A systematic review of interleukin-2-based immunotherapies in clinical trials for cancer and autoimmune diseases
2023, eBioMedicine
The cytokine interleukin-2 (IL-2) can stimulate both effector immune cells and regulatory T (Treg) cells. The ability of selectively engaging either of these effects has spurred interest in using IL-2 for immunotherapy of cancer and autoimmune diseases. Thus, numerous IL-2-based biologic agents with improved bias or delivery towards effector immune cells or Treg cells have been developed. This study systematically reviews clinical results of improved IL-2-based compounds.
We searched the ClinicalTrials.gov database for registered trials using improved IL-2-based agents and different databases for available results of these studies.
From 576 registered clinical trials we extracted 36 studies on different improved IL-2-based compounds. Adding another nine agents reported in recent literature reviews and based on our knowledge totalled in 45 compounds. A secondary search for registered clinical trials of each of these 45 compounds resulted in 141 clinical trials included in this review, with 41 trials reporting results.
So far, none of the improved IL-2-based compounds has gained regulatory approval for the treatment of cancer or autoimmune diseases. NKTR-214 is the only compound completing phase 3 studies. The PIVOT IO-001 trial testing the combination of NKTR-214 plus Pembrolizumab compared to Pembrolizumab monotherapy in metastatic melanoma missed its primary endpoints. Also the PIVOT-09 study, combining NKTR-214 with Nivolumab compared to Sunitinib or Cabozantinib in advanced renal cell carcinoma, missed its primary endpoint. Trials in autoimmune diseases are currently in early stages, thus not allowing definite conclusions on efficacy.
This work was supported by public funding agencies.
Armored modified vaccinia Ankara in cancer immunotherapy
2023, International Review of Cell and Molecular Biology
Cancer immunotherapy relies on unleashing the patient´s immune system against tumor cells. Cancer vaccines aim to stimulate both the innate and adaptive arms of immunity to achieve durable clinical responses. Some roadblocks for a successful cancer vaccine in the clinic include the tumor antigen of choice, the adjuvants employed to strengthen antitumor-specific immune responses, and the risks associated with enhancing immune-related adverse effects in patients.
Modified vaccinia Ankara (MVA) belongs to the family of poxviruses and is a versatile vaccine platform that combines several attributes crucial for cancer therapy. First, MVA is an excellent inducer of innate immune responses leading to type I interferon secretion and induction of T helper cell type 1 (Th1) immune responses. Second, it elicits robust and durable humoral and cellular immunity against vector-encoded heterologous antigens. Third, MVA has enormous genomic flexibility, which allows for the expression of multiple antigenic and costimulatory entities. And fourth, its replication deficit in human cells ensures a excellent safety profile.
In this review, we summarize the current understanding of how MVA induces innate and adaptive immune responses. Furthermore, we will give an overview of the tumor-associated antigens and immunomodulatory molecules that have been used to armor MVA and describe their clinical use. Finally, the route of MVA immunization and its impact on therapeutic efficacy depending on the immunomodulatory molecules expressed will be discussed.
Oncolytic virotherapy in lung cancer
2023, International Review of Cell and Molecular Biology
Lung tumors are one of the most aggressive threats affecting humans. Current therapeutic approaches have improved patients’ survival; however, further efforts are required to increase effectiveness and protection against tumor relapse and metastasis. Immunotherapy presents an alternative to previous treatments that focuses on stimulating of the patient’s immune system to destroy tumor cells. Viruses can be used as part of the immune therapeutic approach as agents that could selectively infect tumor cells, triggering an immune response against the infection and against the tumor cells. Some viruses have been selected for specifically infecting and destroying cancer cells, activating the immune response, enhancing access, amplifying the cytotoxicity against the tumor cells, and improving the long-term memory that can prevent tumor relapse. Oncolytic virotherapy can then be used as a strategy to target the destruction of transformed cells at the tumor site and act in locations distant from the primary targeted tumor site. Some of the current challenges in lung cancer treatment can be addressed using traditional therapies combined with oncolytic virotherapy. Defining the best combination, including the choice of the right settings will be at the next frontier in lung cancer treatment.
Lung cancer and oncolytic virotherapy——enemy's enemy
2023, Translational Oncology
Lung cancer is one of the malignant tumors that seriously threaten human health worldwide, while the covid-19 virus has become people's nightmare after the coronavirus pandemic. There are too many similarities between cancer cells and viruses, one of the most significant is that both of them are our enemies. The strategy to take the advantage of the virus to beat cancer cells is called Oncolytic virotherapy. When immunotherapy represented by immune checkpoint inhibitors has made remarkable breakthroughs in the clinical practice of lung cancer, the induction of antitumor immunity from immune cells gradually becomes a rapidly developing and promising strategy of cancer therapy. Oncolytic virotherapy is based on the same mechanisms that selectively kill tumor cells and induce systemic anti-tumor immunity, but still has a long way to go before it becomes a standard treatment for lung cancer. This article provides a comprehensive review of the latest progress in oncolytic virotherapy for lung cancer, including the specific mechanism of oncolytic virus therapy and the main types of oncolytic viruses, and the combination of oncolytic virotherapy and existing standard treatments. It aims to provide new insights and ideas on oncolytic virotherapy for lung cancer.
Microbes in lung cancer initiation, treatment, and outcome: Boon or bane?
2022, Seminars in Cancer Biology
Lung cancer is the top reason for cancer-related deaths worldwide. The 5-year overall survival rate of lung cancer is approximately 20 % due to the delayed diagnosis and low response rate to regular treatments. Microbiota, both host-microbiota and alien pathogenic microbiota, have been investigated to be involved in a complicated and contradictory relationship with lung cancer initiation, treatments, and prognosis. Disorders of certain host-microbiota and pathogen infection are associated with the risk of lung cancers based on epidemiological evidence, and antibiotics (ATBs) could dramatically impair anti-cancer treatment efficacy, including chemotherapy and immunotherapy. Moreover, probiotics and microbe-mediated drugs are potential approaches to enhance regular anti-tumor treatments. Therefore, the knowledge of the complex dual effect of microbes on lung cancer is beneficial to take their essence and remove their dross. This review offers insight into the current trends and advancements in microbiota or microbial components related to lung cancer.
Purified mucins in drug delivery research
2021, Advanced Drug Delivery Reviews
One of the main challenges in the field of drug delivery remains the development of strategies to efficiently transport pharmaceuticals across mucus barriers, which regulate the passage and retention of molecules and particles in all luminal spaces of the body. A thorough understanding of the molecular mechanisms, which govern such selective permeability, is key for achieving efficient translocation of drugs and drug carriers. For this purpose, model systems based on purified mucins can contribute valuable information. In this review, we summarize advances that were made in the field of drug delivery research with such mucin-based model systems: First, we give an overview of mucin purification procedures and discuss the suitability of model systems reconstituted from purified mucins to mimic native mucus. Then, we summarize techniques to study mucin binding. Finally, we highlight approaches that made use of mucins as building blocks for drug delivery platforms or employ mucins as active compounds.

View all citing articles on Scopus

View full text

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

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Patients

Results

Discussion

J Thorac Oncol

J Thorac Oncol

Cell Host Microbe

Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008

Int J Cancer

Systemic chemotherapy for advanced NSCLC: recent advances and future directions

Oncologist

American Society of Clinical Oncology. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer

J Clin Oncol

Final results of a multi-center, double-blind, randomized, placebo-controlled phase II study to assess the efficacy of MAGE-A3 immunotherapeutic as adjuvant therapy in stage IB/II non-small cell lung cancer (NSCLC)

Proc Am Soc Clin Oncol

A multi-centre phase IIB randomized controlled study of BLP25 liposome vaccine (L-BLP25 or Stimuvax) for active specific immunotherapy of non-small cell lung cancer (NSCLC): updated survival analysis [abstract B1–01]

J Thorac Oncol

Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small-cell lung cancer

J Clin Oncol

TG-4010 Transgene

Curr Opin Investig Drugs

International Union Against Cancer (UICC) TNM classification of malignant tumors

Reporting results of cancer treatment

Cancer

E6 (R1). Good clinical practice: consolidated guideline

Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trials

Biometrics

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