CTLA4: a Novel Target in Non Small Cell Lung Cancer

Abstract

Lung cancer has been one of the leading causes of deaths through cancer worldwide. Non small cell lung cancer accounts about 85% of the lung cancer cases. Accounting over 2.09 million cases as of 2018 worldwide Lung cancer has been one of the leading cases of cancer which has caused over 1.76 million deaths worldwide. Immune checkpoint therapy has opened new ways to treat this dreadly disease leaving minimal side effects. It focusses on blocking antibody targets on cytotoxic T lymphocyte antigen-4 (CTLA-4), doing this the body ensures to keep it’s immune system in full strength against fighting cancer.

CTLA-4 binding to receptors like CD-80 & CD-86 on antigen presenting cell causes initial inactivation of T- cell leading to downregulation in immune responses of the body. Ipilimumab & Tremelimumab are anti- CTLA-4 receptor drugs currently under clinical trials and have been showing effective results so far to prove themselves as drug candidates. Combination therapy using CTLA-4 along with PD-1/PDL-1 & chemotherapy has proved to be showing promising results too. The current review shows CTLA-4 as a novel target in immune checkpoint therapy to treat non-small cell lung cancer along with combination therapy in NSCLC,its probable adverse effects and resistance.1

Introduction

A per WHO lung cancer is the most commonly occurring caner in males and third most in women. Over 1,368,524 new cases of lung cancer in men and 725,352 in women were reported (American Institute for Cancer Research). The standard treatment for lung cancer includes surgery, adjuvant therapy, radiation therapy, chemotherapy, and immunotherapy. Surgery, as well as radiation therapy, cannot be used to treat wide-spread cancer. For better efficacy, a combination of two or more chemo drugs is used. However, chemotherapy may also damage healthy cells in the body, including blood cells, skin cells, and nerve cells. Moreover, chemotherapy may lead to other fatal side effects when it comes to age factor in general public leading to lethality and mortality. Thus, because of several dis-advantages of chemotherapy and recent advantages being offered by immunotherapy, it is used as novel approaches for lung cancer.

Role of Immunotherapy

Immune checkpoint inhibitors (ICIs) are newer, immunotherapy-based drugs that have been shown to improve survival in advanced Non-small cell lung cancer (NSCLC). Unlike traditional chemotherapeutic agents, ICIs work by boosting the body’s natural tumour killing response. The immune checkpoint inhibitor activity works by inhibiting the activity of immune checkpoints. The basic mechanism focusses on upregulating the body’s immunity so as to fight cancer to it’s peak. CTLA-4 on the T-cell binds to receptors like B7-1(CD-80) and B7-2(CD86) on the APC so as to downregulate the body’s immune system as a normal phenomenon of the body to regulate immunity. This is done by CTLA-4 by competing with CD-28 as it has a higher affinity for the receptors on APC. Drugs like ipilimumab & tremelimumab act as antibodies which bind to CTLA-4 and competitively inhibit it’s binding to other receptors on the APC. By this CTLA-4 no more shows it’s action on the immune responses and thereby a stimulated immune response is observed which helps fight the cancerous cells in the body efficiently.2

For most of these inhibitory receptors, antibodies have been developed and tested in clinical trials and pre-clinical models and few of them have now been recognized to be licensed for use in humans. Immunotherapeutic drugs like Nivolumab have been already approved by the US FDA to treat non-small cell lung cancer. It has been proven to show recovery in non-squamous non-small cell lung cancer Nivolumab along with ipilimumab has given appreciable results in clinical trials. Apart from this, combination therapy in NSCLC using antibodies like ipilimumab along with chemotherapeutic drugs has proven successful in many patients.

Non-small Cell Lung Cancer

It accounts approximately 85% of total lung cancer cases reported worldwide. NSCLC has grown in the human population among last two decades. As a class are relatively insensitive to chemotherapy compared to small cell lung cancer. It further includes: i)Adenocarcinoma, ii)Squamous cell carcinoma, iii)Large cell carcinoma.

Factors

1. Smoking: It has been the leading cause of lung carcinoma ever since.
2. Genetics
3. p53 gene: Responsible as a transcription factor in DNA repair, regulation of apoptosis & cell progression.
4. Telomerase activation
5. Angiogenesis & evasion of apoptosis

CTLA-4: Miracle Target Under Discovery for NSCLC

Cytotoxic T lymphocyte antigen-4 is a receptor present over the T-cell of our body’s immune system. It is a member of immunoglobulin superfamily with a pivotal role in regulation of immune responses. This glycoprotein is a coinhibitory molecule expressed by T lymphocytes after their activation and is constantly expressed on the surface of regulatory T cells (CD4þ, CD25þ, Treg cells). CTLA4 downmodulates and terminates immune responses using different pathways. CTLA-4 has structure much similar to CD-28 the other receptor present over the T-cell. The CD-28 is initially bound to the B7-1 (CD-80) & B7-2(CD-86) receptor end found on the APC but CTLA-4 having higer affinity causes B7-1& B7-2 to attach to it. This creates a response of downregulation of the immune response as a result of the normal functioning of the body’s mechanism. The immune upregulation is maintained by the PD-1 & PD-L1 receptors, in this way the overall immune responses are regulated in the human body.

Targeting these CTLA-4 receptors to treat cancer has opened new ways of dealing with this illness. The drugs currently under trials (Ipilimumab, tremelimumab) are CTLA-4 antibodies having high affinity to the receptor and thereby causing its binding to these drugs. As a result the normal mechanism of the receptor to down regulate the immunity is inhibited and this boosts the immune response against cancerous cells causing a detrimental effect over the onco-cells. This also has it’s significant adverse effects though which will be dicussed further in the article.

Statement of Problem

Immune checkpoint inhibitors have so far proved to be a boon to treat lung cancer. Some ICI’s have been approved by the US Food and Drug Administration (FDA) for the treatment of a variety of cancers. Clinical trials are paving the way for new ICI therapy agents and expanding the current use of approved therapies. Ipilimumab, which affects CTLA-4, was the first FDA-approved ICI for the treatment of patients with advanced melanoma. CTLA-4 precludes T-cell inhibition and stimulates the activation and growth of effector T cells. The approval of ipilimumab stimulated the research of other ICIs, such as PD-1 and PDL-1.

Emerging Areas

The drugs like pembrolizumab, nivolumab, avelumab, durvalumab,etc. have proven to be effective but are yet questionable due to the adverse effects caused by them like pulmonary toxicity, hypo/hyper thyroidism, GI disturbances, colitis,etc. This leaves the need to look into the CTLA-4 antibodies as an option to explore drugs being more effective and leaving lesser side effects. Ipilimumab being under Phase 2 clinical trial has shown good results so far, tremelimumab also paves it’s way through the drug discovery process being in the phase 3 clinical trials and leads hope for a novel therapy to fight cancer.

Combination Therapy

Currently in use is the combination therapy which has shown beneficial results in the field of NSCLC. Use of chemotherapy along with these CTLA-4 antibodies shows better results in patients to fight cancer and sustain a longer period overall.

Ipilimumab approved for melanoma, when used in a combination therapy along with chemotherapy in NSCLC shows higher ratio of patients with progressive free survival then chemotherapy used alone. Also ipilimumab used along with nivolumab (approved PD receptor antibody in NSCLC) shows better patient sustainability ratio decreasing mortality in average public.5

This opens new area of hope regarding use of CTLA-4 as a novel target in treating NSCLC.The graphs & charts below show the fact ratios of combination therapy used:

Reference

1. Memon H, Patel BM. Immune checkpoint inhibitors in non-small cell lung cancer: A bird’s eye view. Life Sci. 2019;233:116713. doi:10.1016/j.lfs.2019.116713
2. Banna GL, Passiglia F, Colonese F, et al. Immune-checkpoint inhibitors in non-small cell lung cancer: A tool to improve patients’ selection. Crit Rev Oncol Hematol. 2018;129(February):27-39. doi:10.1016/j.critrevonc.2018.06.016
3. Madden K, Kasler MK. Immune Checkpoint Inhibitors in Lung Cancer and Melanoma. Semin Oncol Nurs. 2019;000:150932. doi:10.1016/j.soncn.2019.08.011
4. Khaghanzadeh N, Erfani N, Ghayumi MA, Ghaderi A. CTLA4 gene variations and haplotypes in patients with lung cancer. Cancer Genet Cytogenet. 2010;196(2):171-174. doi:10.1016/j.cancergencyto.2009.09.001
5. Suresh K, Naidoo J, Lin CT, Danoff S. Immune Checkpoint Immunotherapy for Non-Small Cell Lung Cancer: Benefits and Pulmonary Toxicities. Chest. 2018;154(6):1416-1423. doi:10.1016/j.chest.2018.08.1048