STING Agonists: A new tool in the fight against Bladder Cancer

With the bladder cancer market projected to grow in the upcoming years, the development of new immunotherapies like STING Agonists allow for a breakthrough in the fight against bladder cancer. Written by Omar Aly, Sarah Bortel, Jakob Heinz, and Andrés Melendez.

Bladder Cancer Overview

Bladder cancer is the most expensive cancer per the National Cancer Institute, being ranked first in lifetime treatment costs and is the sixth most frequently diagnosed cancer. Estimates indicate that by the year 2023, the United States bladder cancer market will be close to six billion dollars. In 2018, Datamonitor Healthcare estimated 546,400 incident cases of bladder cancer globally, predicting 605,300 incident cases by 2027 as well. Future growth of this market can be attributed to several key factors: the availability of novel drugs and strong distribution pipeline, the organization of lifestyle and increasing public awareness, and the rise in bladder cancer incidence due to an aging population.

Bladder cancer patients experience three distinct phases. The first stage is non-muscle invasive bladder cancer (NMIBC), often referred to as the early stage of cancer. NMIBC cases account for about 70% of all existing bladder cancer cases. As the cancer progresses, it becomes Muscle Invasive Bladder Cancer (MIBC), accounting for 20% of these bladder cancer cases. The last stage of bladder cancer is Metastatic Disease, which accounts for 10% of all bladder cancer cases in patients.

BCG as a treatment for NMIBC
In the 1950s, scientists discovered that the tuberculosis (TB) vaccine was a potential cancer-fighter. When used in this way, the vaccine is called BCG, and it works to stimulate an immune response to destroy cancer cells. This immunotherapy is made from a live version of the TB bacteria. While BCG treatment is the current standard of care for NMIBC, BCG therapy is unsuccessful for 40% of NMIBC patients. Of this 40%, 45% of patients may progress to MIBC within 5 years. Because BCG may be unsuccessful depending on the patient, an opportunity is created to develop other immunotherapies that can either replace BCG as the standard NMIBC treatment or allow for the treatment of BCG-resistant individuals.

The story behind STING Agonist

10 years ago, Glen Barber was studying the immune system response to pathogens at the University of Miami when he discovered STING. He found that cells missing the STING protein were vulnerable to viral infections. Glen and his laboratory were able to discover the innate immune senator STING and STING controlled cytosolic DNA innate immune signaling pathway.

Afterward, Russel Vance and his team at Berkeley discovered a bacterial molecule called c-di-GMP (cyclic diguanylate monophosphate) that binds to STING receptors in mammals and initiates the innate immune response. c-di-GMP is a cyclic dinucleotide(CDN), which is a class of compounds made by linking 2 DNA nucleotide building blocks.

Later in 2012, Barber discovered that STING proteins can be activated by DNA leaking from dead cells of the same organism. But there was still a problem. Scientists were puzzled by how STING recognized a bulky DNA molecule that was unlike c-di-GMP

Finally, in 2013, Zhijan Chen at the University of Texas Southwestern Medical Center found an enzyme called cyclic GMP-AMP synthase (cGAS) that binds to DNA. cGAS then links two nucleotides to create a CDN molecule called cyclic-GMP-AMP, which is the natural agonist of STING. From these discoveries, scientists were able to find out that our DNA does not normally trigger STING. Only if DNA leaks out of the nucleus into the cytosol where STING receptors face, can an autoimmune reaction be triggered. Moreover, radiation and chemotherapy can also activate STING because of the flotsam of DNA spilled from dying cancer cells.

STING Agonists
The Stimulator of Interferon Genes (STING) is an important component of the body’s innate immune system — the first line of defense against sickness. STING is a master regulator of type 1 interferons and can be activated upon the body’s detection of pathogens. The activation of STING provides two critical anti-tumor responses: the initiation of immune system response and the activation of pathogen-destroying T Cells. Because of STING’s ability to activate T-Cells, several high profile companies such as Novartis, BMS, GSK, and Merck have been pursuing STING Agonists and STING antagonists as cancer immunotherapy, especially for NMIBC. Preclinical STING agonists programs have already led to deals potentially worth more than $2 Billion. Several companies are looking into new ways to combine the benefits of STING agonists with BCG to create more efficacious and effective immunotherapy.

Summary
The bladder cancer market is growing due to higher treatment costs and an efficient treatment and distribution pipeline. Furthermore, the bladder cancer market is being fueled by a rise in incidence rates of cancer, in select countries, due to aging populations. Because of these growth factors, there has been a rise in new immunotherapies to treat BCG-resistant NMIBC patients. One of these developments is the use of STING Agonists to activate the body’s innate immune response to attack tumor cells. Because of these discoveries, many companies are rushing to incorporate STING agonists into their other bladder cancer immunotherapies or even combine STING Agonists with BCG.

APPENDIX

Key Industry Players
Due to the growing bladder cancer market, many key companies have emerged as dominant figures. Several companies are based in the United States such as Merck & Co, Pfizer, and Bristol-Myers Squibb. Other international companies such as Roche (CH), AstraZeneca (UK), GlaxoSmithKline (UK), & Sanofi Pasteur (Fr) have also emerged as dominant players in the bladder cancer industry.

NMIBC Bladder Cancer Cases and Medical Coverage in the USA
The National Cancer Institute predicts an incidence of 62,100 new bladder cancer cases in men and 19,300 in women by the year 2020. The total number of these new cases is 81,400, and the estimated number of NMIBC cases is 56,980.

In the United States, there are two different forms of government health care. Medicare is available for people aged 65 and older, younger people with disabilities, and those with End-Stage Renal Disease. Medicare has two parts, Part A (Hospital Insurance) and Part B (Medical Insurance). Part A covers chemotherapy for those with cancer when hospitalized as inpatients. Part B covers chemotherapy for hospital outpatients. The second health care program in the United States is Medicaid. This health care option is a federal and state program that helps cover medical costs for those with limited income and/or resources. Medicaid also offers benefits that Medicare does not cover, such as nursing home care, personal care services, doctor’s office, or freestanding clinic. Medicaid cancer coverage benefits vary from state to state.