Lung cancer: Targ eted vaccine therapy on wayDecember 13, 2018
Efforts to develop vaccines against lung cancer always stalled in the face of challenges and several previous attempts have proved ineffective. It is now recognised that immune-suppressive factors exist in the microenvironment of tumour cells. The local immunosuppression arises from the interplay of cellular and metabolic functions to regulate inflammation. Understanding the fundamental basis of the cancer-immunity cycle has significantly boosted vaccine efforts.
A recent analysis of the global immune-oncology landscape that appeared in Annals of Oncology shows that there are more cancer vaccines under clinical investigation than any other class of therapeutic agents. There are more than 340 agents under clinical trials and another estimated 260 candidates in preclinical and discovery stages as of September 2017.
CIMAVax-EGF: Combo trials
CIMAvax-EGF is a therapeutic vaccine being tested against advanced NSCLC, developed by the Center of Molecular Immunology, Havana, Cuba. It is composed of recombinant human EGF chemically conjugated to a recombinant carrier protein, p64, from Neisseria meningitidis. Results from a randomized phase III trial conducted in Cuba between 2006 and 2012 on a total of 405 patients with advanced NSCLC showed that the overall survival (OS) was numerically higher in the vaccine arm (receiving at least 1 dose of vaccine) versus control. In the analysis of per-protocol population, consisting of patients who received at least 4 vaccine doses, median OS was 12.4 months versus 9.4 months in the control group. The survival effect was even better for patients who had high EGF concentration (serum EGF >870 pg/ml) at baseline: Median OS for vaccinated patients in this group was 14.7 versus 8.6 months in the matched control group.
A study (NCT02955290) to evaluate the efficacy of CIMAvax-EGF in combination with nivolumab as second-line therapy for advanced NSCLC commenced recruitment in December 2016.
Another randomized international phase III study of CIMAvax-EGF in combination with first-line platinum-based chemotherapy for patients with stage IV NSCLC is ongoing.
Vx-001 targeting TERT
Vx-001, a peptide-based vaccine developed by Paris-based Vaxon Biotech, is currently in Phase II clinical studies. It is designed to elicit immunogenicity of the cryptic epitope derived from telomerase reverse transcriptase (TERT), a universal tumour antigen, in order to bind human leukocyte antigen A2 (HLA-A2) positive T cells. Data from a randomized, double-blind, placebo-controlled, phase IIb clinical trial in about 190 HLA-A2–positive patients with metastatic or recurrent NSCLC after platinum-based first-line chemotherapy found no significant differences in OS between the groups treated with Vx-001 and placebo. However, 29% of patients, who were able to develop a vaccine-specific immune response, demonstrated higher OS compared with non-responders (21 vs 13 months, P = .004). A subset analysis also found better OS with vaccine, among patients who were never-smokers or light smokers and had non-immunogenic tumours, with median OS of 20.2 months versus 7.9 months. Vaxon has plans to investigate Vx-001 in combination with immune checkpoint inhibitors in the population of patients with non-immunogenic NSCLC.
Racotumomab: Anti-idiotype mAb
Racotumomab (Vaxira) is a therapeutic vaccine that is currently under clinical development by Recombio, an international public-private consortium, in association with the Center of Molecular Immunology at Havana, Cuba (CIM) and researchers from Buenos Aires University and the National University of Quilmes in Argentina.
It is an anti-idiotype monoclonal antibody (mAb) against ganglioside containing NeuGcGM3, a Neu glycolyl (NeuGc). NeuGcGM3 ganglioside is expressed in NSCLC. Anti-idiotypic antibodies are capable of eliciting an immunogenic reaction against the original epitope of the selected antigen as they mimic the nominal antigen. Final results are awaited from a randomized phase III trial (NCT01460472) of racotumomab in about 1,080 patients carried out in South America and Southeast Asia.
Tumour neoantigens approach
An alternative vaccine approach gaining currency recently is the targeting of tumour neoantigens that arise from somatic mutations. These neoantigens are tumour-specific and highly immunogenic. They are individualized vaccines comprising multiple RNA or peptide-based neoepitopes identified after whole exome sequencing of the tumour tissue in each patient. Several clinical trials are underway pursuing the neoantigens approach in combination with anti-PD1/PD-L1 drugs. Studies such as NEO-PV-01, RO7198457, mRNA-4157, NCT02897765, NCT03289962 and NCT03313778 are among them.