https://escholarship.org/content/qt76g4v3qj/qt76g4v3qj.pdf?t=qeu5lr

Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry

Tumor resistance to apoptosis and the immunosuppressive tumor microenvironment are two major contributors to poor therapeutic responses during cancer intervention. Pyroptosis, a lytic and inflammatory programmed cell death pathway distinct from apoptosis, has subsequently sparked notable interest among cancer researchers for its potential to be clinically harnessed and to address these problems. Recent evidence indicates that pyroptosis induction in tumor cells leads to a robust inflammatory response and marked tumor regression. Underlying its antitumor effect, pyroptosis is mediated by pore-forming gasdermin proteins that facilitate immune cell activation and infiltration through their release of pro-inflammatory cytokines and immunogenic material following cell rupture. Considering its inflammatory nature, however, aberrant pyroptosis may also be implicated in the formation of a tumor supportive microenvironment, as evidenced by the upregulation of gasdermin proteins in certain cancers. In this review, the molecular pathways leading to pyroptosis are introduced, followed by an overview of the seemingly entangled links between pyroptosis and cancer. We describe what is known regarding the impact of pyroptosis on anticancer immunity and give insight into the potential of harnessing pyroptosis as a tool and applying it to novel or existing anticancer strategies.

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Pyroptosis at the forefront of anticancer immunity.

Summary The discovery that mutations in the EGFR gene are detected in up to 50% of lung adenocarcinoma patients, along with the development of highly efficacious epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), has revolutionized the treatment of this frequently occurring lung malignancy Indeed, the clinical success of these TKIs constitutes a critical milestone in targeted cancer therapy Three generations of EGFR-TKIs are currently approved for the treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC) The first-generation TKIs include erlotinib, gefitinib, lapatinib, and icotinib; the second-generation ErbB family blockers include afatinib, neratinib, and dacomitinib; whereas osimertinib, approved by the FDA on 2015, is a third-generation TKI targeting EGFR harboring specific mutations Compared with the first- and second-generation TKIs, third-generation EGFR inhibitors display a significant advantage in terms of patient survival For example, the median overall survival in NSCLC patients receiving osimertinib reached 386 months Unfortunately, however, like other targeted therapies, new EGFR mutations, as well as additional drug-resistance mechanisms emerge rapidly after treatment, posing formidable obstacles to cancer therapeutics aimed at surmounting this chemoresistance In this review, we summarize the molecular mechanisms underlying resistance to third-generation EGFR inhibitors and the ongoing efforts to address and overcome this chemoresistance We also discuss the current status of fourth-generation EGFR inhibitors, which are of great value in overcoming resistance to EGFR inhibitors that appear to have greater therapeutic benefits in the clinic

Acquired resistance to third-generation EGFR-TKIs and emerging next-generation EGFR inhibitors.

The introduction of targeted treatments and more recently immune checkpoint inhibitors (ICI) to the treatment of metastatic non-small cell lung cancer (NSCLC) has dramatically changed the prognosis of selected patients. For patients with oncogene-addicted metastatic NSCLC harbouring an epidermal growth factor receptor (EGFR) or v-Raf murine sarcoma viral oncogene homologue B1 (BRAF) mutation or an anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) gene alteration (translocation, fusion, amplification) mutation-specific tyrosine kinase inhibitors (TKI) are already first-line standard treatment, while targeted treatment for other driver mutations affecting MET, RET, human epidermal growth factor receptor (HER) 2, tropomyosin receptor kinases (TRK) 1-3 and others are currently under investigation. The role of ICI in these patient subgroups is currently under debate. This article summarises a round-table discussion organised by ESMO Open in Vienna in July 2018. It reviews current clinical data on ICI treatment in patients with metastatic oncogene-addicted NSCLC and discusses molecular diagnostic assessment, potential biomarkers and radiological methods for response evaluation of ICI treatment. The round-table panel concluded ICI should only be considered in patients with oncogene-addicted NSCLC after exhaustion of effective targeted therapies and in some cases possibly after all other therapies including chemotherapies. More clinical trials on combination therapies and biomarkers for ICI therapy based on the specific differing characteristics of oncogene-addicted NSCLC need to be conducted.

Immune Checkpoint Inhibitor Treatment in Patients With Oncogene- Addicted Non-Small Cell Lung Cancer (NSCLC): Summary of a Multidisciplinary Round-Table Discussion

Since the discovery of RET fusion–positive (RET+) NSCLC around late 2011 to early 2012, clinical trials of multikinase inhibitors and highly potent and selective RET tyrosine kinase inhibitors have indicated that RET fusion is an actionable oncogenic driver in NSCLC. There seems to be a differential response to multikinase inhibitors depending on the fusion partner (KIF5B-RET versus non–KIF5B-RET); thus, knowledge of the fusion partners in RET+ NSCLC is important. To date, we identified 48 unique fusion partners in RET from published literature and congress proceedings. Two of the novel fusion partners (CCNYL2 and TRIM24) were identified in RET fusions that emerged as resistant to EGFR tyrosine kinase inhibitors. In addition, multiple intergenic rearrangements were identified.

Catalog of 5' fusion partners in RET+ NSCLC Circa 2020.

Rearranged during transfection (RET) has been proven to be a tumorigenic target in non-small cell lung cancers (NSCLCs). In RET-rearranged NSCLCs, molecular features and their impact on prognosis were not well illustrated, and the activity of mainstay therapeutics has not currently been well compared. Patients diagnosed with NSCLCs with RET rearrangements were analyzed for concomitant mutations, tumor mutation burden (TMB), PD-L1 expression, T cell receptor repertoire and clinical outcomes with chemotherapy, immune checkpoint inhibitors (ICIs), and multikinase inhibitors (MKIs). Among 129 patients with RET-rearranged NSCLC who were analyzed, 41.1% (53/129) had co-occurring genetic alterations by next-generation sequencing, and concomitant TP53 mutation appeared most frequently (20/53, 37.7%). Patients with concurrent TP53 mutation (n = 15) had shorter overall survival than those without (n = 30; median, 18.4 months [95% CI, 8.6–39.1] vs 24.8 months [95% CI, 11.7–52.8]; P < 0.05). Patients with lower peripheral blood TCR diversity (n = 5) had superior overall survival compared with those with higher diversity (n = 6; median, 18.4 months [95% CI, 16.9–19.9] vs 4.8 months [95% CI, 4.5–5.3]; P = 0.035). An association with overall survival was not observed for PD-L1 expression nor for tumor mutation burden level. Median progression-free survival was not significantly different across chemotherapy, ICIs, and MKIs (median, 3.5 vs 2.5 vs 3.8 months). For patients treated with ICIs, the disease control rate was 60% (6/10) and the objective response rate was 20% (2/10). RET-rearranged lung cancers can be heterogeneous in terms of concomitant genetic alterations. Patients with concurrent TP53 mutation or high peripheral blood TCR repertoire diversity have relatively inferior overall survival in this series. Outcomes with traditional systemic therapies in general are suboptimal.

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Association of genetic and immuno-characteristics with clinical outcomes in patients with RET-rearranged non-small cell lung cancer: a retrospective multicenter study

Next-generation sequencing based mutation profiling reveals heterogeneity of clinical response and resistance to osimertinib.

CTX110 Allogeneic CRISPR-Cas9-Engineered CAR T Cells in Patients (Pts) with Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL): Results from the Phase 1 Dose Escalation Carbon Study

Huamin Xu

Papers

Association of genetic and immuno-characteristics with clinical outcomes in patients with RET-rearranged non-small cell lung cancer: a retrospective multicenter study

Next-generation sequencing based mutation profiling reveals heterogeneity of clinical response and resistance to osimertinib.

CTX110 Allogeneic CRISPR-Cas9-Engineered CAR T Cells in Patients (Pts) with Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL): Results from the Phase 1 Dose Escalation Carbon Study