A decade ago, as a young bench scientist, I encountered clinical trial data demonstrating a groundbreaking approach to cancer treatment. It involved stimulating the immune system to target cancer cells with greater efficacy and lower toxicity compared to conventional methods like chemoradiation, which weaken the patient’s immune defenses.

Fast forward to today, immunotherapy drugs are now prominent, and even advertised on primetime television commercials, offering the hope for curing cancer for you or your loved ones. However, what these advertisements fail to make clear is that immunotherapy is only effective in roughly 20% of all cancer patients. Despite this limitation, why are these “miracle” drugs being marketed to millions of Americans as a universal treatment for some of the most aggressive cancers?

In this blog post, we delve into the immunotherapy revolution and its potential to significantly extend survival durations for many late-stage cancers by harnessing the immune system. However, we also highlight the challenge of identifying the right patients who can respond to this treatment. Our exploration will cover anti-cancer applications, potential risks and benefits, and provide reliable sources for further information. Let’s unlock the complexities of immunotherapy patient selection and understand its place in the fight against cancer.

Immunotherapy for Cancer was Known in the 1800s

The rudiments of immunotherapy were first discovered in 1891 when Dr. William Coley witnessed the power of the immune system in anti-cancer processes when a patient with head and neck sarcoma went into full remission after his body fought a streptococcus infection which occurred at the surgical resection site. The more his patient’s immune system fought the infection, as evidenced by high fevers to fend off the unrelated disease, the more the facial tumors shrunk until the patient was in complete remission. This phenomenon was discovered over 130 years ago, yet the role of the patient’s immune system has been overlooked and largely neglected in the fight against cancer for over a century.

The Immunotherapy Revolution

Since the 1920s, the primary approach to treating cancer has involved surgery, often complemented by chemotherapy and/or radiation, which can destroy the patient’s immune system. Despite progress in molecular medicine, the oncology field still faces significant challenges in improving survival rates for stage III and IV cancers, with some types proving particularly difficult to manage. Lung, liver, and esophageal cancers have exhibited five-year survival rates of around 15% for many years, while mesothelioma, pancreatic carcinoma, and glioblastomas have shown distressing single-digit 5-year survival rates. Cancers with distant metastases have a survival rate of less than 10% at the five-year mark. Recently, the FDA has approved 35 immune checkpoint inhibitors for oncology, representing a promising advancement. However, certain hurdles persist, such as the need to identify biomarkers to predict immunotherapy response and effectively manage potential side effects. Based on the overwhelmingly successful results of dozens of clinical trials, Science named cancer immunotherapy the “Scientific Breakthrough of the Year” in 2014. Researchers hope they can effectively treat cancer with fewer side effects than other treatments. Clearly, the immunotherapy revolution brings renewed hope to cancer patients and oncologists worldwide.

Must-read: An Introduction to CAR-T Therapy

What is Immunotherapy?

Immunotherapy is a special treatment that stimulates the patient’s immune system to improve its ability to locate and destroy the cancer. Cancer cells can hide from the immune system by using certain proteins as a disguise. Immunotherapy drugs are made to unmask these “camouflaged” cancer cells and make the immune cells stronger so they can attack the cancer throughout the body.

But sometimes, cancer cells find tricky ways to escape the immune system, by expressing the PD-L1 protein on their surface, fooling the immune cells into thinking the tumor is non-cancerous. Also, since cancer cells start as regular cells, the immune system doesn’t always know they are cancerous. To fix this, researchers have discovered ways to help the immune system identify and attack cancer cells, just like it does with viruses, bacteria, or other invaders (Figure 1).

Figure 1: Immunotherapy in addition to chemotherapy can enhance cancer regression: combined or mono-therapeutic checkpoint inhibitors cytotoxic T-lymphocyte-associated protein (CTLA-4) and Program Death 1 (PD-1), can yield a robust regression of regional and distant metastases along with conferred immunity at both local and distant tumor sites.

Contrary to Perception, Immunotherapy is Only Effective in 1 in 5 Patients.

Finding the right patients who will benefit from immunotherapy has been more challenging than expected. Using a one-size-fits-all approach often leads to prescribing drugs that don’t work for many patients, and can cause harmful side effects. This is especially concerning with cancer drugs, as severe side effects may arise, making it uncertain whether to continue treatment or temporarily pause to protect the patient’s health.

Unfortunately, only about 1 in 5 patients benefit from checkpoint inhibitors. It would be ideal if doctors could accurately identify those who will respond positively to the treatment, allowing for oncologists to optimize treatment plans, while also sparing patients from unnecessary side effects. However, the current tests available to doctors do not reliably predict how a patient’s cancer will respond to this treatment method.

Moreover, immunotherapy is one of the most expensive types of anti-cancer drugs, costing 4000 times the price of gold per ounce. This places a significant financial burden on both the healthcare system and patients, particularly when there is inefficiency in identifying who will truly benefit from checkpoint inhibition.

Current Standard Immunotherapy Placement Tests

The current methods used to identify patients who will respond to immunotherapy, such as Immune Checkpoint Inhibitors (ICIs), have not been very successful. Only around 20.2% of patients show a positive response, and only 13% of those have long-lasting results. Standard immunotherapy response diagnostics currently require resected or biopsied tumor specimen, which is sometimes impossible to attain. These tests also require an unadulterated tumor, free of chemoradiation destruction, which can be rare in the post-therapy setting. Biomarker expressions, such as PD-L1, can yield unreliable results after chemo and/or radiation.

PD-L1 Tumor Staining

PD-L1 is the protein that tumors sometimes express to mask their cells as non-antigens. Many immunotherapies attach to PD-L1 on the tumor surface to block misinformation from being signaled from the tumor to the immune system. Presumably, if a tumor has a lot of PD-L1, it should be responsive to immunotherapy. However, this theory has had discordant results across hundreds of studies. Confusingly, five immunotherapies require five different PD-L1 antibody stains to determine its presence in the tumor. The calculations of these expression scores are also inconsistent between indications. Some studies have even shown that low to no PD-L1 patients survived longer than patients with PD-L1 overexpression. According to the PREDAPT study (2022) PD-L1 staining had a 42% accuracy in predicting response to immunotherapy.

Tumor Mutational Burden (TMB)

Tumor mutational burden (TMB) is a helpful biomarker that can predict how likely immunotherapies will work. TMB looks at the number of genetic mutations in a tumor’s DNA, which shows the genetic instability of the tumor. Tumors with a high TMB usually have more genetic mutations, leading to the creation of abnormal proteins (neoantigens) on the cancer’s surface. These neoantigens act as signals for the immune system to attack the cancer cells. However, this method has shown varying results in different studies, and it has some limitations. It can be affected by the diversity of tissues in the tumor, lacks standardized testing methods, and is not predictive for all types of cancer.

Alternative Approaches for Immunotherapy Patient Stratification?

A new blood test was introduced last year, which can forecast if a patient will respond to immunotherapies, regardless of the cancer type or the brand of checkpoint inhibitor being considered. This advanced test, called EpiSwitch® CiRT, accurately predicts patient outcomes by analyzing the 3D genomic information within their immune cells. Unlike traditional tests that focus on the cancer itself, EpiSwitch CiRT examines the patient’s 3D immunogenic profile of immune cells in the blood to predict their response to immunotherapy. Unlike most anti-cancer drugs, immunotherapy stimulates the immune system to attack the cancer, while the drug itself doesn’t affect the cancer directly.  Since the target of immunotherapies is the host’s immune system and not the actual tumor, it makes the analysis of the patient’s immune cells in the blood a much better predicter than the PD-L1 content of the tumor.

EpiSwitch CiRT is currently available to registered physicians in the United States and the United Kingdom, offering a first-of-its-kind prediction and guidance for immunotherapy treatment. With this innovative blood test, doctors can make more-informed decisions about the most suitable immunotherapy approach for their patients. For more information, you can visit myCiRT.com.

Immuno-Oncology Therapeutic Options in Pediatric Cancers

Immunotherapy has shown promising results in some pediatric patients, particularly those with certain types of cancers. Research and clinical trials continue to explore and expand the use of immunotherapy in pediatric oncology, aiming to improve outcomes for young patients with cancer. For more information on immunotherapy uses in pediatric cancer, please see our blog post which covers the current state of this entire field. https://heretoserve.org/blog/checkpoint-inhibitors-for-pediatric-cancer-whats-new-in-immunotherapy/

Conclusion

Cancer is predicted to become the leading cause of death globally, surpassing heart disease. Last year, President Joe Biden launched the “Cancer Moonshot” initiative, declaring a “War on Cancer.” This isn’t the first time the American government has acted against cancer, as former President Richard Nixon declared a war on cancer with the National Cancer Act, aiming to find a cure within five years. It has been 52 years since this act was passed in congress.

With such a critical focus on cancer research, it’s crucial to explore innovative approaches like immuno-oncology and use effective diagnostics to improve patient management. Immuno-oncology harnesses the power of the immune system, which has evolved over millennia to fight cancer. It’s now gaining more significance in the field of oncology, especially if we can identify which patients will respond well to these therapies. Fortunately, there are already less invasive methods available to retrieve molecular information that can predict the likelihood of immunotherapy response. These methods will hopefully play a key role in refining the use of this potent tool in our national fight against cancer.

Sources and Where to Find More Information

If you wish to learn more about immunotherapy patient stratification, its applications, and future research, reliable sources include:

• American Cancer Society: Immune Checkpoint Inhibitors and Their Side Effects: https://www.cancer.org/cancer/managing-cancer/treatment-types/immunotherapy/immune-checkpoint-inhibitors.html
• Cancer Cell: The Challenges of Tumor Mutational Burden as an Immunotherapy Biomarker: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878292/
• Cureus: Limitations of Immunotherapy in Cancer: https://www.cureus.com/articles/114969-limitations-of-immunotherapy-in-cancer#!/
• Oncogene: Is PD-L1 a consistent biomarker for anti-PD-1 therapy? https://www.nature.com/articles/s41388-020-01611-6
• Cancers: 3D genomic conformation informs on patient response to immunotherapy https://www.mdpi.com/2072-6694/15/10/2696

Here to Serve has been assisting families on their cancer journeys for over twelve years. In addition to organizing care communities, go-fund-me pages, and other daily needs, they have an extensive knowledge of resources that may be beneficial to finding new and effective cancer treatments. If you or someone you know is in need of assistance, please contact Here to Serve.

About the Authors

Dr. Joe Abdo is a clinical scientist in the fields of molecular oncology, genomics, proteomics, immunotherapy and gastrointestinal diseases – placing advancements in patient care at the forefront of his work. Joe is a pediatric brain cancer survivor channeling his passion for novel anticancer modalities through active clinical research projects and progressive patient advocacy programs. Joe Abdo is the Vice President of Clinical Diagnostics at Oxford BioDynamics, an Anglo-American biotechnology organization that markets and sells EpiSwitch^® CiRT.

Joos Berghausen is a PhD candidate in Pharmacology at Georgetown University School of Medicine and works part-time as a molecular oncology associate at Oxford BioDynamics.

This blog is for informational and educational purposes only. For specific medical needs, please contact the appropriate medical professional.

The figure in this article is original and available in the Here to Serve photo archive.