Modulating immune inhibitory pathways has been a major recent breakthrough in cancer treatment. Checkpoint blockade antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programed cell-death protein 1 (PD-1) have demonstrated acceptable toxicity, promising clinical responses, durable disease control, and improved survival in some patients with advanced melanoma, non-small cell lung cancer (NSCLC), and other tumor types. About 20 % of advanced NSCLC patients and 30 % of advanced melanoma patients experience tumor responses from checkpoint blockade monotherapy, with better clinical responses seen with the combination of anti-PD-1 and anti-CTLA-4 antibodies. Given the power of these new therapies, it is important to understand the complex and dynamic nature of host immune responses and the regulation of additional molecules in the tumor microenvironment and normal organs in response to the checkpoint blockade therapies. In this era of precision oncology, there remains a largely unmet need to identify the patients who are most likely to benefit from immunotherapy, to optimize the monitoring assays for tumor-specific immune responses, to develop strategies to improve clinical efficacy, and to identify biomarkers so that immune-related adverse events can be avoided. At this time, PD-L1 immunohistochemistry (IHC) staining using 22C3 antibody is the only FDA-approved companion diagnostic for patients with NSCLC-treated pembrolizumab, but more are expected to come to market. We here summarize the current knowledge, clinical efficacy, potential immune biomarkers, and associated assays for immune checkpoint blockade therapies in advanced solid tumors.

Immunotherapy has become the central pillar of cancer therapy. Immune checkpoint inhibitors (ICIs), a major category of tumor immunotherapy, reactivate preexisting anticancer immunity. Initially, ICIs were approved only for advanced and metastatic cancers in the salvage setting after or concurrent with chemotherapy at a response rate of around 20–30% with a few exceptions. With significant progress over the decade, advances in immunotherapy have led to numerous clinical trials investigating ICIs as neoadjuvant and/or adjuvant therapies for resectable solid tumors. The promising results of these trials have led to the United States Food and Drug Administration (FDA) approvals of ICIs as neoadjuvant or adjuvant therapies for non-small cell lung cancer, melanoma, triple-negative breast cancer, and bladder cancer, and the list continues to grow. This therapy represents a paradigm shift in cancer treatment, as many early-stage cancer patients could be cured with the introduction of immunotherapy in the early stages of cancer. Therefore, this topic became one of the main themes at the 2021 China Cancer Immunotherapy Workshop co-organized by the Chinese American Hematologist and Oncologist Network, the China National Medical Products Administration and the Tsinghua University School of Medicine. This review article summarizes the current landscape of ICI-based immunotherapy, emphasizing the new clinical developments of ICIs as curative neoadjuvant and adjuvant therapies for early-stage disease.

Purpose: Although patients with advanced-stage non–small cell lung cancers (NSCLC) harboring MET exon 14 skipping mutations (METex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, clinical benefit is limited by primary and acquired drug resistance. The molecular basis for this resistance remains incompletely understood. Experimental Design: Targeted sequencing analysis was performed on cell-free circulating tumor DNA obtained from 289 patients with advanced-stage METex14-mutated NSCLC. Results: Prominent co-occurring RAS–MAPK pathway gene alterations (e.g., in KRAS, NF1) were detected in NSCLCs with METex14 skipping alterations as compared with EGFR-mutated NSCLCs. There was an association between decreased MET TKI treatment response and RAS–MAPK pathway co-occurring alterations. In a preclinical model expressing a canonical METex14 mutation, KRAS overexpression or NF1 downregulation hyperactivated MAPK signaling to promote MET TKI resistance. This resistance was overcome by cotreatment with crizotinib and the MEK inhibitor trametinib. Conclusions: Our study provides a genomic landscape of co-occurring alterations in advanced-stage METex14-mutated NSCLC and suggests a potential combination therapy strategy targeting MAPK pathway signaling to enhance clinical outcomes.

Development of anticancer treatments based on microRNA (miRNA/miR) such as miR-34a replacement therapy is limited to the use of synthetic RNAs with artificial modifications. Herein, we present a new approach to a high-yield and large-scale biosynthesis, in Escherichia coli using transfer RNA (tRNA) scaffold, of chimeric miR-34a agent, which may act as a prodrug for anticancer therapy. The recombinant tRNA fusion pre–miR-34a (tRNA/mir-34a) was quickly purified to a high degree of homogeneity (>98%) using anion-exchange fast protein liquid chromatography, whose primary sequence and post-transcriptional modifications were directly characterized by mass spectrometric analyses. Chimeric tRNA/mir-34a showed a favorable cellular stability while it was degradable by several ribonucleases. Deep sequencing and quantitative real-time polymerase chain reaction studies revealed that tRNA-carried pre–miR-34a was precisely processed to mature miR-34a within human carcinoma cells, and the same tRNA fragments were produced from tRNA/mir-34a and the control tRNA scaffold (tRNA/MSA). Consequently, tRNA/mir-34a inhibited the proliferation of various types of human carcinoma cells in a dose-dependent manner and to a much greater degree than the control tRNA/MSA, which was mechanistically attributable to the reduction of miR-34a target genes. Furthermore, tRNA/mir-34a significantly suppressed the growth of human non–small-cell lung cancer A549 and hepatocarcinoma HepG2 xenograft tumors in mice, compared with the same dose of tRNA/MSA. In addition, recombinant tRNA/mir-34a had no or minimal effect on blood chemistry and interleukin-6 level in mouse models, suggesting that recombinant RNAs were well tolerated. These findings provoke a conversation on producing biologic miRNAs to perform miRNA actions, and point toward a new direction in developing miRNA-based therapies.

Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programed cell death protein 1 (PD-1) or its ligand PD-L1 have increased the survival and cure rates for patients with many cancer types in various disease settings. However, only 10–40% of cancer patients benefited from these ICIs, of whom ~ 20% have treatment interruption or discontinuation due to immune-related adverse events that can be severe and even fatal. Current efforts in precision immunotherapy are focused on improving biomarker-based patient selection for currently available ICIs and exploring rationale combination and novel strategies to expand the benefit of immunotherapy to more cancer patients. Neoantigens arise from ~ 10% of the non-synonymous somatic mutations in cancer cells, are important targets of T cell-mediated anti-tumor immunity for individual patients. Advances in next generation sequencing technology and computational bioinformatics have enable the identification of genomic alterations, putative neoantigens, and gene expression profiling in individual tumors for personal oncology in a rapid and cost-effective way. Among the genomic biomarkers, defective mismatch DNA repair (dMMR), microsatellite instability high (MSI-H) and high tumor mutational burden (H-TMB) have received FDA approvals for selecting patients for ICI treatment. All these biomarkers measure high neoantigen load and tumor antigenicity, supporting the current development of neoantigen-based personalized cancer vaccines for patients with high TMB tumor. Several studies have shown neoantigen vaccines are feasible, safe and have promising clinical activity in patients with high TMB tumors in both metastatic and adjuvant settings. This review summarizes the emerging data and technologies for neoantigen-based personalized immunotherapy.

Over the past decade, targeted therapy for oncogene-driven NSCLC and immune checkpoint inhibitors for non-oncogene-driven NSCLC, respectively, have greatly improved the survival and quality of life for patients with unresectable NSCLC. Increasingly, these biomarker-guided systemic therapies given before or after surgery have been used in patients with early-stage NSCLC. In March 2022, the US FDA granted the approval of neoadjuvant nivolumab and chemotherapy for patients with stage IB-IIIA NSCLC. Several phase II/III trials are evaluating the clinical efficacy of various neoadjuvant immune checkpoint inhibitor combinations for non-oncogene-driven NSCLC and neoadjuvant molecular targeted therapies for oncogene-driven NSCLC, respectively. However, clinical application of precision neoadjuvant treatment requires a paradigm shift in the biomarker testing and multidisciplinary collaboration at the diagnosis of early-stage NSCLC. In this comprehensive review, we summarize the current diagnosis and treatment landscape, recent advances, new challenges in biomarker testing and endpoint selections, practical considerations for a timely multidisciplinary collaboration at diagnosis, and perspectives in emerging neoadjuvant precision systemic therapy for patients with resectable, early-stage NSCLC. These biomarker-guided neoadjuvant therapies hold the promise to improve surgical and pathological outcomes, reduce systemic recurrences, guide postoperative therapy, and improve cure rates in patients with resectable NSCLC.