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Targeting biomarkers in immuno-oncology: current agents and its clinical impact

By: Jonathan Mercado (PharmD Candidate c/o 2019), Rebecca Sin (PharmD Candidate c/o 2019)

Immuno-oncology is an advanced and rapidly growing area of research focused on utilizing the body’s immune system to help fight cancer. Immunotherapy has demonstrated clinical efficacy and unprecedented rates of response in treating specific cancers, usurping the classical approach to chemotherapy and becoming the standard of care when applicable. There are two general approaches to immunotherapy in cancer. The first is a nonspecific approach that involves strengthening the immune system by utilizing interleukins, interferons and colony stimulating factors to increase white blood cell production, help control cell proliferation, and further regulate a plethora of cell functions. The second approach that has shown to be the most efficacious and continues to be extensively researched involves using a class of drugs known as checkpoint inhibitors. Nivolumab (Opdivo®), pembrolizumab (Keytruda®), ipilimumab (Yervoy®), and atezolizumab (Tecentriq®) are classic examples of checkpoint inhibitors. Checkpoint inhibitors block the body’s natural restrictive proteins and receptors designed to prevent white blood cells from attacking normal cells. By inhibiting those checkpoints, the drug induces the immune system to begin assailing oncogenic cells when it previously could not. These proteins, also known as biomarkers, are the core focus of immuno-oncology. Currently, there are a handful that are being targeted in contemporary practice.1

A significant targeted biomarker in oncology is programmed cell death protein 1 (PD-1), which functions to facilitate the development, immunity evasion, and prognosis of several solid tumors.2 Another critical biomarker is programmed cell death-ligand 1 (PD-L1), a ligand that interacts with PD-1 to diminish immune response. In certain tumors the up-regulation of PD-L1 occurs and signaling through this pathway contributes to inhibition of active T-cell immune surveillance of tumors. Binding of PD-L1 to the PD-1 receptor located on T cells inhibits T-cell proliferation and cytokine production, which is associated with negative outcomes.3,4 PD-L1 tumor expression is measured using a diagnostic assay known as an immunohistochemistry (IHC) test which predicts the response rate to certain checkpoint inhibitors. The results of an IHC test guide clinicians in determining a patient’s course of treatment. Tumors with a low expression of PD-L1 may respond to anti-PD-1/PD-L1 therapy. On the other hand, clinical trials have demonstrated greater response rates and longer progression-free survival in tumors with a high expression of PD-L1.5

Two checkpoint inhibitors which are classified as PD-1 inhibitors are nivolumab and pembrolizumab. Nivolumab is a human IgG4 monoclonal antibody which binds mostly to the N-loop of the PD-1 receptor.3,6 Therefore, nivolumab blocks the PD-1 receptor from interacting with PD-L1 and PD-L2. Consequently, the PD-1 pathway mediated inhibition of the immune response is suppressed. Nivolumab is approved for numerous types of cancers including melanoma, metastatic non-small cell lung cancer, advanced renal cell carcinoma, classical Hodgkin’s lymphoma, head and neck squamous cell carcinoma, urothelial carcinoma, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer, and hepatocellular carcinoma.3 Pembrolizumab targets the PD-1 biomarker through a similar mechanism.7 Compared to nivolumab, pembrolizumab mostly binds to the CD loop of the PD-1 receptor.6  Pembrolizumab is approved for melanoma, non-small cell lung cancer, head and neck cancer, classical Hodgkin’s lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, MSI-H solid or colorectal tumors, gastric cancer, and cervical cancer.7 Certain indications of the two aforementioned drugs overlap and comparative data for pembrolizumab’s and nivolumab’s efficacy in the treatment of certain cancers has been published.6

On the opposite side of the coin, a class of drugs known as PD-L1 inhibitors target the other end of the same pathway. PD-L1 inhibitors target only the specific ligand rather than the receptor. This is critical because the binding of PD-L2 to the PD-1 receptor boosts activation of CD3 proteins and inducible costimulator (ICOS) in T-cells which provides increased immune response against oncogenic cells. Furthermore, the PD-L1 ligand separately targets another receptor known as the B 7.1 receptor. The combination of this ligand and receptor attenuates T-cell activation and cytokine proliferation. Studies have not shown a significant difference in response rates due to these mechanisms, however, further investigation is warranted. It has also been noted that PD-L2 may have some benefit in reducing pulmonary toxicity by reducing cytokine release from invariant natural killer T-cells (iNKT-cells). This diminished level of release decreases airway hyperactivity and inflammation.4

There are currently three Food and Drug Administration (FDA)-approved agents in the PD-L1 class of medication – atezolizumab, durvalumab (Imfinzi®), and avelumab (Bavencio®). The main differences between the three medications are their indications as well as one notable difference in their mechanisms of action. All three agents have been approved for use in urothelial carcinoma, but only atezolizumab and durvalumab are approved for non-small cell lung cancer and avelumab is the only agent in the group indicated for use in Merkel cell carcinoma.8-10 Avelumab is also the only agent in the class that has been shown to cause antigen-dependent cytotoxicity (ADCC) which can lead to increased eradication of oncogenic cells or potentially more side effects.4 Further research is necessary to confirm its specific effects.4

Another key biomarker in oncology is cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), an immunoglobulin that is inhibitory in nature. Typically the immune system responds to infection and foreign bodies by activating T-cells. This is achieved when antigen presenting cells (APCs), in combination with the actual antigen and major histocompatibility complex (MHC) I or II, bind to T-cell receptors and induce stimulation. The stimulation is then translated into activation when the B7 molecules on the APCs bind with CD28 proteins on T-cells. CTLA-4 is responsible for limiting T-cell activation and proliferation by binding to B7 and CD28 proteins. A fully human IgG1 monoclonal antibody known as ipilimumab was designed to be a checkpoint inhibitor that blocks CTLA-4 and allows for continuous T-cell activation that can be used to fight oncogenic cells.11 While another monoclonal antibody by the name tremelimumab shares the same mechanism of action, ipilimumab is the only FDA-approved drug of its class. It is utilized to treat an assortment of cancers including unresectable or metastatic melanoma, advanced renal cell carcinoma, and MSI-H or dMMR metastatic colorectal cancer.12 Combining nivolumab with ipilimumab results in enhanced T-cell function which is greater than the therapeutic effects of monotherapy with either drug. Treatment with combination therapy for metastatic melanoma and advanced renal cell carcinoma yields improved anti-tumor responses.3

Unlike the adverse effects of traditional chemotherapy, patients may experience immune-mediated adverse reactions from immunotherapy where immune cells not only attack oncogenic cells but also healthy, normal cells. Immune-mediated adverse reactions can be as simple as nausea, vomiting, diarrhea and fatigue or as complex as pneumonitis, colitis, hepatitis, dermatitis, nephritis, and neuropathies. Assessing the severity (Grade 1-4) determines the treatment approach in managing immune-mediated adverse reactions.13 Management of some adverse effects such as nausea, vomiting and fatigue may only require lifestyle changes such as eating more soluble fibers, avoiding fatty foods, and taking naps or breaks throughout the day with symptomatic treatment as needed.1 Management of more severe adverse effects may include symptomatic treatment, corticosteroid treatment, or withholding or discontinuation of immunotherapy. Appropriate corticosteroid treatment in most cases resolves the immune-mediated adverse effects along with preserving the anti-tumor response.13

Due to the specificity of checkpoint inhibitors, screening tools to determine the prevalence of these biomarkers in tumors are essential in determining which patients these immunotherapy agents will be effective in. Currently, the assays that have been developed which are able to detect PD-L1 protein in tumors are the Ventana SP263 assay, Dako 22C3 assay, and Dako 28-8 assay. All the aforementioned assays have proven to be effective and have shown over ninety percent agreement as to whether tumors are positive for the biomarker.14 RNA In Situ Hybridization (ISH), which is used to detect in situ transcripts of PD-L1, has also shown to be effective in combination with any of the three previously mentioned assays.15 Unfortunately, assays for other targets are not yet fully developed or used. Moving forward, developing assays and other methods to screen for relevant biomarkers will be vital in propelling immuno-oncology to the frontline.

Despite its recent implementation in medicine over the last decade, immuno-oncology has swiftly made a positive impression and is widely being used in clinical practice. The concept of targeting vital biomarkers in the immune system to promote a patient’s own body to defeat cancer is extraordinary and certainly preferable to using toxic chemotherapeutic medications when applicable. The identification of additional biomarkers from extensive research will broaden treatment selections for better tumor response rates and assist in tailoring immunotherapy regimens. Currently, a multitude of drugs are being investigated that target countless biomarkers including T-cell immunoglobulin and mucin-domain containing-3 (TIM3), lymphocyte-activation gene 3 (LAG3), and glucocorticoid-induced TNFR-related protein (GITR) to name a few. Identifying these biomarkers and determining which patients could potentially benefit from their checkpoint inhibitors is the core of this field. Further research is necessary, however, its clinical impact thus far is undeniable and the likelihood that it will dominate the practice of oncology within the next decade is almost certain.

SOURCES:

  1. Understanding the Role of Immuno-Oncology in Treating Cancer. CancerCare. Cancercare.org. https://www.cancercare.org/publications/285-understanding_the_role_of_immuno-oncology_in_treating_cancer#!types-of-immunotherapy. Last updated 7/2/2018. Accessed 7/10/2018.
  2. Dong Y, Sun Q, Zhang X. PD-1 and its ligands are important immune checkpoints in cancer. Oncotarget. 2017;8(2):2171-2186. doi:10.18632/oncotarget.13895.
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  6. Fessas P, Lee H, Ikemizu S, Janowitz T. A molecular and preclinical comparison of the PD-1–targeted T-cell checkpoint inhibitors nivolumab and pembrolizumab. Seminars in Oncology. 2017;44(2):136-140. doi:10.1053/j.seminoncol.2017.06.002.
  7. Keytruda (Pembrolizumab) [package insert]. Whitehouse Station, NJ; Merck & Co., Inc.; Revised 6/2018.
  8. Tecentriq (Atezolizumab) [package insert]. South San Francisco, CA; Genentech, Inc.; Revised 07/2018.
  9. Imfinzi (Durvalumab) [package insert]. Wilmington, DE; AstraZeneca Pharmaceuticals LP; Revised 02/2018.
  10. Bavencio (Avelumab) [package insert]. Rockland, MA; EMD Serono, Inc.; Revised 10/2017.
  11. Camacho LH. CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations. Cancer Med. 2015 May;4(5):661-72.
  12. Yervoy (Ipilimumab) [package insert]. Princeton, NJ; Bristol-Myers Squibb Company; Revised 07/2018.
  13. Recognizing and Managing Immune-Specific Adverse Events. Institute of Clinical Immuno-Oncology. Accc-iclio.org. https://accc-iclio.org/resources/recognizing-and-managing-immune-specific-adverse-events/. Accessed 7/8/2018.
  14. Comparison of Three Different PD-L1 Diagnostic Tests Shows a High Degree of Concordance. American Association for Cancer Research. AACR.org. https://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=872#.W00FHdVKipo. Last updated 4/18/2016. Accessed on 7/16/2018.
  15. Sheffield BS, Fulton R, Kalloger SE, et al. Investigation of PD-L1 Biomarker Testing Methods for PD-1 Axis Inhibition in Non-squamous Non-small Cell Lung Cancer. J Histochem Cytochem. 2016 Oct;64(10):587-600.

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