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Immunotherapy for Colorectal Cancer

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  • Colorectal Cancer
  • Treatment Options
  • CRI's Impact
  • Clinical Trials

How is Immunotherapy Changing the Outlook for Patients with Colorectal Cancer?

Reviewed By: Dirk Jäger, M.D.
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National Center for Tumor Diseases, University of Heidelberg, Germany
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Colorectal cancer, referring to both colon cancer and rectal cancer, begins in the lining of the colon or rectum and has the ability to spread to other organ systems and lymph nodes. Over 95% of colorectal cancers are adenocarcinomas, a type of tumor that originates in the mucus-producing glands of the colon or rectum. Recently, the role of Lynch syndrome—an inheritable genetic disorder—in the development of colorectal has come to be recognized. It’s estimated that Lynch syndrome results in about 5,000 new cases of colorectal cancer year in the United States.

Colorectal cancer is the third most common cancer type in the U.S. and the second most deadly. In 2017, there were an estimated 144,000 new cases of colorectal cancer that were diagnosed and 51,000 colorectal cancer-related deaths in the U.S. Globally, there are approximately 1.8 million cases of colorectal cancer diagnosed each year, along with over 800,000 deaths caused by the disease. 

Though overall death and incidence rates among both men and women have declined over the past two decades—largely due to screening tests that detect pre- and early stage disease—underuse of these screening tests means that only 40% of colorectal cancers are diagnosed as early stage, when the survival rate is highly favorable at 90%. As such, new treatments for colorectal cancer are urgently needed.

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Colorectal Cancer Treatment Options

Traditional treatments for colorectal cancer include chemotherapy, radiation, and surgery. Though currently the most common treatment for colorectal cancer is surgical, there are several FDA-approved immunotherapy options.

Targeted Antibodies

  • Bevacizumab (Avastin®): a monoclonal antibody that targets the VEGF/VEGFR pathway and inhibits tumor blood vessel growth; approved for subsets of patients with advanced colorectal cancer, including as a first-line therapy
  • Cetuximab (Erbitux®): a monoclonal antibody that targets the EGFR pathway; approved for subsets of patients with advanced, EGFR-positive colorectal cancer, including as a first-line therapy
  • Panitumumab (Vectibix®): a monoclonal antibody that targets the EGFR pathway; approved for subsets of patients with advanced, EGFR-positive colorectal cancer
  • Ramucirumab (Cyramza®): a monoclonal antibody that targets the VEGF/VEGFR2 pathway and inhibits tumor blood vessel growth; approved for subsets of patients with advanced colorectal cancer, including as a first-line therapy

Checkpoint Inhibitors

  • Nivolumab (Opdivo®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced, MSI-high colorectal cancer
  • Pembrolizumab (Keytruda®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced, MSI-high colorectal cancer

Many immunotherapies that show promise in addressing other types of cancer are in clinical testing for colorectal cancer.

Find a Colorectal Cancer Clinical Trials

CRI's Impact on Colorectal Cancer

The Cancer Research Institute has a long history of supporting scientific research for the advancement of colorectal cancer treatment, seeing many major breakthroughs that have made immunotherapy a promising approach for this disease.

  • One landmark study in 1998 by Haruo Ohtani, M.D., provided early evidence that immunotherapy treatments can act as a catalyst or enhancement for ideal immunologic conditions that could extend the lives of colorectal cancer patients.
  • The recent development of the Immunoscore tool, by Jérôme Galon, Ph.D., a new way to classify tumors, better predicts the rate of relapse and survival in patients with colorectal cancers, providing essential prognostic information that can then improve the confidence of clinical decisions and rational stratification of patient treatment.
  • Research by Dirk Jäger, M.D., a member of the CRI clinical trials network at the University of Heidelberg in Germany, elucidated how immune parameters correlate with prognosis in colorectal cancer.
  • In one study, former CRI postdoctoral fellow Eran Elinav, M.D., Ph.D., along with former CRI predoctoral scholar Till Strowig, Ph.D., showed that deficiencies in caspase-1, an enzyme involved in the activation and maturation of inflammatory immune molecules, resulted in enhanced tumor formation in a colitis-associated colorectal cancer model.

Explore CRI’s current funding for colorectal cancer research in our funding directory.

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Featured Patient

In my 20 years of experience, I have never seen before such a fast pace of research progress!

Tom Marsilje
Colorectal Cancer  |  Diagnosed June 4, 2012
Read My Story
Featured Scientist
Ignacio Melero, M.D., Ph.D.
Foundation for Applied Medical Research (FIMA) (Spain)
CLIP Investigator  |  2017
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Colorectal Cancer Statistics

3rd Most common cancer in the United States
Over 95% Of colorectal cancers are adenocarcinomas

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Colorectal Cancer Clinical Trial Targets

Discover the different proteins, pathways, and platforms that scientists and physicians are pursuing to develop new cancer treatments. Use this information to consider your clinical trial options.

Therapies
  • Targeted Antibodies
  • Cancer Vaccines
  • Adoptive Cell Therapy
  • Immunomodulators
  • Oncolytic Virus Therapy

Targeted antibodies are proteins produced by the immune system that can be customized to target specific markers (known as antigens) on cancer cells, in order to disrupt cancerous activity, especially unrestrained growth. Antibody-drug conjugates (ADCs) are equipped with anti-cancer drugs that they can deliver to tumors. Bi-specific T cell-engaging antibodies (BiTEs) bind both cancer cells and T cells in order to help the immune system respond more quickly and effectively. Antibody targets under evaluation in colorectal cancer clinical trials include:

  • Angiopoietin: this pathway can promote the growth of blood vessels in tumors
  • DLL/Notch: a pathway that can promote cell growth
  • EGFR: a pathway that controls cell growth and is often mutated in cancer
  • HER2: a pathway that controls cell growth and is commonly overexpressed in cancer and  associated with metastasis
  • TROP2: a protein that is commonly overexpressed in cancer and appears to aid cancer cell self-renewal, proliferation, invasion, and survival
  • VEGF/VEGF-R: a pathway that can promote blood vessel formation in tumors

Cancer vaccines are designed to elicit an immune response against tumor-specific or tumor-associated antigens, encouraging the immune system to attack cancer cells bearing these antigens. Cancer vaccines can be made from a variety of components, including cells, proteins, DNA, viruses, bacteria, and small molecules. Cancer vaccine targets under evaluation in colorectal cancer clinical trials include:

  • 5T4: an antigen often expressed by several different types of cancers
  • CEA: a protein involved in cellular adhesion normally produced only before birth; often abnormally expressed in cancer and may contribute to metastasis
  • Human Papilloma Virus (HPV)-related antigens: foreign viral proteins expressed by HPV-infected cancer cells
  • MUC-1: a sugar-coated protein that is commonly overexpressed in cancer
  • P53: a tumor suppressor protein that is often mutated, nonfunctional, and overexpressed in cancer
  • Personalized neoantigens: these abnormal proteins arise from a patient’s unique mutations and are expressed exclusively by tumor cells
  • Survivin: a protein that can prevent cellular death and is overexpressed by a number of cancer cell types
  • Telomerase: an enzyme that helps maintain the health of cellular DNA; exploited by cancer cells to achieve immortality
  • Tumor-associated antigens (TAAs): proteins often expressed at abnormally high levels on tumor cells that can be used to target them; also found on normal cells at lower levels

Adoptive cell therapy takes a patient’s own immune cells, expands or otherwise modifies them, and then reintroduces them to the patient, where they can seek out and eliminate cancer cells. In CAR T cell therapy, T cells are modified and equipped with chimeric antigen receptors (CARs) that enable superior anti-cancer activity. Natural killer cells (NKs) and tumor infiltrating lymphocytes (TILs) can also be enhanced and reinfused in patients. Cell-based immunotherapy targets under evaluation in colorectal cancer clinical trials include:

  • CEA: a protein involved in cellular adhesion that is normally produced only before birth, but is often abnormally expressed in cancer and may contribute to metastasis

Immunomodulators manipulate the “brakes” and “gas pedals” of the immune system. Checkpoint inhibitors target molecules on immune cells to unleash new or enhance existing immune responses against cancer. Cytokines regulate immune cell maturation, growth, and responsiveness. Adjuvants can stimulate pathways to provide longer protection or produce more antibodies. Immunomodulator targets under evaluation in colorectal cancer clinical trials include:

  • CD40: activating this co-stimulatory pathway can kickstart adaptive immune responses
  • CD73 or A2AR: blocking these pathways can help prevent the production of immunosuppressive adenosine
  • CD137 (also known as 4-1BB): activating this co-stimulatory pathway can help promote the growth, survival, and activity of cancer-fighting T cells
  • CSF1/CSF1R: blocking this pathway can help reprogram cancer-supporting macrophages      
  • CTLA-4: blocking this pathway can help promote expansion and diversification of cancer-fighting T cells
  • GITR: activating this pathway can help prevent immunosuppression and increase the survival of cancer-fighting T cells
  • ICOS: activating this co-stimulatory pathway on T cells can help enhance immune responses against cancer
  • IDO: blocking this enzyme’s activity can help prevent cancer-fighting T cells from being suppressed
  • IL-2/IL-2R: activating this cytokine pathway can help promote the growth and expansion of cancer-fighting T cells
  • LAG3: blocking this pathway may be able to help prevent suppression of cancer-fighting T cells
  • OX40: activating this co-stimulatory pathway can help promote T cell survival after activation
  • PD-1/PD-L1: blocking this pathway can help prevent cancer-fighting T cells from becoming “exhausted,” and can restore the activity of already-exhausted T cells
  • STAT3: activating this intracellular signaling protein can help stimulate adaptive immune responses
  • Toll-like receptors (TLRs): activation of these innate immune receptors can help stimulate vaccine-like responses against tumors

Oncolytic virus therapy uses modified viruses that can infect tumor cells and cause them to self-destruct. This can attract the attention of immune cells to eliminate the main tumor and potentially other tumors throughout the body. Viral platforms under evaluation in colorectal cancer clinical trials include:

  • Adenovirus: a family of common viruses that can cause a wide range of typically mild effects including sore throat, fatigue, and cold-like symptoms
  • Herpes simplex virus: a virus that can cause the formation of sores on the mouth and genitals
  • New Castle Virus: a virus primarily found in birds; can cause mild conjunctivitis and flu-like symptoms in humans
  • Reovirus: a family of viruses that can affect the gastrointestinal and respiratory tracts in a range of animal species
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Sources: National Cancer Institute Physician Data Query (PDQ), American Cancer Society Facts & Figures 2016, National Comprehensive Cancer Network (NCCN) Guidelines for Patients, ClinicalTrials.gov, GLOBOCAN 2012, GLOBOCAN 2018, CRI grantee progress reports and other grantee documents, the Mayo Clinic Lynch Syndrome Page

Updated November 2018

*Immunotherapy results may vary from patient to patient. Consult a healthcare professional about your treatment options.

*Immunotherapy results may vary from patient to patient.

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