Immunotherapy For Colorectal Cancer

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Introduction

The large intestine, comprising the colon, rectum, and anus, is divided into three distinct parts. When cells in the colon or rectum undergo mutations and exhibit uncontrolled proliferation, they can transform into cancerous cells, leading to colorectal cancer (CRC).

Colorectal cancer affects approximately 1.8 million people each year, ranking as the third most common cancer type in the United States and the second most deadly. Despite these alarming statistics, there has been a positive trend in declining overall death and incidence rates over recent decades. This improvement is primarily attributed to increased screening efforts, enabling the early detection of cancer when it is most treatable.1

Traditionally, surgery and chemotherapy have been the mainstays of colorectal cancer treatment. However, in recent years, immunotherapy has gained prominence due to its high effectiveness in combating other solid cancers, such as tumours in organs like the breast or prostate. 

In this article, we’ll understand what immunotherapy is, its potential in treating colorectal cancer, what treatments are available and being investigated, and some risk factors associated with the disease. 

What is immunotherapy and why it is important

Immunotherapy is a type of cancer treatment that uses molecules made by the body or a laboratory to activate the immune system, helping your immune cells find and destroy cancer cells. It can be given alone or in combination with other treatments, such as chemotherapy, and used in many different cancers.

Chemotherapy differs from immunotherapy in that it uses chemicals to kill cancerous cells in your body, instead of boosting your natural fighters (the immune cells) to kill the cancer themselves.

Immunotherapy has great potential for fighting tumours because cancer cells often hide and deactivate your immune system to survive and multiply. By boosting your immune system with immunotherapy, we can improve your immune cells ‘sight’ and make them better at seeing the cancerous cells, outsmarting them.3

Understanding colorectal cancer

As stated above, the main treatment for colorectal cancer is surgery. While surgery solves tumour-related complications, such as intestinal obstruction, perforation, and bleeding, it does not reduce mortality. For this reason, a combination of treatments is often used, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy. 

Although immunotherapy has been promising at fighting certain types of cancer, it is important to understand that there are many types of colorectal cancer. This is because every person has a different genetic makeup and because every cancer can have a different root cause, implying each tumour can grow and behave differently depending on the person. This means that not everyone will respond in the same way to treatment, and some treatments may be more efficient for specific types of CRC due to their specific root cause. 

For this reason, immunotherapy is only used to treat CRC types that grow after hiding from your immune cells and by reducing their activity.4

What are immune checkpoint inhibitors?

Your immune system is always regulating its response to ensure it doesn’t harm your healthy cells. One way this is done is by communication through protein interactions which are expressed on the surface of your T cells (a specific immune cell) and the rest of your healthy cells. These regulatory proteins are called immune checkpoint proteins. When your healthy cells touch your T cells through their checkpoint proteins, they send a ‘turn-off’ signal, deactivating the T cell to prevent it from causing unnecessary damage. Cancer cells take advantage of this system, touching the T cells’ checkpoint proteins themselves, preventing your T cells from attacking them.

Some immunotherapy drugs called checkpoint inhibitors target these checkpoint proteins, covering them so that they can’t be touched and hence deactivated by the cancer cells, allowing them to stay active and attack the cancer.5

A Subset of CRC patients that can benefit from checkpoint inhibitors

People with colorectal cancer whose cancer cells have tested positive for specific gene changes can benefit from checkpoint inhibitor treatments. These are changes in mismatch repair (MMR) genes, which are genes responsible for fixing DNA damage and preventing mutations (therefore preventing cancer from forming and evolving), or patients with a high level of microsatellite instability (MSI-H), which implies their tumour is very unstable and will most likely drastically change as it evolves (1).

From September 2017, immunotherapy based on checkpoint inhibitors (specifically Pembrolizumab) started to be used to treat metastatic colorectal cancer (cancer that has spread to other tissues). However, this immunotherapy fails to elicit significant anti-tumour responses in most CRC patients. Thus, other immunotherapy treatments are being studied in clinical trials to incorporate them as future treatments for CRC (4,6). Some immune checkpoint inhibitors currently used to treat colorectal cancer are described below:

  • PD-1 inhibitors: PD-1 inhibitors bind to PD-1, a checkpoint protein expressed by the T cells. When PD-1 is hit by a cancer cell, it turns the T cell off. Some drugs targeting PD-1 that are used in some advanced colorectal cancers include:1
    • Pembrolizumab (Keytruda) is used as a first-line treatment for people with advanced or metastatic CRC. It is administered by an intravenous infusion every 3 to 6 weeks.
    • Nivolumab (Opdivo) which can be used alone or together with other drugs for people with  colorectal cancer that has kept growing despite chemotherapy treatment. If given alone, it is given as an intravenous infusion every 2 to 4 weeks. If given alongside other drugs, it is usually given every 3 weeks.
    • Dostarlimab (Jemperli) may be used to treat recurrent or metastatic colorectal cancers that have deficient mismatch repair proteins. Similar to the others, it is given intravenously every 3 or 6 weeks (7)
  • CTLA-4 inhibitor:

CTL-4 inhibitors block CTLA-4, which is another protein present in T cells that can send the ‘turn-off’ signal. The main CTLA-4 inhibitor used for CRC is Ipilimumab (Yervoy), which is normally given alongside nivolumab (Opdivo) intravenously every 3 weeks.

While immune checkpoint inhibitors have demonstrated significant promise in prolonging the life expectancy of patients with specific types of metastatic colorectal cancer (CRC), utilising immunotherapy for the treatment of colorectal cancer poses considerable challenges. This complexity arises from the potential for serious side effects associated with immunotherapy, the fact that not all colorectal cancers develop by deactivating the immune system, and the occurrence of resistance in many patients, which means that patients stop responding to immunotherapy treatment.4

Side effects of immunotherapy

Like any drug, immunotherapy drugs have side effects, which usually derive from inducing an overly active immune system. These side effects depend on how healthy you are before treatment, your type of cancer, how advanced the cancer is, and the type and dose of immunotherapy you receive. Some common side effects include:1,5

  • Fatigue
  • Cough
  • Nausea
  • Diarrhoea
  • Skin rash and itching
  • Loss of appetite
  • Constipation
  • Joint pain

However, there are other serious side effects that occur less often:

  • Infusion reactions, which are similar to allergic reactions can vary in severity and can manifest as rash, chills, fever, nausea, and a headache
  • Autoimmune reactions, where your immune system mistakenly attacks your healthy cells. This is because checkpoint inhibitors block one of the ‘control’ mechanisms your body uses to prevent your immune system from attacking your healthy cells. Checkpoint inhibitors therefore heighten the risk of developing autoimmune diseases

Risk factors for colorectal cancer

Although anyone can develop colorectal cancer, the risk increases as you grow older. Nine out of ten people diagnosed with the disease are over 50.8 Despite this, other factors heightening your risk include having:9

  • Inflammatory bowel disease, like Crohn’s disease or ulcerative colitis
  • Family history of colorectal cancer
  • Genetic syndromes like familial adenomatous polyposis (FAP), or Lynch syndrome
  • Lifestyle factors: a lack of regular exercise, high-fat, high-salt, high-red meat, and low-fibre diet, being overweight, alcohol as well as tobacco consumption

Future directions

Although they haven’t been approved for CRC, some other treatments relying on the immune system to kill colorectal cancer are currently being investigated. Some of these include:

  • Neo-antigen-based or cell-based vaccines: These are vaccines given to the patient after having developed the cancer. In most cases, their function is not to prevent cancer from appearing (unfortunately this is still not possible for CRC), but instead, to boost your immune system to fight it. Some clinical trials are exploring this type of treatment in CRC.10
  • Adoptive cell therapy: This treatment consists of three main steps. First, some of your immune cells with the potential to attack the cancer are extracted from your body. Next, scientists engineer them to make them specific against your tumour and encourage their proliferation. Lastly, they are put back in your body to kill the cancer.
  • Microbiota therapy: Your gut hosts millions of beneficial bacteria that have a huge impact on the way your immune system behaves. This community of microorganisms is known as your microbiota. Differences in the numbers and species of gut microbiota have contributed to different responses to immunotherapy treatment, inflammation, and cancer progression in mice.10,11 Researchers are trying to understand how this applies to humans in the context of CRC.

Summary

Colorectal cancer also referred to as bowel cancer, affects the large intestine and ranks as the third most common cancer and the second most lethal in the U.S. Standard treatments encompass chemotherapy and radiotherapy, with recent advancements introducing immunotherapy. Immunotherapy involves enhancing the immune system to combat cancer. While promising in other solid cancers, its application in colorectal cancer is restricted to a specific subset of patients. A type of immunotherapy currently used in advanced CRC is immune checkpoint inhibitors. Checkpoint inhibitors help your immune cells attack the cancer by preventing cancer cells from deactivating them, a tactic commonly employed by cancer cells to sustain growth. While this form of immunotherapy extends life expectancy in some patients, it poses the risk of significant side effects, including autoimmune diseases. Consequently, ongoing studies and clinical trials are exploring alternative immunotherapies with the hope of advancing treatment options for colorectal cancer in the future.

References

  1. Cancer Research Institute [Internet]. [cited 2024 Jan 6]. Immunotherapy for Colorectal Cancer. Available from: https://www.cancerresearch.org/cancer-types/colorectal-cancer
  2. Golshani G, Zhang Y. Advances in immunotherapy for colorectal cancer: a review. Therap Adv Gastroenterol. 2020 Jun 1;13:1756284820917527.
  3. Cancer.Net [Internet]. 2013 [cited 2024 Jan 6]. What Is Immunotherapy? Available from: https://www.cancer.net/navigating-cancer-care/how-cancer-treated/immunotherapy-and-vaccines/what-immunotherapy
  4. Weng J, Li S, Zhu Z, Liu Q, Zhang R, Yang Y, et al. Exploring immunotherapy in colorectal cancer. Journal of Hematology & Oncology. 2022 Jul 16;15(1):95.
  5. Immune Checkpoint Inhibitors - NCI [Internet]. 2019 [cited 2024 Jan 6]. Available from: https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/checkpoint-inhibitors
  6. Thomas EM, Wright JA, Blake SJ, Page AJ, Worthley DL, Woods SL. Advancing translational research for colorectal immuno-oncology. Br J Cancer. 2023 Oct;129(9):1442–50.
  7. Shuvo PA, Tahsin A, Rahman MdM, Emran TB. Dostarlimab: The miracle drug for the treatment of colorectal cancer. Ann Med Surg (Lond). 2022 Aug 27;81:104493.
  8. Lewandowska A, Rudzki G, Lewandowski T, Stryjkowska-Góra A, Rudzki S. Title: Risk Factors for the Diagnosis of Colorectal Cancer. Cancer Control. 2022 Jan 9;29:10732748211056692.
  9. What Are the Risk Factors for Colorectal Cancer? | CDC [Internet]. 2023 [cited 2024 Jan 6]. Available from: https://www.cdc.gov/cancer/colorectal/basic_info/risk_factors.htm
  10. Cornista AM, Giolito MV, Baker K, Hazime H, Dufait I, Datta J, et al. Colorectal Cancer Immunotherapy: State of the Art and Future Directions. Gastro Hep Advances. 2023 Jan 1;2(8):1103–19.
  11. Park JS, Gazzaniga FS, Wu M, Luthens AK, Gillis J, Zheng W, et al. Targeting PD-L2-RGMb overcomes microbiome-related immunotherapy resistance. Nature. 2023 May;617(7960):377–85.

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This content is purely informational and isn’t medical guidance. It shouldn’t replace professional medical counsel. Always consult your physician regarding treatment risks and benefits. See our editorial standards for more details.

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Gabriel Aurelio Ortega Toledo

Immunology degree - Bsc (Hons), Immunology, Biology, The University of Edinburgh

Gabriel is a recent graduate with a BSc in Immunology from the University of Edinburgh. While his academic foundation lies in immunology, his professional focus has expanded into the domains of education, media, and science communications. Gabriel has actively participated in various facets of medical research, contributes to a biology podcast, and collaborates with an autoimmune disease charity as a patient interviewer. His enthusiasm for medical writing stems from a profound interest in healthcare science, a commitment to simplifying complex data, and a genuine passion for connecting with people.

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