Immunotherapy in the First-Line Treatment of NSCLC: Current Status and Future Directions in China

Zhang

et al. 2022

Front. Oncol.

Lung cancer is the leading cause of cancer-related deaths worldwide. As the most prevalent molecular mutation subtypes in non-small cell lung cancer (NSCLC), EGFR-TKIs are currently a standard first-line therapy for targeting the mutated EGFR in advanced NSCLC patients. However, 20-30% of this subset of patients shows primary resistance to EGFR-TKIs. Patients with co-mutations of EGFR and several other genes have a poor response to EGFR-TKIs, whereas the prognostic and predictive significance of EGFR/TP53 co-mutation in NSCLC patients remains controversial. Meanwhile, little is known about how to choose an optimal therapeutic strategy for this subset of patients. Presently, no drugs targeting TP53 mutations are available on the market, and some p53 protein activators are in the early stage of clinical trials. A combination of EGFR-TKIs with antiangiogenic agents or chemotherapy or other agents might be a more appropriate strategy to tackle the problem. In this review, we describe the prognostic and predictive value of EGFR/TP53 co-mutation in NSCLC patients, investigate the mechanisms of this co-mutation affecting the response to EGFR-TKIs, and further explore optimal regimens effectively to prolong the survival time of the NSCLC patients harboring this co-mutation.

Section: Clinical Implications In Advanced Egfr-mutated Nsclc Patient...mentioning

confidence: 99%

TP53 Co-Mutations in Advanced EGFR-Mutated Non–Small Cell Lung Cancer: Prognosis and Therapeutic Strategy for Cancer Therapy

Zhang

et al. 2022

Front. Oncol.

“…The incidence and mortality of cancer have increased rapidly in recent years, of which solid tumors account for the majority ( 1 ). According to the data from the Global Cancer Observatory, lung cancer accounts for 23.8% of all cancer deaths ( 2 ), of which non-small cell lung cancer (NSCLC) accounts for 85% of the diagnoses ( 3 ). Studies on antitumor treatments have greatly developed, but an effective therapy is still important and urgent ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

A SIRPαFc Fusion Protein Conjugated With the Collagen-Binding Domain for Targeted Immunotherapy of Non-Small Cell Lung Cancer

Meng

et al. 2022

Front. Immunol.

The SIRPαFc fusion protein can block the immunosuppressive CD47-SIRPα signal between macrophages and tumor cells as a decoy receptor and has demonstrated its immunotherapeutic efficacy in various tumors. However, its clinical application was limited because of the potential hematologic toxicity. The heptapeptide “TKKTLRT” is a collagen-binding domain (CBD) which can bind collagen specifically. Herein, we aim to improve the tumor targeting of SIRPαFc and therefore avoid its unnecessary exposure to normal cells through synthesizing a TKKTLRT–SIRPαFc conjugate. Experiments at molecular and cellular levels indicate that the TKKTLRT–SIRPαFc conjugate-derived collagen-binding affinity and the introduction of CBD did not impact the CD47-binding affinity as well as its phagocytosis-promoting effect on NSCLC cells. In vivo distribution experiments showed that CBD–SIRPαFc accumulated in tumor tissue more effectively compared to unmodified SIRPαFc, probably due to the exposed collagen in the tumor vascular endothelium and stroma resulting from the abnormal vessel structure. On an A549 NSCLC nude mouse xenograft model, CBD–SIRPαFc presented more stable and effective antitumor efficacy than SIRPαFc, along with significantly increased CD11b+F4/80+ macrophages especially MHC II+ M1 macrophages within tumors. All of these results revealed that CBD brought a tumor-targeting ability to the SIRPαFc fusion protein, which contributed to the enhanced antitumor immune response. Altogether, the CBD–SIRPαFc conjugate may have the potential to be an effective tumor immunotherapy with improved antitumor efficacy but less non-tumor-targeted side effect.

“…Immune checkpoint inhibitors (ICIs), including programmed death molecule 1 (PD-1) and cytotoxic T cell associated antigen 4 (CTLA-4) inhibitors, have substantially improved the prognosis of a variety of cancers ( 1 – 3 ). Although ICIs have become the first-line treatment for a variety of solid tumors, immune related adverse events (irAEs) are increasingly recognized with the widespread utilization of these drugs ( 4 , 5 ).…”

Section: Introductionmentioning

confidence: 99%

“…Physiologically, PD-1 or CTLA-4 combined with its ligands can inhibit T cell activation, prevent over activation of human immune system and avoid autoimmune diseases ( 1 – 3 ). As important advances in tumor therapy in recent years, ICIs mainly take effect by inhibiting immune checkpoints through antibodies [such as PD-1, Programmed cell death 1 ligand 1 (PD-L1), CTLA-4, etc.…”

Section: Introductionmentioning

confidence: 99%

Cardiotoxicity Related to Immune Checkpoint Inhibitors: A Real-World Retrospective Analysis

She

Front. Cardiovasc. Med.

et al. 2022

BackgroundCardiotoxicity related to immune checkpoint inhibitors (ICIs) is a rare but potentially lethal. In ICI-associated adverse events, evidence of cardiotoxicity and clinical predictive factors related to ICI is lacking. Here, we aim to assess the incidence and predictive factors of cardiotoxicity related to ICIs in real-world practice.ObjectiveWe retrospectively analyzed consecutive patients who received PD-1 or PD-L1 at the First Affiliated Hospital of Xi'an Jiaotong University. Clinical characteristics and cardiac lesion markers were collected both at baseline and during longitudinal follow-up from the Biobank database. Follow-up CKMB and NT-proBNP levels and ratios were then evaluated.ResultsA total of 2,304 patients with either PD-1 or PDL-1 utilization between August 2018 and April 2021 were collected. The average age was 59.44 ± 11.45 among PD-1 inhibitor utilizer and 58.97 ± 12.16 among PDL-1 inhibitor utilizer. The baseline creatine kinase isoenzyme MB (CKMB) levels were 17 ± 19 U/L in PD-1 inhibitor users and 17 ± 23 U/L in PDL-1 inhibitor users. Majority of patients were male, with advanced stage cancer, and received ICIs as second-line therapy. The longitudinal change of cardiac enzymes and NT-pro BNP were collected. Cardiac lesion as defined by three times increase of CKMB happens in only minority of patients receiving ICIs therapy. It is also identified that increased CKMB happened in PD-1 inhibitor groups, but not PDL-1 inhibitor groups.ConclusionWe evaluated the profile of cardiotoxicities caused by ICIs based on real-world experience. The cardiac lesion markers are generally unaltered, but it appears that the increased CKMB happened in PD-1 inhibitor groups, but not PDL-1 inhibitor groups.