1. Advances in the Management of Lung Cancer:
Vaccines, Their Use and Future
Mr Syed Mohiyaddin1, Dr Nathan Tyson1, Dr Kire Temov1
1Department of Cardiothoracic Surgery, Morriston Hospital
Background
Objectives
Methodology
The last updated figures on lung cancer in 2012 revealed, an estimated 1.8 million were diagnosed with lung cancer — of which 46, 403 were diagnosed in the UK in 2014 (Cancer Research UK). The 5-year overall survival rate for lung cancers is 18%. Overall, incidence rates have declined about 2% per year over the past decade and death rates have declined at about the same rate.
Investigational monotherapies and combinatorial immunotherapies may help to improve these outcomes and are under investigation, including chimeric antigen receptor (CAR) T cell therapies, immune checkpoint inhibitors, and cancer vaccines2,3. Efforts to develop lung cancer vaccines began more than 20 years ago but initially met with disappointment.
In the past clinical trials for at least 7 therapeutic vaccines were initiated against non–small cell lung cancer (NSCLC) in the United States but, most failed to yield clear evidence of efficacy, at least in part because of insufficient immune activation against lung tumors 4-6. Large phase 3 clinical trial results dashed hopes for 3 different NSCLC vaccines that showed promise in phase 2 trials: MAGE-A3, tecemotide, and belagenpumatucel-L 5.
Two other NSCLC vaccines — TG4010 and CIMAvax-EGF — appear to be promising may be long-awaited advances in this field 7-9.
TG4010 is an attenuated, recombinant vaccinia virus that expresses interleukin 2 and the tumour-expressed antigen MUC1.7 The CIMAvax-EGF vaccine was developed in Cuba, where it is now approved for use. It is a recombinant conjugate vaccine with human epidermal growth factor (EGF) attached to a carrier protein8,10,11. Both vaccines show promise in clinical studies.
In a phase 2b component of the TIME study (ClinicalTrials.gov Identifier: NCT ), adding TG4010 to standard frontline chemotherapy improved progression-free survival (PFS) among patients with advanced NSCLC (5.9 months vs 5.1 months in placebo-group patients) — without serious grade 3 or 4 vaccine-related adverse reactions.
CIMAvax-EGF induces immune responses against EGF to block cancer cell proliferation.10 Already used to treat more than 5000 patients in Cuba, CIMAvax-EGF is under study in combination with nivolumab at Roswell Park Cancer Institute in Buffalo, New York, in collaboration with the Center of Molecular Immunology in Cuba 9. The binational, 2-part phase 1/2 study (ClinicalTrials.gov Identifier: NCT ) was initiated in January 2017, enrolling patients with advanced, previously treated NSCLC12.
An automated search for "vaccine" and "EGF" was conducted in PubMed, resulting in 17 articles published by Cuban authors between January 1, 1994 and September 30, Main findings were described and discussed, along with unpublished preliminary findings of an initial ongoing phase III clinical trial.
Overall aim is to review pre-clinical and clinical research conducted during development of CIMAvax EGF, primarily studies published by Cuban investigators in international peer-reviewed scientific journals, and evaluate the evidence for vaccine use in lung cancer.
Results
Discussion
Articles reviewed describe five phase I/II and one phase II clinical trials conducted in Cuba in
A non-controlled study resulted in the earliest published scientific evidence of the feasibility of inducing an immune response against autologous EGF in patients with different advanced stage tumours.
Subsequent controlled, randomized trials included patients with advanced stage (IIIB/IV) NSCLC. The 2 and 3rd phase I/II trials differentiated immunized patients as poor antibody responders (PAR) and good antibody responders (GAR), according to their anti-EGF antibody response, and confirmed greater immunogenicity with Montanide ISA 51 adjuvant in the vaccine formulation, as well as the benefits of low-dose cyclophosphamide treatment 72 hours before the first immunization.
The 4th phase I/II trial found increased immunogenicity with an increased dose divided in 2 anatomical sites and also established correlation between Ab titers, serum EGF concentration and length of survival. In the first 4 phase I/II trials and the phase II trial, vaccine was administered after chemotherapy (ChTVV schedule).
In the 5th phase I/III trial, longer survival and increased immunogenicity were achieved using a VChTV schedule and dividing the vaccine dose in 4 anatomical sites.Longer survival was observed in all vaccinated patients compared to controls, and the difference was significant (p < 0.05) in the group aged <60 years.
Currently, vaccination against lung carcinomas is not in routine clinical practice. Whilst is has been difficult to develop immunotherapies in NSCLC in particular, a number of authors have reported promising survival outcomes in a number of clinical trials.
Mostly directed against EGF, three immunotherapy agents have been shown to significantly increase survival, particularly in patients aged <60 years.
Phase II/III trials have clearly demonstrated that immunotherapies against NSCLC have a proven role in the management of carcinoma as part of a treatment regime alongside traditional immunotherapy drugs.