Lymph node spread is the defining feature of stage III, locally advanced non-small cell lung cancer (NSCLC), often indicating a poorer prognosis. Following concurrent chemoradiation, consolidation durvalumab has improved the survival of this patient cohort (the Pacific trial) and is now a standard of care. To assess the optimal integration of immunotherapy, we launched a phase 2 clinical trial testing concurrent immunotherapy instead of chemotherapy alongside radiation. Despite expecting better efficacy with fewer side effects, we observed a high rate of adverse events and early disease progression. We are delving into these findings to better the treatment for patients with lymph node metastases through several ongoing projects:
- A biomarker trial to investigate the chemokines and cytokines associated with toxicities in cancer patients undergoing immunotherapy and radiotherapy.
- Examination of the tumor microenvironment in a humanized mouse model of NSCLC treated with immunotherapy and radiation.
- Establishment of an ultrasensitive, optical imaging-guided orthotopic model for locally advanced lung cancer, in collaboration with the BIRT laboratory and the Kim laboratory.
- Validation of targets generated from an in vivo CRISPR screen designed to uncover metabolic regulators of lymph node metastasis.
Potential impact
We anticipate providing mechanistic understanding of clinical trial observations through the examination of patient biospecimens and in vivo modeling in mice. We expect to establish an ultrasensitive, optical imaging-guided animal model for locally advanced lung cancer enabling preclinical therapeutic testing to inform future clinical trial designs. Through the validation of in vivo CRISPR screens designed to unveil metabolic regulators of lymph node metastasis, we aim to develop therapies to prevent lymph node metastasis.
Techniques
In vivo CRISPR screens, modeling lymph node metastasis in orthotopic and syngeneic mouse models, optical/functional/metabolic imaging techniques, biochemical engineering, multiplex cytokine analysis, CYTOF, multi-omics analysis and metastatic assays, patient biospecimen analyses and outcome assessment.