Case Reports and Literature Review Future Medicine Immunotherapy
J Thorac Dis. 2020 Sep; 12(nine): 5119–5127.
Biomarkers in immunotherapy: literature review and future directions
Rebecca Pharaon
1Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Centre, Duarte, CA, USA;
Maria A. Koczywas
2Wroclaw Medical University, Wybrzeze L. Pasteura i, 50-367 Wroclaw, Poland
Sabrina Salgia
aneSection of Medical Oncology and Therapeutics Research, City of Hope National Medical Eye, Duarte, CA, USA;
Atish Mohanty
iDepartment of Medical Oncology and Therapeutics Research, Metropolis of Hope National Medical Center, Duarte, CA, United states;
Erminia Massarelli
1Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, U.s.a.;
Received 2019 Dec 28; Accustomed 2020 Mar 31.
Abstract
Within the past decade, immunotherapy has revolutionized the treatment of advanced non-pocket-size lung cancer (NSCLC). Immune checkpoint inhibitors (ICIs) such as pembrolizumab, nivolumab, atezolizumab, and durvalumab accept shown superiority over chemotherapy regimens in patients with programmed death-ligand 1 (PD-L1) expression. Several predictive molecular biomarkers, including PD-L1 expression and high tumor mutation burden, have shown utility in discovering lung cancer patient groups that would benefit from ICIs. Nevertheless, there remains to be a reliable imaging biomarker that would clearly select patients, through baseline or restaging imaging, who would reply or take a prolonged response to ICIs. The purpose of this review is to highlight the role of ICIs in patients with advanced NSCLC and past or electric current studies in potential biomarkers besides as time to come directions on the function of imaging in immunotherapy.
Keywords: Not-small prison cell lung cancer (NSCLC), immunotherapy, molecular biomarkers, in vivo imaging, imaging biomarkers
Introduction
Immunotherapy has revolutionized the handling of patients diagnosed with non-small cell lung cancer (NSCLC), a cancer estimated to cause the most cancer deaths in the United States in 2019 in both males and females (1). Introduction of anti-programmed jail cell expiry protein 1 (PD-1) and anti-programmed death-ligand one (PD-L1) monoclonal antibodies such as pembrolizumab, nivolumab, atezolizumab, and durvalumab in the field of lung cancer showed efficacy of these drugs in terms of overall survival and progression complimentary survival over or in addition to traditional chemotherapy (2-6). Selection of patients who will benefit is crucial to maximize response to handling and limit treatment toxicities associated with immunotherapy (7).
Currently, to predict if patients volition benefit from immune checkpoints inhibitors (ICIs), known molecular biomarkers such as PD-L1 and tumor mutation burden (TMB) are determined via immunohistochemical (IHC) assays or side by side-generation sequencing (NGS) testing. These biomarkers take shown efficacy in selecting patients to undergo treatment with immunotherapy over traditional cytotoxic chemotherapy handling. A landmark Phase I trial demonstrated prolonged progression-costless survival (PFS) with nivolumab and ipilimumab in patients with loftier tumor mutation brunt regardless of PD-L1 expression (eight), and most recently, results from a Phase 3 trial confirmed efficacy of this combination as beginning-line treatment in NSCLC irrespective of any biomarker (nine). Keynote-024 reported superior overall survival (OS) and PFS with monotherapy pembrolizumab in patients with high PD-L1 expression [≥50% tumor proportion score (TPS)] (2). However, predicting initial or connected response to immunotherapy remains largely unknown and further research is necessary to develop reliable biomarkers.
A new field of investigating response to treatment has recently gained traction: using imaging to determine different biomarkers that tin help guide treatment decisions for oncologists. Many ongoing trials are investigating imaging biomarkers that tin be used in computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography-computed tomography (PET/CT) scans including cluster of differentiation 8 (CD8) cells, chimeric antigen receptor-based T (Car T) cells, and TMB. These noninvasive examinations would coincide with routine imaging and are ameliorate tolerated by patients compared to biopsy procedures or claret samples that are required at dissimilar timepoints to determine the evolving tumor molecular signature past NGS or IHC. Visual detection of CD8 cells represents a good predictive indicator to judge anti-tumor response; in fact, it helps scientists to better sympathise the dynamic of immune response on cancer growth and possible regression. Similarly, applying this thought in the field of CAR T-cells therapies is extremely beneficial equally these cells could exist exploited for repeated imaging. Without the capabilities of tracking specific cells that were used or targeted during therapy, information technology is nearly impossible to monitor and assess the efficacy or safety of the treatment.
This review focuses on established and promising molecular and imaging biomarkers that could help in selecting patient groups that would do good from immunotherapy.
Immune checkpoint inhibitors in NSCLC
Allowed checkpoints inhibitors (ICIs) work by blocking the natural inhibitory receptors/ligand interaction on immune cells (T-cells) and cancer cells to unleash immune response confronting cancer cells ( Effigy one ). The binding of PD-1, a T-cell inhibitory receptor, with PD-L1 leads to inhibition of T-cells function and allows tumor cell to escape from immune system response ( Figure i ). Past blocking PD-one/PD-L1 interaction with anti-PD-1/PD-L1 monoclonal antibodies, the immune system can recognize tumor cells as strange bodies. Well-nigh notably, ICIs have radically transformed treatment direction of advanced NSCLC. Due to numerous landmark clinical trials, 4 agents have been approved by the Food and Drug Assistants (FDA) as standard of care treatment of NSCLC: pembrolizumab, nivolumab, atezolizumab and durvalumab. Nivolumab, an anti-PD-1 monoclonal antibody, was kickoff examined in NSCLC in comparing with standard chemotherapy and demonstrated improved overall survival in patients who had failed at least one prior line of chemotherapy (ten,xi), establishing the potential significance of monotherapy immunotherapy in lung cancer. This concept was further proven with pembrolizumab which showed similar superior Os in NSCLC patients in second line (12). Later studies considered the effectiveness of ICIs as first-line treatment (2,viii,9), and for select patient groups with PD-L1 TPS ≥fifty%, pembrolizumab was approved as first-line standard of care for advanced NSCLC. There are many ongoing trials investigating ICI combinations with other immune-oncology (IO), incorporating immune and molecular biomarkers in NSCLC (6,9,13). In this by yr, long-term results from the Phase III Checkmate-017 and Checkmate-057 clinical trials were presented and demonstrated continued Bone benefit of nivolumab in all accomplice subgroups equally a second-line treatment versus docetaxel (14). Although nivolumab was canonical by the FDA in 2015 as a 2nd-line therapy, these results bear witness encouraging 4-year results even among patients who have a PD-L1 score ≤ane%. Recently, a Phase 3 trial of recurrent or metastatic NSCLC patients published results demonstrated a survival benefit of combining nivolumab and ipilimumab, a fully human being anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibiotic, compared with chemotherapy as first-line treatment irrespective of PD-L1 expression (9).
Anti-PD-1, anti-PD-L1, and anti-CTLA-4 monoclonal antibodies targets and mechanisms.
Molecular biomarkers of immunotherapy in NSCLC
Testing PD-L1 expression using IHC has rapidly get a standardized test ordered at initial cancer diagnosis in addition to the advised NGS that includes established EGFR, ALK, ROS1, and BRAF de novo testing. Diverse antibodies have been studied to notice PD-L1 expression by IHC based on tumor histology and the utilize of the 22C3 anti-PD-L1 antibody has get standardized for PD-L1 by IHC testing in NSCLC (xv). The incorporation of PD-L1 testing into standard of care was established from several clinical trials indicating the strongest benefit of ICI in selected groups of patients expressing high PD-L1 (TPS ≥50%) (2,3). The estimated percentage of NSCLC patients who limited PD-L1 ranges from 24% to sixty% (16). Although information technology is unclear whether NSCLC patients with loftier PD-L1 expression have amend prognosis than those with low or no levels of PD-L1, published information seems to suggest a poor prognosis associated with high PD-L1 levels (17-19). PD-L1 past IHC diagnostic has its disadvantages as information technology does not take into account tumor heterogeneity. Moreover, the dynamic nature of this marker causes changes in its expression levels in response to different factors, including radiation therapy, chemotherapy, wound formation, and the use of allowed suppressing drugs. In fact, clinical benefit has been demonstrated in NSCLC patients whose tumors evidence depression or no PD-L1 expression. However, despite its variability, as of today, PD-L1 expression remains the all-time biomarker to predict response to immunotherapy thus far.
Another potential predictive marker of response to ICIs in NSCLC is TMB, which measures the boilerplate number of mutations carried by tumor cells. Tumors with high TMB can atomic number 82 to more neoantigens in the body that are formed from mutations, resulting in a strong immune response to ICIs due to T-cells recognizing these neoantigens. Many studies have shown that patients with high TMB (greater or equal to 10 mutations per megabase) who undergo treatment with anti-PD-1/PD-L1 antibodies results in better PFS, objective response rate (ORR), and OS (8,xx,21). Limitations associated with TMB include: variability in TMB levels beyond different tumor types, inconsistent detection methods, and a lack of a standardized cutoff to define high TMB status. Recently, involvement has risen in utilizing TMB in combination with PD-L1 expression to more specifically decide groups of patients who would reply to ICIs.
Human leukocyte antigen (HLA) is a complex of genes that encode the major histocompatibility complex (MHC) which regulates the allowed organisation. Initially, tumor cells have a high level of class I MHC expression, which is the key for activating cytotoxic T-lymphocytes (CTLs). Over time, tumor cells that present with MHC-I are destroyed by CTLs and tin transform to become MHC-I negative, thus making them less susceptible to CTLs destruction and immunological treatment (22). Loss of HLA course I expression has been reported in multiple cancers and studies have shown that expression of HLA-I on tumor cells is an important factor in evaluating immune infiltration (22). High expression of HLA-I is associated with high expression of PD-L1. In tumors with high expression of HLA-I and PD-L1, there exists a high intratumoral infiltration with CD8 cells. On the other hand, when the tumor is HLA-I negative, a significant reduction has been observed in the population of tumor infiltrating CD8 cells. Since immunotherapy activates the immune organization, including CD4/CD8 cells and tumor-infiltrating lymphocytes, the importance of detecting HLA-I expression in patient tumors will also inform oncologists in estimating potential response to immunotherapy.
Various mutations and gene signatures in NSCLC have been reported to predict response to ICIs besides. The upregulation of interferon-gamma (IFN-γ), typically triggered by an immune stimulus, is a known marking of tumor response in unlike cancer types treated with immunotherapy, equally described in several papers (23-25). A clinical trial in patients with NSCLC who received durvalumab demonstrated that a high IFN-γ cistron signature corresponded to better response rates and PFS (26). Multiple ongoing trials are examining therapies targeting IFN-γ alone or in combination with ICIs in ovarian cancer, glioblastoma, and other solid tumors. On the other hand, studies have shown that specific mutations in NSCLC are associated with poor response to ICIs. In KRAS-mutated NSCLC, response to ICIs has been examined in various subgroups defined by co-mutations associated with KRAS. Information technology was discovered that KRAS-mutated NSCLC tumors that also express STK11 or LKB1 mutations cause main resistance to anti-PD-L1 antibodies and predict poor outcomes (27). Numerous studies are currently underway to further classify patient subgroups who will respond or progress on ICIs.
Immunotherapy response in imaging
Response Evaluation Criteria in Solid Tumors (RECIST) is the standard criteria used to determine responses to therapy in clinical trials. This classification is based on the alter in size of the tumor and is divided into four categories: complete response, partial response, stable disease, and progressive affliction. Even so, RECIST tin can exist insufficient in capturing pseudoprogression—a hallmark response in a subset of patients treated with anti-PD-1/PD-L1 antibodies—and it may cause an incorrect response evaluation of immunotherapy. Psuedoprogression, a rare upshot which has been reported to occur in an estimated 2–5% of NSCLC cases (28-thirty), has been thought to be caused by the infiltration of immune cells causing an increase in the tumor which could mistakenly exist attributed to growth due to progression of disease. Considering of this phenomenon, three additional criteria were adult to provide a better assessment of the result of immunotherapeutic agents: immune RECIST (iRECIST), allowed-related RECIST (irRECIST), and allowed-related response criteria (irRC). These criteria are typically used meantime with RECIST to evaluate treatment response and whatsoever adverse events (AEs), particularly immune-related AEs (irAEs). irAEs incidence rates vary in published clinical trials and retrospective analyses of patients treated with immunotherapy but are relatively common (7). Full general irAEs include colitis, thyroiditis, fatigue, and more, which are graded based on severity. Direction of patients on immunotherapy requires medical oncologists and radiologists trained with the ability to recognize response clinical and radiologic response patterns of ICIs besides every bit adverse symptoms caused by ICIs.
Imaging biomarkers of immunotherapy
As immunotherapy became a pregnant therapeutic strategy across many cancer types, a new field of research opened to notice imaging biomarkers in addition to predictive molecular biomarkers. PET and unmarried-photon emission computed tomography (SPECT) imaging utilize radioisotopes to label specific cells to target and visualize through imaging. Many clinical trials are currently underway to examine various imaging markers or radiolabels that could provide prognostic insight of response to anti-PD-ane/PD-L1 antibodies ( Table 1 ).
Tabular array 1
Ongoing clinical trials to predict response to immunotherapy in NSCLC using molecular imaging biomarkers
| Trial | Identifier | Status | Disease | Tracer | Phase |
|---|---|---|---|---|---|
| 89Zr-labeled Pembrolizumab in Patients With Non-minor Jail cell Lung Cancer | {"type":"clinical-trial","attrs":{"text":"NCT03065764","term_id":"NCT03065764"}}NCT03065764 | Active, not recruiting | Not-small cell lung cancer | 89Zr-Pembrolizumab | Phase Ii |
| PD-L1 Imaging in Non-small Cell Lung Cancer (PINNACLE) | {"type":"clinical-trial","attrs":{"text":"NCT03514719","term_id":"NCT03514719"}}NCT03514719 | Recruiting | Not-small-scale jail cell lung cancer | 89Zr-Avelumab | Phase I |
| Imaging Tumor-infiltrating T-cells in Not-small-scale Cell Lung Cancer (Donan) | {"blazon":"clinical-trial","attrs":{"text":"NCT03853187","term_id":"NCT03853187"}}NCT03853187 | Recruiting | Non-modest cell lung cancer | 89Zr-Durvalumab | Stage 2 |
| 99mTc Labeled Anti-PD-L1 sdAb SPECT/CT in Cess of PD-L1 Expression in NSCLC | {"type":"clinical-trial","attrs":{"text":"NCT02978196","term_id":"NCT02978196"}}NCT02978196 | Recruiting | Non-small-scale cell lung cancer | 99mTc-labeled anti-PD-L1-sdAb | Stage I |
| 18F-PD-L1 PET/CT in Nivolumab Treated Patients With NSCLC | {"type":"clinical-trial","attrs":{"text":"NCT03564197","term_id":"NCT03564197"}}NCT03564197 | Recruiting | Stage Four non-small cell lung cancer | eighteenF-PD-L1 | Northward/A |
| ImmunoPET With an Anti-CD8 Imaging Amanuensis | {"blazon":"clinical-trial","attrs":{"text":"NCT04029181","term_id":"NCT04029181"}}NCT04029181 | Recruiting | Solid tumors | Anti-CD8 PET imaging agent | Stage I/Two |
| 89Zr-Df-IAB22M2C (CD8 PET Tracer) for PET/CT in Patients With Metastatic Solid Tumors | {"type":"clinical-trial","attrs":{"text":"NCT03802123","term_id":"NCT03802123"}}NCT03802123 | Recruiting | Metastatic solid tumors | 89Zr-Df-IAB22M2C | Phase Two |
| MPDL3280A-imaging-IST-UMCG | {"blazon":"clinical-trial","attrs":{"text":"NCT02453984","term_id":"NCT02453984"}}NCT02453984 | Recruiting | Locally advanced or metastatic solid tumors | 89Zr-MPDL-3280A | Due north/A |
Currently, detection of CD8 cells by any imaging technique is existence investigated in various in vivo studies and clinical trials. CD8 cells vest to a larger group of cells called tumor infiltrating lymphocytes (TILs) which penetrate the tumor and its microenvironment to mediate immune response against tumor cells. CD8 cells have a pregnant role in eliminating tumor cells thus suggesting that high levels of CD8 cells can exist a good prognostic mark of response in dissimilar cancer types (31,32). Detection of CD8 through imaging could be helpful in not only assessing the usefulness of ICIs but to ameliorate visualize the influence of TILs on the tumor and its environment. A recent written report by Seo et al. demonstrated feasibility of tracking CD8 cells past PET imaging utilizing an anti-CD8 cys-diabody radiolabeled with 64Cu in mouse models transplanted with an analogous form of HER2 breast cancer (33). Another study radiolabeled an anti-CD8 cys-diabody with 89Zr for non-invasive tracking of CD8 cells to visualize response, or lack of response, in syngeneic murine models via immuno-PET (34). The results demonstrated accurate bounden of the anti-CD8 cys-diabody to CD8 T-cells and specific detection of CD8 T-cells past immuno-PET including after treatment with anti-CD137 antibody, a treatment that targets CD137 to broaden activation of immune cells (34). Lord's day et al. studied a radiomic signature for CD8 cells in a retrospective cohort of patients using imaging data applied to different patient cohorts in the TCGA (35). The authors were able to use the CD8 cell radiomic signature to predict the tumor immune phenotype classifying tumors into 3 different types: immune inflamed, immune-excluded, or allowed-desert. Generally, immune-inflamed types of tumors have the best chance to respond well to immunotherapy due to high CD8, immune jail cell infiltration, and PD-ane/PD-L1 pathway activation (36,37). This stresses the importance of visually tracking CD8 cells in vivo in patients undergoing treatment with immunotherapy to assess response and cell interaction with the tumor. Currently, there is an agile Stage I/Ii clinical trial utilizing an anti-CD8 PET imaging amanuensis, ZED88082A, radiolabeled with 89Zr in solid tumor patients treated with anti-PD-1 or anti-PD-L1 solitary or in combination with anti-CTLA-4 antibiotic ipilimumab. Some other ongoing phase II clinical trial investigates the CD8 tracer, 89Zr-Df-IAB22M2C, in patients with metastatic solid tumors treated with standard of care monotherapy or combination ICIs ( Table 1 ). Trials like these are comparing clinical response and immune infiltrates with uptake of radiolabeled CD8 tracers in PET/CT imaging before and after treatment with ICI.
Probes targeting other known immune markers have been investigated in preclinical settings and are currently undergoing clinical trials to make up one's mind efficacy and safety in human being patients. Interleukin-2 (IL-two) receptors are expressed on activated T lymphocytes. Radiolabeled IL-2 has already shown efficacy for in vivo imaging of tumor-infiltrating CD25+ activated T lymphocyte to monitor CXCR4 adversary therapy (38), a targeted therapy used for handling of breast cancer. Anti-CTLA-4 monoclonal antibody ipilimumab has been proven to be effective in treating lung cancer when combined with nivolumab (eight,9). Results from a preclinical study have shown success in visualizing CTLA-4 on PET imaging through labeling with 64Cu-i,4,7,ten-tetraazacyclododecane-N,N′,Due north″,North‴-tetraacetic acrid-anti-mouse CTLA-four mAb (64Cu-DOTA-anti-CTLA-4 mAb) (39). PD-L1 probes have too been investigated in numerous preclinical studies in vitro and in murine mouse models (40-45). Moreover, multiple ongoing clinical trials are evaluating the efficacy of PET tracers with high affinity to PD-L1 such as 99mTc labeled anti-PD-L1 unmarried domain antibiotic and 18F-PD-L1 ( Tabular array 1 ). Other active trials are radiolabeling a small dose of anti-PD-1/PD-L1 agents such as avelumab, pembrolizumab, and durvalumab with 89Zr, a mutual radiolabel that attaches to monoclonal antibodies, in patients undergoing treatment with ICIs ( Table one ) (46). Since PD-L1 expression has become an established molecular biomarker in tumor tissue, it is logical to replicate the results in imaging. If successful, this would reduce the need of invasive serial tissue biopsies that are currently used to consecutively map changes in mutational status throughout treatment. In the case for immunotherapy, oncologists would be able to longitudinally track PD-L1 expression based on probe activeness on imaging.
Machine T-cell therapy has emerged within the past decade equally a revolutionary treatment that genetically engineers a patient'southward T-cells to produce structures on their surface called chimeric antigen receptors (CARs) that are attuned to specific markers on tumor cells. These cells are so reinfused in the patient and are able to connect with proteins on tumor cells enabling recognition and killing of tumor cells, resulting in arming the patient's own immune organisation to respond confronting their cancer. Unfortunately, the difficulty in utilizing Auto T-cell therapy lies in identifying a target on tumor cells that is unique to them. Machine T therapies are approved by the Food and Drug Administration (FDA) in two cancer types—acute lymphoblastic leukemia in children (47) and advanced lymphoma in adults (48)—and both target CD19, a transmembrane glycoprotein that is expressed on the bulk of B cell malignancies rendering it an platonic target. Aside from hematologic malignancies, this treatment and then far has not shown equivalent success in solid tumors, with modest efficacy demonstrated in glioblastoma patients by targeting interleukin-thirteen receptor blastoff 2 (IL-xiii Rα2) and other receptors that are specific to glioblastoma cancer cells (49,50). Researchers are currently investigating whether imaging tin can exist used to serially visualize response to Automobile T-cells and contempo information demonstrated preclinical efficacy of a prostate-specific membrane antigen-(PSMA-)targeting radiotracer to visualize Auto T-cells in NOD-SCID-Gamma mice using PET imaging (51,52).
Time to come directions
Despite many advances in the field of cancer, specifically in NSCLC, oncologists yet face many challenges in selecting patients who will derive benefit from ICIs and predicting tumor response. While a number of molecular biomarkers have been established every bit prognostic tools for immunotherapy response, they can be unreliable and farther research is necessary in optimizing a selection of universal biomarker for immunotherapy. In add-on, biomarker selection tin help to lower the cost and toxicity of ineffective treatment. Preclinical data on radiolabeled probes is existence published at rapid rates as numerous additional probes proceed to exist discovered. In vivo imaging tin be a very useful non-invasive tool to assess the efficiency of immunotherapy and to predict potential resistance or toxicity of the treatment. Compared to biopsied tissue samples, it illuminates information about the heterogeneity of the entirety of tumors as well as the whole body, it is not restricted to the collected specimen, and it involves little to no risk for the patients. It tin also be beneficial in dividing patients into 2 treatment groups of likely responders and probable non-responders. Furthermore, it can be an instrument to understand the mechanisms of action of different drugs, especially in immunotherapy considering that in vivo models have a very limited potential in studying the host-tumor heterogeneity. Therefore, it is very articulate that molecular imaging as a not-invasive tool to predict and sequentially monitor response to immunotherapy has the potential to revolutionize cancer care and patient quality of life.
Acknowledgments
Funding: None.
Notes
Upstanding Statement: The authors are answerable for all aspects of the piece of work in ensuring that questions related to the accurateness or integrity of any office of the work are appropriately investigated and resolved.
Open Access Statement: This is an Open Admission article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs iv.0 International License (CC BY-NC-ND four.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are fabricated and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). Run into: https://creativecommons.org/licenses/by-nc-nd/iv.0/.
Footnotes
Provenance and Peer Review: This article was deputed by the Invitee Editor (Ammar Chaudhry) for the serial "Function of Precision Imaging in Thoracic Illness" published in Journal of Thoracic Illness. The article was sent for external peer review organized by the Guest Editor and the editorial part.
Conflicts of Interest: All authors have completed the ICMJE compatible disclosure class (available at http://dx.doi.org/10.21037/jtd.2020.04.fifteen). The serial "Role of Precision Imaging in Thoracic Disease" was commissioned by the editorial office without any funding or sponsorship. EM has received honoraria from Astra Zeneca Pharmaceuticals, Merck & Co, and received research support from Pfizer, Astra Zeneca, Merck, BMS, GSK, and Tessa Pharmaceuticals. The other authors have no other conflicts of interest to declare.
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Articles from Journal of Thoracic Disease are provided here courtesy of AME Publications
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578474/
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