Lymph node metastases associate with an aggressive disease progression and decreased survival of patients suffering from various solid malignancies. In the case of HNSCC, lymph nodes (LNs) metastasis is a critical clinical manifestation that predicts patient survival. Accordingly, the survival of patients with LN metastases is about half of that of patients without the tumor being spread to the LNs. Although many efforts have been invested in recent years to profile primary HNSCC tumors to enable interventions through precision oncology-based therapies, the genomics of HNSCC LN metastases remain largely unexplored.
In this broad collaborative study that we have initiated a few years ago, we have been employing whole-exome sequencing to profile the genomic landscapes of matched normal, primary, and metastatic tissues from a cohort of HNSCC patients in terms of mutations and copy number variations. The genomic findings are being correlated with clinical parameters, which are available for all patients. Of particular interest are genomic aberrations that correlate with patient responses to various treatment modalities and molecular signatures that may link to and predict various clinical features. Likewise, efforts are in progress to identify and characterize various molecular subtypes of HNSCC that could be subjected to precision-based interventions and to understand phylogenetic processes underlying the evolution of these tumors.
Despite major investigational efforts, GBM remains a main clinical challenge due to the limited efficacies of the currently used intervention modalities. The MET receptor tyrosine kinase is ubiquitously and aberrantly expressed in GBM. Along with immune checkpoint inhibitors (ICIs), CAR T-based immunotherapy is establishing itself as an important and highly efficient therapeutic strategy. So far, CAR T interventions have been clinically approved for hematopoietic malignancies, however, major attempts are performed to overcome hurdles associated with efficient tumor eradication of solid cancers. In the case of ICIs, remarkable preclinical, as well as clinical results have been reported when combined with RT due to the so-called abscopal effect. Moreover, the mechanisms underlying immune pre-conditioning by RT, which enable the abscopal effect, have been elucidated.
In our studies, we aim to evaluate an anti-MET CAR T strategy along with RT (employing the irradiation-imaging SMART platform) for GBM. The studies use a panel of both long-term as well as GBM stem cells that are being evaluated both in vitro and within orthotopic animal models. Patients-derived xenograft orthotopic models will be established as well.
It is foreseen that additional CAR T-based approaches using antigens other than MET and in combination with RT for additional tumor types, will be established in the near future.