Translational studies in the GEMMK trial: Optimising immunotherapy in leiomyosarcoma and undifferentiated pleomorphic sarcoma
Despite significant advances taking place for immunotherapies across many cancers, success in soft tissue sarcomas (STS) has been limited. Patient outcomes for advanced/metastatic sarcomas are poor, and since the early 1970s the standard first-line therapy of doxorubicin-based chemotherapy for advanced/metastatic STS has remained unchanged. Immunotherapies including the immune checkpoint inhibitor (CPI) pembrolizumab (Pem) have shown modest benefit in certain subtypes of STS, including undifferentiated pleomorphic sarcomas (UPS). However, the majority of STS tumours are considered “immune cold” and therefore there is rationale to evaluate combination therapies that can modulate immunotherapy response. STS are highly heterogeneous, and in particular there is an incomplete understanding of the biology of STS tumours and the immune landscape that dictates therapy response. Accordingly, there are no predictive biomarkers available to identify the patients most likely to benefit from treatment. The GEMMK trial (NCT03123276) is a phase I study to establish the safety, tolerability and pharmacokinetics of Pem in combination with gemcitabine (Gem) in patients with newly diagnosed metastatic or inoperable leiomyosarcoma (LMS) and UPS. We hypothesize that defining the molecular and immune features in paired patient specimens will a) delineate candidate mechanisms of therapy resistance in LMS and UPS and b) lead to the identification of candidate biomarkers of therapy response. Tumour specimens from patients enrolled on the GEMMK trial from 2 timepoints (pre-treatment and at cycle 3 of treatment with Gem/Pem) will be subjected to multi-omic profiling by RNAseq and mass spectrometry-based proteomics. Ontology analysis and protein-protein interaction mapping will be used to define the key molecular alterations associated with Gem/Pem treatment. In addition, we will perform multiplexed immunofluorescence using markers for immune cells to generate spatial proteomic maps of tumour cell-immune cell and cell-microenvironmental interactions in situ. Integrating the immune landscape alterations in response to Gem/Pem therapy with multi-omic characterization of tumours will lead to a better mechanistic understanding of the factors that influence response or resistance. This translational work will address our current knowledge gap to better understand the heterogeneity that underlies treatment responses to CPI + chemotherapy in STS. The potential to impact patients is through the identification of biomarkers that can target therapy to patients most likely to receive long-term durable benefit, while sparing those with inadequate benefit from toxicities associated with futile drug exposure. In addition, a deeper biological understanding may lead to the identification of novel therapeutic strategies to overcome CPI resistance. Ultimately, we anticipate translating these discoveries into prospective trials to deliver better outcomes for STS patients.