Tumor mutational burden is since October 2018 NCCN’s (National Comprehensive Cancer Network) newest and most recommended biomarker for selecting checkpoint-inhibitor Immunotherapy in Non-Small Cell Lung Cancer. Immunotherapy is often regarded as the promising cancer-cure solution and has undergone drastic investigations and improvement in last time. Tumor mutational burden comes as a novel result of the necessity of establishing emerging biomarkers for predicting treatments.
But why is TMB introducing a new scenario for checkpoint-inhibitor treatment when PD-1 also showed revolutionary therapy improvements?
Same as tumor-genesis, tumor treatment prescription is multifactorial including many features which must be taken into consideration when selecting the most convenient therapy since only one biomarker is not enough reliable. It is well known that tumor cells evade and remain undetectable for the host’s immune system.
What is more, they simulate to form part of the host’s organism and inactivate its protection mechanism. Responsible for this are receptors primarily expressed on T-lymphocytes called CTLA-4 (Cytotoxic T-lymphocyte antigen 4) and PD-1 (programmed death-1). Opposite, programmed death-ligand 1 (PD-Ll) is expressed on antigen-presenting cells (APC) and on tumor cells as well as CD80/86 ligands are found on APC. Once these ligands are bound to their respective receptors they down-regulate T-lymphocyte activation pathways and act as inhibitory checkpoint signals.
In 2011 the first checkpoint-inhibitor drug called Ipilimumab and targeting CTLA-4 was approved. Many other drugs blocking PD-1 such as Pembrolizumab and Nivolumab are nowadays available. However, PD-1, when targeted with inhibitory-checkpoint drugs, emerged to be too unreliable as little correlation was often observed regarding its concentration. Furthermore, there were cases reported in which negative PD-1 patients profited from Nivolumab.
Most probable reasons refer to transcriptional factors and expression pathways in different stages when analyzing PD-1 concentration in sample cells. On the other hand tumor, the mutational burden is attracting scientific community’s attention
because it appears to be a solider and more promising biomarker. TMB quantifies the number of nonsynonymous mutations carried out by a cancer cell per megabase (1MB=1000000 DNA basepairs) resulting in neoantigens which increasingly elicit an immune response. The high mutational load of the tumoral cell correlates with alterations in its DNA mismatch repair genes promoters like PMS2 (Mismatch repair endonuclease). It is also associated with Microsatellite instability (MSI) resulting from dysregulated DNA repair pathways and mutations in the polymerase ε gene (POLE). Probably to constant smoke exposure it is especially increased in Non-Small Cell Lung Cancer.
The NCNN alludes to one large scale trail (checkmate 026) to conclude that regardless PD-1 concentration, first-line combination therapy with Nivolumab and Ipilimumab register higher-free progression survival than chemotherapy in high TMB-NSCLC patients (42.6% vs. 13.2%). It also refers to Checkmate 227 trial to highlight no longer progression-free survival with Ipilumab than with chemotherapy regardless of high PD-1 expression among enrolled untreated NSCLC patients.
This finding may improve treatment guidelines also avoiding toxic platinum-based chemotherapy since immunotherapy in the first line is currently only prescribed in high PD-1 patients. However many issues concerning practical and theoretical use of TMB yet require to be solved. A lack of homogeneity regarding TMB numeric definition as well as inadequacy in TMB implementation in routine practice, still constitute main unsolved problems. Next-generation sequencing technique (NGS) is implementing rapidly but is until now not available for routine clinical diagnostics. Furthermore unsatisfactory time-frame obtaining results, as well as poor biopsy availability and different degree-immunogenicity mutations, are also limiting issues.
Although TMB is showing great benefit it is yet in an early stage and is too diffuse as to base a clear treatment guideline on it.
Nevertheless harnessing own immune-system with enhanced Immunotherapy biomarkers is ushering in cancer cure treatments to a new level. In this respect, the pursuit of promising immunohistochemistry markers in the tumor microenvironment as well as peripheral blood in order to establish an algorithm for prescribing the optimum first-line treatment has just begun.