Introduction

Lung cancer is the leading cancer killer in both men and women in the Unites States, with over 135,000 deaths expected during 2020 [1]. Small cell lung cancer accounts for 15%, and non-small cell lung cancer (NSCLC) for 85% of lung cancer cases [2]. Immunotherapy for NSCLC uses monoclonal antibodies that targets immune system T cells or ligands on the tumors cells, and results in enhanced immune system mediated tumor-cell-kill [3].

T-cells primed to respond to tumor cell, are exposed continuously to tumor antigens during active malignancy, which may result in upregulation of multiple inhibitory receptors, culminating in less action against the tumor cell, in what is known as T-cell exhaustion [4]. T-cell exhaustion could be overcome by modulating the inhibitory pathways that are upregulated during this process [4]. Programmed death receptor 1 (PD-1) is expressed on the surface of T cells, and functions as an immune checkpoint that suppresses autoimmunity through multiple mechanisms [5], and is actually a marker of T-cell exhaustion. NSCLC tumor cells expressing programmed death-ligand 1 (PD-L1) could attach to PD-1 receptor on T cells, and result in decreased tumor cell kill by the immune system [6]. Pembrolizumab [7] and Nivolumab [8] are monoclonal antibodies that target PD-1 on T cells, and shield it from activation by tumors expressing PD-L1 (Figure 1), and thus results in enhanced immune activity. Atezolizumab is a monoclonal antibody that target PD-L1 on tumor cells, prevent it from activating PD-1 on T cells, which results in less suppression of T cell function [9] (Figure 1).

Figure 1. Non-small cell lung cancer (NSCLC) cells expressing programmed death-ligand 1 (PD-L1) could interact with programmed death receptor 1 (PD-1) expressed on the surface of T cells, and result in decreased tumor cell kill by the immune system. Atezolizumab is an anti PD-L1 monoclonal antibody. Nivolumab and Pembrolizumab are anti PD-1 monoclonal antibodies. Ipilimumab is a monoclonal antibody that targets Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on the surface of T cells. Bevacizumab is a monoclonal antibody that targets Vascular Endothelial Growth Factor (VEGF) in the circulation and functions as an angiogenesis inhibitor.

Chemotherapeutic Agents Used for Treatment of NSCLC Together with Immunotherapy

2.1. Platinum Based Chemotherapeutic Agents

Chemotherapy for NSCLC usually includes combination of two drugs (chemotherapy doublet), with one of the agents is cisplatin or carboplatin. In 2002, Schiller at al. published in the New England Journal of Medicine, a study that compared four chemotherapy regimens for advanced NSCLC, cisplatin and paclitaxel, cisplatin and gemcitabine, cisplatin and docetaxel, and carboplatin and paclitaxel [80]. The study was well powered, with 1207 patients enrolled. None of the four chemotherapy regimens offered a significant advantage over the others [80]. In 2008, Scagliotti et al. [81] published in the Journal of Clinical Oncology a study that compared cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced NSCLC [81]. Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma and large-cell carcinoma histology, while patients with squamous cell histology had a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed [81]. These two studies made significant impact on the chemotherapy choices for treating NSCLC, with cisplatin or carboplatin as the backbone of all the chemotherapy treatments protocols. Pemetrexed is provided with platinum-based chemotherapy to patients with nonsquamous NSCLC. Gemcitabine is provided with platinum-based drug to patients with squamous NSCLC.

2.1.1. Cisplatin

Cisplatin is composed of a central atom of platinum with two chloride atoms and two ammonia molecules attached to it in the cis position. Cisplatin is provided intravenously and exerts its cytotoxic effects through binding to the deoxyribonucleic acid (DNA) strands, making inter- and intra- strands cross-links, which results in disruption of transcription and translation of DNA. Nephrotoxicity is the dose limiting toxicity of cisplatin, which results mainly from proximal tubular injury [82]. Other side effects of cisplatin include nausea and vomiting which usually necessitate premedication with antiemetic medications before cisplatin infusion, ototoxicity which could manifest in varying levels of hearing loss, peripheral neuropathy, and myelosuppression.

2.1.2. Carboplatin

Carboplatin, like cisplatin is composed of a central atom of platinum and two ammonia molecules, but the two chloride atoms are substituted by a cyclobutanedicarboxylate moiety. Carboplatin is provided intravenously and exerts its cytotoxic effects through inter- and intra- DNA strands cross-links, which results in disruption of transcription and translation of DNA. Bone marrow suppression is the dose-limiting toxicity of carboplatin. Carboplatin is much less nephrotoxic compared to cisplatin and is used as an alternative to cisplatin for patients with preexisting renal failure.

2.2. Taxanes

Taxanes are microtubule-stabilizing drugs which induces mitotic arrest at the G2/M transition phase of the cell cycle, resulting in cell death. Paclitaxel was isolated from bark extract of the Pacific yew tree. Docetaxel is a semisynthetic taxane and nab-paclitaxel is a nanoparticle albumin-bound paclitaxel.

2.2.1. Paclitaxel

Paclitaxel binds to tubulin and stabilizes the microtubules which leads to inhibition of cell division. Paclitaxel is provided intravenously, with a dose limiting toxicity of peripheral neuropathy. Peripheral sensory neuropathy presents with numbness and tingling in a stocking-and-glove distribution [83], which may disturb daily function of the patients. Hematologic toxicity include anemia, neutropenia, and less frequently thrombocytopenia.

2.2.2. Docetaxel

Docetaxel is provided intravenously, and acts in similar manner to paclitaxel. Docetaxel binds to tubulin, the protein component of the microtubules, and inhibits its disassembly, which results in disruption of mitosis and cell death. Docetaxel appears twice as active as paclitaxel in microtubules depolymerization inhibition [84]. Some clinical studies show that Docetaxel seems to be more potent compared with Paclitaxel, especially for treatment of breast cancer patients [85,86]. Hematological toxicities are the dose limiting toxicity of Docetaxel with neutropenia and anemia. Other side effects include alopecia, stomatitis, diarrhea, nausea, vomiting, fluid retention, onycholysis, and skin toxicity [87,88].

2.2.3. Nanoparticle Albumin-Bound Paclitaxel

Nanoparticle albumin-bound (nab) paclitaxel is an Albumin bound with high affinity to the hydrophobic molecules of paclitaxel, which results in higher accumulation of the cytotoxic drug in tumors. A recent meta-analysis showed that when compared to Paclitaxel, nab-paclitaxel has significant beneficial effects in terms of overall response rate, progression free survival, and overall survival [89]. Side effects of nab-paclitaxel include anemia, neutropenia, alopecia, and peripheral neuropathy [90].

2.3. Gemcitabine

Gemcitabine is structurally similar to cytarabine and functions as a pyrimidine analog, and blocks the progression of cells through the G1/S-phase [91]. Gemcitabine is metabolized by nucleoside kinases to Gemcitabine diphosphate and Gemcitabine triphosphate. Gemcitabine diphosphate inhibits ribonucleotide reductase, resulting in reductions in deoxynucleotide concentrations, including deoxycytidine triphosphate. Gemcitabine triphosphate competes with deoxycytidine triphosphate for incorporation into DNA [91]. Side effects of Gemcitabine includes myelosuppression manifested by neutropenia, thrombocytopenia, and anemia [91,92]; pulmonary toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome [91,93,94]; capillary leak syndrome [95–97]; and posterior reversible encephalopathy syndrome [98,99].

2.4. Pemetrexed

Pemetrexed functions as an antimetabolite. Pemetrexed inhibits thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase. Pemetrexed induces cell cycle arrest in the G1/S phase. Side effects of Pemetrexed includes myelosuppression [100], renal failure [100], bullous and exfoliative skin toxicity [100–102], diarrhea, nausea, and vomiting [100]

This entry is adapted from the peer-reviewed paper 10.3390/ph13110373