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Abstract Lung cancer remains the leading cause of cancer-related mortality in both men and women in the US and worldwide. Non-small cell lung cancer is the most common variety accounting for 84% of the cases. For a subset of patients with actionable mutations, targeted therapy continues to provide durable responses. Advances in molecular and immunohistochemical techniques have made it possible to usher lung cancer into the era of personalized medicine, with the patient getting individualized treatment based on these markers. This review summarizes the recent advances in advanced NSCLC targeted therapy, focusing on first-in-human and early phase I/II clinical trials in patients with advanced disease. We have divided our discussion into different topics based on these agents' mechanisms of action. This article is aimed to be the most current review of available and upcoming targeted NSCLC treatment options. We will also summarize the currently available phase I/II clinical trial for NSCLC patients at the end of each section.

Abstract Co-stimulatory and co-inhibitory molecules play a critical role in T cell function. Tumor cells escape immune surveillance by promoting immunosuppression. Immunotherapy targeting inhibitory molecules like anti-CTLA-4 and anti-PD-1/PD-L1 were developed to overcome these immunosuppressive effects. These agents have demonstrated remarkable, durable responses in a small subset of patients. The other mechanisms for enhancing anti-tumor activities are to target the stimulatory pathways that are expressed on T cells or other immune cells. In this review, we summarize current phase I/II clinical trials evaluating novel immunotherapies targeting stimulatory pathways and outline their advantages, limitations, and future directions.

Abstract The immune system is the core defense against cancer development and progression. Failure of the immune system to recognize and eliminate malignant cells plays an important role in the pathogenesis of cancer. Tumor cells evade immune recognition, in part, due to the immunosuppressive features of the tumor microenvironment. Immunotherapy augments the host immune system to generate an antitumor effect. Immune checkpoints are pathways with inhibitory or stimulatory features that maintain self-tolerance and assist with immune response. The most well-described checkpoints are inhibitory in nature and include the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1). Molecules that block these pathways to enhance the host immunologic activity against tumors have been developed and become standard of care in the treatment of many malignancies. Only a small percentage of patients have meaningful responses to these treatments, however. New pathways and molecules are being explored in an attempt to improve responses and application of immune checkpoint inhibition therapy. In this review, we aim to elucidate these novel immune inhibitory pathways, potential therapeutic molecules that are under development, and outline particular advantages and challenges with the use of each one of them.

Abstract Advanced non-small cell lung cancer (NSCLC) is the most common type of lung cancer, with a poor prognosis and no known cure. Survival time is often short because of limited treatment options. Recent advances in targeted therapy and immunotherapy have changed the landscape for the treatment of advanced NSCLC. In the last 10 years, the US Food and Drug Administration (FDA) has approved more than 17 new medications for this devastating disease and more are coming. Molecular and immunogenic testing makes personalized medicine possible for patients with advanced NSCLC. The new medications provide promising efficacy and safety resulting in improved long-term survival for a significant number of patients. In this review, we summarize the recent advances in advanced/metastatic NSCLC therapeutics with a specific focus on first in-human or early-phase I/II clinical trials. These drugs either offer better alternatives to current standard drugs in the same class or are a completely new class of drugs with novel mechanisms of action. Advances are divided into (1) targeted agents, (2) antibody-drug conjugates, and (3) immunotherapies. Finally, we present a brief review of the emerging agents and ongoing clinical studies.

Abstract Background Mutant peptides presented by cancer cells are superior vaccine candidates than self peptides. The efficacy of mutant K-Ras, P53 and EGFR (Epidermal Growth Factor Receptor) peptides have been tested as cancer vaccines in pancreatic, colorectal, and lung cancers. The immunogenicity of EGFR Del19 mutations, frequent in Chinese lung adenocarcinoma patients, remains unclear. Results We predicted the HLA binding epitopes of Del19 mutations of EGFR in Chinese lung adenocarcinoma patients with NetMHC software. Enzyme-linked immunosorbent assay (ELISA) was performed to detect the EGFR-reactive IgG in lung cancer patients. Del19 mutations may be presented by multiple HLA Class I molecules, with delE746_A750 presented by 37.5% of Chinese population. For HLA Class II molecules, Del19 mutations of EGFR may be presented by multiple HLA-DRB1 molecules, with delE746_A750 presented by 58.1% of Chinese population. Serum reactivity to wild type EGFR protein was significantly higher in patients with Del19 EGFR mutations than those with EGFR L858R point mutation or with EGFR wild type genotype. Conclusions These findings suggest that Del19 mutations of EGFR, with an estimated frequency of 40% in Chinese lung adenocarcinoma patients, may serve as unique targets for immunotherapy in Chinese lung cancer patients.

Abstract Background Mutant peptides presented by MHC (major histocompatibility complex) Class II in cancer are important targets for cancer immunotherapy. Both animal studies and clinical trials in cancer patients showed that CD4 T cells specific to tumor-derived mutant peptides are essential for the efficacy of immune checkpoint blockade therapy by PD1 antibody. Results In this study, we analyzed the next generation sequencing data of 147 lung adenocarcinoma patients from The Cancer Genome Atlas and predicted neoantigens presented by MHC Class I and Class II molecules. We found 18,175 expressed clonal somatic mutations, with an average of 124 per patient. The presentation of mutant peptides by an HLA(human leukocyte antigen) Class II molecule, HLA DRB1, were predicted by NetMHCIIpan3.1. 8804 neo-peptides, including 375 strong binders and 8429 weak binders were found. For HLA DRB1*01:01, 54 strong binders and 896 weak binders were found. The most commonly mutated genes with predicted neo-antigens are KRAS, TTN, RYR2, MUC16, TP53, USH2A, ZFHX4, KEAP1, STK11, FAT3, NAV3 and EGFR. Conclusions Our results support the feasibility of discovering individualized HLA Class II presented mutant peptides as candidates for immunodiagnosis and immunotherapy of lung adenocarcinoma.

Abstract Immune checkpoints consist of inhibitory and stimulatory pathways that maintain self-tolerance and assist with immune response. In cancer, immune checkpoint pathways are often activated to inhibit the nascent anti-tumor immune response. Immune checkpoint therapies act by blocking or stimulating these pathways and enhance the body’s immunological activity against tumors. Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1(PD-L1) are the most widely studied and recognized inhibitory checkpoint pathways. Drugs blocking these pathways are currently utilized for a wide variety of malignancies and have demonstrated durable clinical activities in a subset of cancer patients. This approach is rapidly extending beyond CTLA-4 and PD-1/PD-L1. New inhibitory pathways are under investigation, and drugs blocking LAG-3, TIM-3, TIGIT, VISTA, or B7/H3 are being investigated. Furthermore, agonists of stimulatory checkpoint pathways such as OX40, ICOS, GITR, 4-1BB, CD40, or molecules targeting tumor microenvironment components like IDO or TLR are under investigation. In this article, we have provided a comprehensive review of immune checkpoint pathways involved in cancer immunotherapy, and discuss their mechanisms and the therapeutic interventions currently under investigation in phase I/II clinical trials. We also reviewed the limitations, toxicities, and challenges and outline the possible future research directions.

Abstract Malignant cells have the capacity to rapidly grow exponentially and spread in part by suppressing, evading, and exploiting the host immune system. Immunotherapy is a form of oncologic treatment directed towards enhancing the host immune system against cancer. In recent years, manipulation of immune checkpoints or pathways has emerged as an important and effective form of immunotherapy. Agents that target cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1) are the most widely studied and recognized. Immunotherapy, however, extends beyond immune checkpoint therapy by using new molecules such as chimeric monoclonal antibodies and antibody drug conjugates that target malignant cells and promote their destruction. Genetically modified T cells expressing chimeric antigen receptors are able to recognize specific antigens on cancer cells and subsequently activate the immune system. Native or genetically modified viruses with oncolytic activity are of great interest as, besides destroying malignant cells, they can increase anti-tumor activity in response to the release of new antigens and danger signals as a result of infection and tumor cell lysis. Vaccines are also being explored, either in the form of autologous or allogenic tumor peptide antigens, genetically modified dendritic cells that express tumor peptides, or even in the use of RNA, DNA, bacteria, or virus as vectors of specific tumor markers. Most of these agents are yet under development, but they promise to be important options to boost the host immune system to control and eliminate malignancy. In this review, we have provided detailed discussion of different forms of immunotherapy agents other than checkpoint-modifying drugs. The specific focus of this manuscript is to include first-in-human phase I and phase I/II clinical trials intended to allow the identification of those drugs that most likely will continue to develop and possibly join the immunotherapeutic arsenal in a near future.

Abstract Lung cancer continues to be the most common cause of cancer-related mortality worldwide. Recent advances in molecular diagnostics and immunotherapeutics have propelled the rapid development of novel treatment agents across all cancer subtypes, including lung cancer. Additionally, more pharmaceutical therapies for lung cancer have been approved by the US Food and Drug Administration in the last 5 years than in previous two decades. These drugs have ushered in a new era of lung cancer managements that have promising efficacy and safety and also provide treatment opportunities to patients who otherwise would have no conventional chemotherapy available. In this review, we summarize recent advances in lung cancer therapeutics with a specific focus on first in-human or early-phase I/II clinical trials. These drugs either offer better alternatives to drugs in their class or are a completely new class of drugs with novel mechanisms of action. We have divided our discussion into targeted agents, immunotherapies, and antibody drug conjugates for small cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). We briefly review the emerging agents and ongoing clinical studies. We have attempted to provide the most current review on emerging therapeutic agents on horizon for lung cancer.