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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 5  |  Issue : 2  |  Page : 29-33

The anti-programmed cell death 1 antibody immunotherapy: A paradigm shift in the treatment of nonsmall-cell lung cancer


Department of Medicine, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK

Date of Submission13-Aug-2021
Date of Acceptance16-Oct-2021
Date of Web Publication29-Jan-2022

Correspondence Address:
Dr. Victor Chiagoziem Ezenwajiaku
School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, AB25 2ZD
UK
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njct.njct_9_21

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  Abstract 

With an increasing annual incidence, lung cancer remains the second most common cancer after breast cancer and the most common cause of cancer death worldwide. The distinctive features of its histological subtypes and the multifactorial etiologies ranging from tobacco smoking to genetic predisposition contribute to the associated poor clinical outcomes. Nonsmall-cell lung cancer (NSCLC) which constitutes most of the cases is a molecularly heterogeneous disease associated with poorer prognosis and risk of recurrence. However, this tumoral heterogeneity, which is disadvantageous to traditional chemotherapy, has been shown to be advantageous to immunotherapy in this review. Hence, the application of immune checkpoint inhibitors (ICIs) such as antiprogrammed cell death-1 antibodies has brought a change in thinking in the management of NSCLC, with future combination therapies looking promising in reducing the lung cancer burden. This review focuses on lung cancer background and treatment setbacks, exploring ICIs and antiprogrammed cell death-1 antibody mechanisms, the clinical trials leading to Food and Drug Administration approvals and future advancements.

Keywords: Anti-programmed cell death 1 antibody, immune checkpoint inhibitors, nonsmall-cell lung cancer, pembrolizumab, tumoral heterogeneity


How to cite this article:
Ezenwajiaku VC. The anti-programmed cell death 1 antibody immunotherapy: A paradigm shift in the treatment of nonsmall-cell lung cancer. Niger J Cardiovasc Thorac Surg 2020;5:29-33

How to cite this URL:
Ezenwajiaku VC. The anti-programmed cell death 1 antibody immunotherapy: A paradigm shift in the treatment of nonsmall-cell lung cancer. Niger J Cardiovasc Thorac Surg [serial online] 2020 [cited 2022 Jul 2];5:29-33. Available from: http://www.nigjourcvtsurg.org/text.asp?2020/5/2/29/336868


  Introduction Top


Lung cancer remains the second most diagnosed cancer worldwide, with about 2.2 million new cases in 2020, thus accounting for 11.4% of the global cancer burden and an estimated 1.8 million deaths in 2020.[1] In the United Kingdom, it is ranked the third most common cancer, accounting for 13% of all new cancer cases in 2017; however, it remains the second most common cancer in both genders, as well as in the United States. Interestingly, from 2015 to 2017 rates in males decreased by about 11% while that of females increased by around 15%.[2] Histologically, lung cancers are divided into small-cell lung cancer (SCLC) and non-SCLC (NSCLC). NSCLC, which constitutes 85% of lung cancers, is divided into adenocarcinoma (35%–40%), squamous cell carcinoma (25%–30%), and large cell carcinoma (10%–15%).[3] While the later subtypes are associated with smokers, adenocarcinoma remains common in nonsmokers.[4] The etiology of lung cancer centers around tobacco smoking in about 90%, and the pathophysiology is based on exposure to carcinogens through smoking, which leads to DNA damage and mutations in oncogenes or tumor suppressor genes.[3] However, not all smokers have lung cancer and not all lung cancer patients were smokers, hence in never smokers, etiology is considered multifactorial ranging from environmental exposures (second-hand smoking), pollution, and occupational carcinogens to inherited genetic susceptibility.[4] For Genetic alterations, mutations in the Kirsten rat sarcoma and epidermal growth factor receptor genes were indicated in tumor initiation,[5] while mutations in tumor protein p53 played roles during tumor progression.[6] With symptoms usually insidious and associated with late presentations, diagnosis is based on imaging modalities and histology, while management includes surgery with or without adjuvant chemotherapy, chemotherapy, and radiation.


  Treatment Setbacks Top


NSCLC is a molecularly heterogeneous disease associated with poorer prognosis and risk of recurrence. Approximately 80% of patients with advanced NSCLC are considered for chemotherapy or adjuvant chemotherapy at some points,[7] which is usually platinum-based chemotherapy, as recommended by the American Society for Clinical Oncology.[3] However, some studies have shown that histological subtypes and genetic factors affect the responsiveness or resistance to platinum compounds, contributing to the poor prognosis in advanced NSCLC. A Phase III trial comparing upfront cisplatin-pemetrexed with cisplatin-gemcitabine in advanced NSCLC showed similar primary outcomes. On histological stratification, survival in patients with adenocarcinoma and large cell subtypes was significantly better with cisplatin-pemetrexed than with cisplatin-gemcitabine which was better for patients with squamous cell subtype.[8] A similar study also showed that the ERCC1 gene determined the pattern of outcomes,[9] hence studies like these emphasized the need to redirect therapy from the generalized cytotoxic agents to molecularly targeted agents. Targeted therapy, like Crizotinib targets echinoderm microtubule-associated protein-like 4, fused to anaplastic lymphoma kinase gene that is found in ~5% of NSCLC patients.[10] Nevertheless, a Phase III trial versus platinum-based chemotherapy by Shaw et al. showed that, despite the positives, it had no overall survival benefit.[11]


  Advancement of Immune Checkpoint Blockade Top


The 2018 Nobel Prize in Physiology/Medicine was jointly awarded to James Allison and Tasuku Honjo, for their discovery of cancer therapy based on the inhibition of these immune checkpoint receptors, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and programmed cell death protein 1 (PD-1), respectively. PD-1 is a member of the B7/CD28 family of receptors expressed by activated T cells, B cells, and myeloid cells that bind to PD-ligand 1 (PD-L1) or -L2 ligands (B7 ligands). PD-L1 is expressed by antigen-presenting cells (APCs) and nonhematopoietic cells,[12] while PD-L2 is expressed by APCs and bone marrow-derived mast cells. As stated by Fujii et al., T cells are “activated by antigenic determinants presented by APCs, in the context of co-stimulation of CD28 on the T cells by B7 molecules on the APCs.”[13] As negative regulators or checkpoints, CTLA-4 and PD-1 exert suppressive effects on T cell function when these receptors are bound to specific B7 homologues on APCs or tumor cells, displacing the CD28 receptors.[14] According to Abril-Rodriguez and Ribas, immune checkpoints are a set of inhibitory pathways used by immune cells to regulate and control the durability of their response while maintaining self-tolerance.[15] Thus, the aim of immune checkpoint inhibition is to intercept the co-inhibitory receptor-ligand interactions of CTLA-4 and PD-1 with their respective ligands, resulting in a one-way T-cell activation and antitumor activity [Figure 1]. In terms of immunotherapy, the complexity of T-cell activation which was misunderstood as a one-step pathway in the late 1980s led to cancer vaccine failures.[16] Subsequently, the receptor-antigen and costimulatory molecules activation were understood, and this advanced immunotherapy. By the mid-1990s, further experiments showed that T-cell priming did not initiate only stimulatory signals but also inhibitory signals mediated by CTLA-4 and these were demonstrated in murine studies.[16] This discovery then shifted the immunotherapy approach from initiating T-cell activation to unshackling T cell antitumor activities, leading to the resurgence of immunotherapy for cancer treatment.[13]
Figure 1: This image depicts the co-inhibitory receptors-ligands interactions and targets for checkpoint blockade in T cell activation. During immunotherapy, the anti- CTLA-4 antibody binds to CTLA-4 promoting T cell activation and proliferation, while reducing Treg-mediated immunosuppression. Similarly, anti-PD-1 binds to PD-1 to produce a stimulatory effect, restoring the activity of antitumor T cells that have become quiescent and favoring the killing of cancer cells. CTL-4: Cytotoxic T-lymphocyte-associated antigen 4, Treg: Regulatory T cell, PD-1: Programmed cell death 1, APC: Antigen-presenting cells, MHC: Major histocompatibility complex, TCR: T-cell receptor. From CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition, E. Buchbinder and A. Desai, American Journal of Clinical Oncology, 2016; 39: 98-106. Reprinted with permission: License 4.0 (CCBY-NC-ND).

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  Nonsmall Cell Lung Cancer Susceptibility to Anti-Programmed Cell Death 1 Therapy Top


The application of immune checkpoint inhibitors (ICI) such as anti-PD-1 antibodies in lung cancer treatment is based on understanding the complexity of T-cell activity, the tumor microenvironment (TME) and tumor mutational burden (TMB). Like most malignancies, the intratumoral heterogeneity of NSCLC emanates from its subpopulations of diverse cells, and this determines the nature of its microenvironment.[5] Aptly, immune response is strongly dependent on the cells in the TME or the balance between immunosuppressive and antitumor immune responses.[17] For example, upregulation of PD-L1 on tumor cells would increase PD-1/PD-L1 interaction producing an immunosuppressive TME which protects tumor cells.[13] On the other hand, NSCLC is well known for its high somatic TMB, hence the metastases are significantly characterized by a higher number of mutations than in the primary lesion.[18] This leads to the generation of neoantigens that are well recognized by tumor-infiltrating cytotoxic T cells.[19] Thus, a high clonal neoantigen burden was associated with an inflamed TME characterized by the increased presence of tumor-infiltrating lymphocytes and was correlated with improved patient survival and durable response to immunotherapy.[20] This susceptibility of neoantigens to T cell activity has been proven by several human and murine studies[16] and further demonstrates how metastatic NSCLC have remained sensitive to PD-1 therapies. Relying on the above mechanisms, anti-PD-1 antibodies marked a paradigm shift in the management of NSCLC.


  Debut Food and Drug Administration Approvals Top


Following successful approval of the first ICI, a CTLA-4 inhibitor ipilimumab in March 2011, PD-1/PD-L1 inhibitors have garnered remarkable feats in lung cancer immunotherapy. In March 2015, nivolumab a monoclonal anti-PD-1 antibody was approved for the second-line treatment of metastatic squamous NSCLC, based on the results of the CheckMate 017 clinical trial and became the first approved immunotherapy for NSCLC. The key outcome of this trailblazing trial showed that nivolumab had a survival advantage (hazard ratio: 0.59; 95% confidence interval: 0.44–0.79; P < 0.001) over docetaxel.[21] Furthermore, in October 2015, nivolumab expanded its approval as second-line treatment for both squamous and nonsquamous subtypes of metastatic NLCSC following a similar trial (CheckMate057). Subsequently, other PD-1 and PD-L1 inhibitors such as pembrolizumab, atezolizumab, durvalumab, and cemiplimab marked their debut approvals, as shown in [Table 1].
Table 1: The debut Food and Drug Administration approvals for programmed cell death-1/programmed cell death-ligands 1 inhibitors in nonsmall cell lung cancer treatment, with their clinical trials, settings, and target population

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  Outstanding Pembrolizumab Top


Outstandingly, pembrolizumab, a humanized monoclonal anti-PD-1 antibody has received several approvals, mostly for first-line treatments in NSCLC clinical settings. In October 2015, pembrolizumab (Keytruda) was approved for advanced or metastatic NSCLC following the KEYNOTE-001 trial, where it achieved an overall response rate of 20% in 495 previously treated and treatment-naive PDL1-positive patients.[22] In October 2016, it was ratified as first-line monotherapy for metastatic NSCLC patients whose tumors have high PD-L1 expression (TPS ≥50%), following KEYNOTE-024 Phase III trial.[23] Same time, it also received approval as second-line monotherapy in PD-L1-positive patients based on the KEYNOTE-010 trial which concluded that pembrolizumab prolongs overall survival.[24] Approval for first-line multitherapy with carboplatin and pemetrexed was received in May 2017 for metastatic non-squamous NSCLC, following the KEYNOTE-021 trial involving treatment-naive patients irrespective of their genomic composition and PD-L1 expression.[25] In April 2019, its use as first-line monotherapy was extended to patients with locally advanced NSCLC and low PD-L1 expression, after the KEYNOTE-042 trial that compared pembrolizumab with platinum-based chemotherapy.[26] Furthermore, following the KEYNOTE-189 trial which involved the addition of pembrolizumab to pemetrexed and a platinum-based agent, it was approved in August 2018 as first-line combination treatment for patients with metastatic nonsquamous NSCLC.[27] In addition, in October 2018, it received endorsement as first-line multitherapy (pembrolizumab in combination with carboplatin and either paclitaxel or nab-paclitaxel) for metastatic squamous NSCLC following the KEYNOTE-407 trial.[28] Finally, On April 11, 2019, the Food and Drug Administration approved Keytruda for first-line treatment of patients with Stage III NSCLC who are not undergoing surgical resection or definitive chemoradiation, regardless of their genomic aberrations.[29] This approval was based on the KEYNOTE-042 trial conducted in treatment-naive patients whose tumors expressed PD-L1.[26] Notwithstanding these feats, pembrolizumab and nivolumab demonstrated similar survival benefits in advanced NSCLC following a comparative study.[30]


  Biomarkers Top


The KEYNOTE-010 and KEYNOTE-024 trials showed that studies in PD-L1 selected patients resulted in significantly improved overall survival and were associated with a better safety profile, thus validating the selection of patients before therapy. This necessitates the need for biomarkers by investigating the expression of PD-L1 on tumor cells and in their microenvironment. Thus, PD-L1 expression is currently approved as a predictive biomarker of response to ICIs only for advanced NSCLC; however, this has been reported as unreliable in certain settings.[13] For example, the impressive outcomes found in the KEYNOTE-010 and 024 studies were the opposite for nivolumab with PD-L1 selected patients.[31] These disparities could be attributed to both biological and technical reasons. Technically, immunohistochemistry is the most utilized assay for PD-L1 expression, and it depends on many variables; hence, it is difficult to normalize between different centers.[32] Second, several methods such as flow cytometry, quantitative immunofluorescence, and real-time PCR have been used in different human studies, hence no unifying approach.[13] Biological limitations include the dynamic and complex nature of the TME; the site of collection, as metastatic site or regional lymph node microenvironment can differ from that of the primary tumor; and finally, PD-L1 expression may vary at the time of assay and onset of treatment.[32] Notwithstanding these shortfalls, assaying for PD-L1 expression remains the basis of NSCLC patient selection in PD-1 inhibitor immunotherapy. However, other biomarkers such as tumor-infiltrating lymphocytes (CD3+, CD4, and CD8+ T cells) and interferon γ are currently understudied.[13]


  Combination Therapies and Recent Advances Top


In view of synergistic therapies, pembrolizumab has demonstrated better outcomes when combined with platinum duplet-based therapies; however, there is optimism that the newer therapies may offer better synergism. Efforts are currently being made in combining PD-1 inhibitors and other molecular-targeted therapies, irrespective of trials such as ECHO-301/KEYNOTE-252 that failed.[33] This prospective combination of newer therapies has been projected to be successful, bearing in mind their mechanisms of action. Fujii et al. in their study submitted that “genomically targeted therapies could serve as cancer vaccines, inducing the killing of tumor cells and resulting in the release of tumor antigens and neoantigens, which can then be presented by APCs to tumor-specific T cells.”[13] In future, there are possibilities of having combinations of PD-1 antagonists and other ICIs, as newer receptors such as LAG-3, TIM-3 and VISTA and costimulatory molecules (ICOS, O × 40, and 4-1BB) are undergoing preclinical evaluations.

Limitations

Sadly, this spectacular therapy is affected by limitations which include immune-mediated adverse effects and acquired resistance. Endocrine toxicities include pituitary dysfunction complicated by hypophysitis and hypothyroidism usually preceded by thyrotoxicosis, while pneumonitis remains the main pulmonary condition with an incidence of 3%–7%. The cardiotoxic effects include heart failure, cardiomyopathy, conduction abnormalities, myocardial fibrosis, myocarditis, and pericarditis; however, the incidence is <1%. Gastrointestinal complications represent the most common adverse reaction and include diarrhea, gastritis, enterocolitis, and hepatitis.[14] Nonetheless, the incidence of these events for anti-PD-1 therapy is slightly lower than that of anti-CTLA-4[34] and has been shown by other studies to have a better safety profile than traditional cytotoxics.[22],[23] In terms of resistance, interferons play a significant role in mediating antitumor responses through the IFN-γ/IFNGR/JAK/STAT/IRF1 axis leading to the upregulation of PD-L1 on tumor cells, as a defense mechanism against T-cells. In the context of PD-1 inhibitor therapy, this favors antitumor activity; however, mutation of mediators of the IFN-γ/IFNGR/JAK/STAT/IRF1 axis could lead to the loss of sensitivity to the IFN-γ pathway, leading to acquired resistance to checkpoint blockade.[15]


  Conclusion Top


Targeted therapies such as anti-PD-1 antibodies remain critical in reducing the morbidity and mortality associated with an insurmountable etiology (tobacco smoking). However, the use of monoclonal anti-PD-1 antibodies has clearly improved treatment outcomes in advanced NSCLC by taking advantage of the molecular heterogeneity of this tumor, especially in selected patients. Research toward future synergisms with genomically targeted agents will help sustain this advancement, alongside developing mechanisms to limit acquired resistance.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368:2385-94.  Back to cited text no. 11
    
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Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000;192:1027-34.  Back to cited text no. 12
    
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Fujii T, Naing A, Rolfo C, Hajjar J. Biomarkers of response to immune checkpoint blockade in cancer treatment. Crit Rev Oncol Hematol 2018;130:108-20.  Back to cited text no. 13
    
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Lewis AL, Chaft J, Girotra M, Fischer GW. Immune checkpoint inhibitors: A narrative review of considerations for the anaesthesiologist. Br J Anaesth 2020;124:251-60.  Back to cited text no. 14
    
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Pitt JM, Marabelle A, Eggermont A, Soria JC, Kroemer G, Zitvogel L. Targeting the tumor microenvironment: Removing obstruction to anticancer immune responses and immunotherapy. Ann Oncol 2016;27:1482-92.  Back to cited text no. 17
    
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Ward JP, Gubin MM, Schreiber RD. The role of neoantigens in naturally occurring and therapeutically induced immune responses to cancer. Adv Immunol 2016;130:25-74.  Back to cited text no. 19
    
20.
McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016;351:1463-9.  Back to cited text no. 20
    
21.
Kazandjian D, Suzman DL, Blumenthal G, Mushti S, He K, Libeg M, et al. FDA approval summary: Nivolumab for the treatment of metastatic non-small cell lung cancer with progression on or after platinum-based chemotherapy. Oncologist 2016;21:634-42.  Back to cited text no. 21
    
22.
Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015;372:2018-28.  Back to cited text no. 22
    
23.
Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016;375:1823-33.  Back to cited text no. 23
    
24.
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Introduction
Treatment Setbacks
Advancement of I...
Nonsmall Cell Lu...
Debut Food and D...
Outstanding Pemb...
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Combination Ther...
Conclusion
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