Undisclosed immune evasion therapeutic / Tango Therap, Gilead - LARVOL DELTA

TNG260 is a Small-Molecule CoREST Inhibitor that Sensitizes STK11-Mutant Tumors to Anti-PD-1 Immunotherapy. (PubMed, Cancer Res) - P1/2 | "In the tumors of patients with STK11-deficient cancers on a clinical trial (NCT05887492), treatment with a combination of TNG260 and pembrolizumab increased intratumoral histone acetylation, PD-L1 tumor proportion scores, and T cell infiltration into the tumor microenvironment. This study illustrates a promising treatment strategy for addressing immune evasion in STK11-mutant NSCLC patients."

IO biomarker • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HDAC1 • PD-L1 • STK11

TNG260, a small molecule CoREST inhibitor, sensitizes STK11-mutant NSCLC to anti-PD1 immunotherapy (AACR 2024) - P1/2 | "In vivo CRISPR screens in tumor-bearing immune competent mice identified the Corepressor of Repressor Element 1 Silencing Transcription (CoREST) complex as a synthetic lethal immune evasion target for STK11- mutant tumors. This work identifies new vulnerabilities in STK11 LOF cancers that can be exploited therapeutically. TNG260 is currently being investigated in combination with pembrolizumab for the treatment of STK11-mutant cancer (NCT05887492), including NSCLC."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CDK7 • KRAS • STK11 • TP53

CoREST inhibition by TNG260 increases expression of immunomodulatory genes in STK11-mutant cancer and sensitizes to immune checkpoint blockade (SITC 2023) - "Background Loss of function mutations in STK11 drive immune evasion and cause resistance to immune checkpoint blockade...Similarly, the AXL inhibitor, bemcentinib, provided a minor enhancement to the tumor growth inhibition seen with anti-PD1 as a single agent in this model...Unlike other small molecules being combined with anti-PD1 for STK11-deficient NSCLC, the combination of TNG260 with anti-PD1 drives tumor regressions in STK11-deficient models that are typically resistant to anti-PD1 monotherapy. TNG260 is under investigation in a Phase 1/2 study as a single agent and in combination with pembrolizumab for patients with STK11-mutated, advanced solid tumors."

Checkpoint block • Checkpoint inhibition • Immunomodulating • IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IFNG • STK11

In vivo CRISPR screens identify HDAC1 as an immune sensitizer reversing immune resistance driven by STK11 loss (SITC 2022) - "A two-step approach was taken to uncover tumor suppressor gene loss driving immune evasion as step one, and immune sensitizers specifically reversing the immune evasion driven by certain tumor suppressor loss as step two...STK11 mutations are found in ~15% of non-squamous non-small cell lung cancer and have been reported as a predictor of primary resistance to PD-1 blockade. Inhibitors selectively targeting HDAC1 & 2 in combination with anti-PD1 represent a promising therapeutic opportunity for non-small cell lung cancer patients with STK11 mutations."

IO biomarker • Preclinical • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HDAC1 • STK11

TNG260, a CoREST-selective deacetylase inhibitor, reverses anti-PD1 resistance driven by loss of STK11 (SITC 2022) - "It reverses the immune evasion phenotype caused by loss of STK11 and induces tumor regressions in an STK11-mutant model in combination with α-PD1. The TNG260 clinical development plan will be among the first to combine the power of genetic patient selection and immunotherapy, evaluating patients with STK11 mutant cancers in a trial combining TNG260 and a checkpoint inhibitor."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HDAC3 • STK11

"#TumorBoardTuesday Tango Therapeutics is looking to develop an undisclosed target to reverse the immune evasion effects of STK11 loss-of-function mutations. 🔗⬇️ https://t.co/JvbXMKVMCH" (@ShimaghavimiMD)

Oncology • STK11

[VIRTUAL] In vivo CRISPR screen identifies tumor suppressors as drivers of tumor cell-intrinsic immune evasion (AACR 2021) - "STK11/LKB1 and/or KEAP1 genomic alterations are found in ~25% of non-squamous non-small cell lung cancer and have been reported as a major predictor of primary resistance to PD-1 blockade. Together, these data demonstrate that high-throughput in vivo genetic screens can identify tumor cell-intrinsic drivers of immune evasion and establish murine system relevant to the study of primary resistance to PD-1 axis immunotherapy and more generally, tumor cell-intrinsic immune evasion."

IO biomarker • Preclinical • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ADAR • CD47 • KEAP1 • STK11