Cancer Immunotherapy

Colorectal Cancer

Colorectal cancer is one of the major cancer types for which new immune-based cancer treatments are currently in development. This page features information on colorectal cancer and immunotherapy clinical trials for colorectal cancer patients, and highlights the Cancer Research Institute’s role in working to bring effective immune-based cancer treatments to people with colorectal cancer.

Colorectal cancer is the third most common type of cancer among both men and women in the United States, and is the second most deadly. The name may refer to colon cancer or rectal cancer, which share many of the same disease characteristics.

Colorectal cancer begins in the lining of the colon or rectum. It can spread deeper into the colon or rectum wall or, in the case of advanced cancer, into other organs 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.

Brief statistics

It is estimated that 1 in every 20 people will develop colorectal cancer. In 2014, it is projected that there will be 96,830 new cases of colon cancer and 40,000 new cases of rectal cancer in the U.S. Approximately 50,310 deaths are expected in the U.S. and 600,000 worldwide.

Overall death and incidence rates among men and women have been declining for the past 20 years, thanks largely to screening tests that help detect early-stage cancer and pre-cancerous polyps. Among adults under 50, however, incidence has been rising by 1.7% annually since 1992.

Due to underuse of screening tests, only 39% of colorectal cancers are diagnosed at an early, localized stage, when the 5-year survival rate is 90%. At the locally advanced stage, when the cancer has invaded nearby organs or lymph nodes, the 5-year survival rate is 69%. If the cancer has distant organs, the 5-year survival rate drops to 12%.

Lifestyle-related risk factors include physical inactivity, obesity, high intake of processed or red meat, long-term smoking, alcohol consumption, and a diet lacking in vegetables and fruits. Personal or family history of colorectal cancer (and/or polyps), and a personal history of type 2 diabetes, chronic inflammatory bowel disease or genetic disease such as Lynch syndrome or familial adenomatous polyposis, have also been associated with increased risk.               
 

Colorectal Cancer Treatment

The most common treatment for colorectal cancer is surgery. In the case of localized tumors, surgery may completely eliminate the cancer. When the cancer has invaded the bowel wall deeply or the lymph nodes, chemotherapy (sometimes in combination with radiation therapy) is administered before or after surgery.

Standard first-line chemotherapy for metastatic colon cancer can consist of one of two regimens: FOLFOX (5-FU, leucovorin, and oxaliplatin) or FOLFIRI (5-FU, leucovorin, and irinotecan). Adding bevacizumab (Avastin), a monoclonal antibody that helps cut off the nutrient supply to the tumor by suppressing blood vessel growth (anti-angiogenesis), may also help improve survival when included with either treatment regimen. Cetuximab (Erbitux) and panitumumab (Vectibix), both monoclonal antibodies against the epidermal growth factor receptor (EGFR), have also been shown to improve survival when administered with multi-agent chemotherapy; these antibodies, however, are only effective in patients whose tumors lack RAS mutations.

Aflibercept (Zaltrap), a fusion protein binding the growth factors VEGF-A, VEGF-B, and PGF was also approved for second line treatment with chemotherapy.

In September 2012, the FDA also approved regorafenib (Stivarga), an oral drug that targets multiple tyrosine kinases, for patients who progressed on prior therapy.

Approximately 50% of colon cancer patients will be diagnosed with liver metastases. This may occur either at the time of initial diagnosis or as a result of disease recurrence. Only a small proportion of patients with liver metastases are candidates for surgery, and other techniques and systemic treatments provide some alternative options, including ones currently being tested in clinical trials.
 

When Are Clinical Trials Recommended?

For colon cancer, clinical trials may be appropriate or encouraged in the following cases:

  • For all stage IV or recurrent colorectal cancer
  • For patients with stage IIa or III colorectal cancer following surgery (i.e., in the adjuvant setting)

Go to our Clinical Trial Finder to find clinical trials of immunotherapies for colorectal cancer that are currently enrolling patients.
 

Immunotherapy for colon cancer

Current immunotherapies for colorectal cancer fall into three broad categories: checkpoint inhibitors, cancer vaccines, and adoptive cell therapy. These therapies are still in early-phase clinical testing (phase I and II) for colorectal cancer, but their successful use in other types of cancers suggests that they may ultimately prove useful for colorectal cancer as well.

Checkpoint Inhibitors

A promising avenue of clinical research in colorectal cancer is the use of immune checkpoint inhibitors. These drugs work by targeting molecules that serve as brakes on the immune response. By blocking these inhibitory molecules, checkpoint inhibitors are designed to unleash or enhance pre-existing anti-cancer immune responses. The following trial is currently recruiting patients:

  • A phase I trial of tremelimumab (anti-CTLA-4) and MEDI4736 (anti-PD-L1) used in combination for patients with advanced solid tumors (NCT01975831). This trial is sponsored jointly by the CRI/Ludwig Clinical Trials Network. Patients with advanced solid tumors, including colorectal cancer, are eligible for the trial.

Cancer Vaccines

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. Tumor antigens that have been targeted in colorectal cancer include carcinoembryonic antigen (CEA), MUC1, guanylyl cyclase C, and NY-ESO-1. Several clinical studies of cancer vaccines for colorectal cancer are open, including: 

  • A phase III study of Imprime PGG® in combination with cetuximab in subjects with recurrent or progressive KRAS wild type colorectal cancer (PRIMUS) (NCT01309126).
  • A phase II adjuvant chemotherapy ± FANG™ in colorectal carcinoma with liver metastases (FANG-CLM) (NCT01505166).
  • A phase I study of guanylyl cyclase C vaccine in Stage I/II colon cancer (NCT01972737).
  • A phase I study of vaccine therapy with or without sirolimus in treating patients with NY-ESO-1 expressing solid tumors (NCT01522820).

Adoptive Cell Therapy

In this approach, immune cells are removed from a patient, genetically modified or treated with chemicals to enhance their activity, and then re-introduced into the patient with the goal of improving the immune system’s anti-cancer response. Clinical trials include:

  • A phase I/II trial of anti-VEGFR2 gene engineered CD8+ lymphocytes for metastatic cancer (NCT01218867).
     

CRi contributions and impact

Immunotherapy as a potentially promising approach for treatment of colorectal cancer is based on several lines of evidence. The earliest came from a landmark study in 1998 by Haruo Ohtani, M.D., who demonstrated that the presence and location of CD8+ killer T cells within the tumor microenvironment (aka “tumor-infiltrating lymphocytes,” or TILs) correlated with colon cancer outcomes. Specifically, he showed that the accumulation of CD8+ T cells within the tumor correlated with and could predict improved patient survival, whereas accumulation of the same cells in the tumor periphery did not. These studies  provided early evidence that immunotherapies that can induce or enhance optimal immunologic conditions within colorectal cancers may hold promise for extending the lives of colorectal cancer patients.

Studies to characterize immunological parameters that can aid prognosis have recently led to the development of a new tool, the Immunoscore, by Jérôme Galon, Ph.D., which provides a novel way of classifying tumors that works better than the current staging system in predicting rate of relapse and survival in colorectal cancer patients. The traditional tumor staging system (TNM classification) provides limited prognostic information, and does not predict response to therapy. The Immunoscore, as an addition to TNM staging, may provide an essential prognostic and potentially predictive tool that can facilitate clinical decision-making, including rational stratification of patient treatment. An international task force, involving investigators in more than 20 countries, is now under way to validate the Immunoscore, the results of which may lead to the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune). A recent paper, on which CRI CEO Jill O’Donnell-Tormey, Ph.D., is a co-author, discusses these efforts in more detail. (Access the Paper)

Other studies by CRI scientists that are shedding light on the understanding and treatment of colorectal cancer include:

  • Research by Dirk Jäger, M.D., a member of the CRI/Ludwig Cancer Vaccine Collaborative (CVC) at the University of Heidelberg in Germany, is also working to elucidate how immune parameters correlate with prognosis in colorectal cancer. In 2011, he published a study demonstrating that T cell infiltrates at the invasive margin of liver metastases from colorectal cancer predicted response versus no response to chemotherapy, and represented the strongest independent prognostic factor in metastatic colorectal cancer. With his colleagues, he has established a platform that allows him to assess and monitor the complex interplay of different immune cell subsets with tumor cells and other cells in the tumor microenvironment. These studies will not only provide important prognostic clues for patients with colorectal cancer, but also open up new avenues for immune invention based on a better understanding of the immunological milieu in and around colorectal tumors and colorectal cancer metastases. Jäger and colleagues are now testing how to make the tumor better accessible to the immune system by modulating the local inflammatory tumor environment.
  • Chronic inflammation is a key contributor to the development of colon cancer, and several clinical and epidemiological studies have shown that patients diagnosed with inflammatory bowel diseases (IBD), such as Crohn’s disease or ulcerative colitis, have an increased incidence of colorectal cancer. Several CRI-funded investigators are exploring inflammatory pathways and how they contribute to colon cancer development. In one study, former CRI postdoctoral fellow Eran Elinav, M.D., Ph.D., at Yale University, 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. They further showed that caspase-1 plays a role in colorectal cancer development by regulating colonic cell proliferation in early stages of injury-induced tumor formation and cell death in advanced tumors, shedding new light on inflammation-initiated tumor formation, as well as offering new strategies to prevent or inhibit colon cancer development.
  • Timothy Eitas, Ph.D., a CRI postdoctoral fellow at the University of North Carolina, Chapel Hill, is also exploring the role of inflammation in colorectal cancer. In his CRI-funded project, Dr. Eitas is studying a protein called NLRX1 and its role in mediating the production of inflammatory molecules called cytokines in ulcerative colitis and colitis-associated cancer. To date, Dr. Eitas’s research has shown that NLRX1 functions to protect against worse clinical outcomes in a model of colitis-associated cancer. In models lacking NLRX1, innate immune cells called macrophages produce higher levels of IL-6, a signaling molecule that has a central role in colorectal cancer development. He has also elucidated several downstream effects of IL-6 production in the progression of colitis-associated colon cancer, each of which may offer novel immunological and molecular targets for colorectal cancer treatment.
  • CRI Investigator Wendy Garrett, M.D., Ph.D., of the Harvard School of Public Health, Boston, MA, is studying the contributions that gut bacteria make to the development of colon cancer. She and her colleagues have made substantial progress on this front, showing for example that a bacterium called Fusobacterium nucleatum is associated with human colorectal cancer and can cause cancer in mice. They have also identified bacterial proteins that allow cancer-promoting bacteria to attach and live in tumors. Because these bacteria are found in human colon cancer and can spur colonic tumor formation in mice, they represent potential targets for colon cancer treatment and prevention.
  • Cancer-testis (CT) antigens have been a large focus of therapeutic vaccine approaches, but colorectal cancer and other gastrointestinal cancers very infrequently express CT antigens. CRI researchers are employing several strategies to overcome this limitation, including new approaches to try to increase expression of CT antigens in colorectal cancer. In one approach, CRI postdoctoral fellow Jeffrey Chou, M.D., Ph.D., at Fred Hutchinson Cancer Research Center, is using the chemotherapy decitabine to enhance the expression of the NY-ESO-1 antigen in colorectal cancer cells.
  • Strategies to target immune checkpoints to enhance anti-cancer immunity, similar to anti-CTLA-4 therapy for melanoma, are showing promise in the treatment of colorectal cancer. In a phase I trial of a monoclonal antibody targeting the PD-1 molecule, researchers at the Johns Hopkins University School of Medicine, including CRI SAC member Drew M. Pardoll, M.D., Ph.D., achieved a complete durable response in a patient with metastatic colorectal cancer, a result that is particularly encouraging given that CRC is not typically considered a promising candidate for immune-based therapies [1].

Sources: National Cancer Institute Physician Data Query (PDQ), American Cancer Society Facts & Figures 2013, National Comprehensive Cancer Network (NCCN) Guidelines for Patients, ClinicalTrials.gov.

Updated March 2014
 


[1] Brahmer et al. (2010) Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: Safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Onc; 28 (19): 3167-3175.

 

 

Colorectal Cancer News & Stories

Reviewed By:

Dirk Jäger, M.D.
National Center for Tumor Diseases, University of Heidelberg, Germany

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