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 this kind of 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 2015, it is projected that there will be 93,090 new cases of colon cancer and 39,610 new cases of rectal cancer in the U.S. Approximately 23,600 deaths are expected in the U.S. and 700,000 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. But due to underuse of screening tests, only 40% 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 71%. If the cancer has distant organs, the 5-year survival rate drops to 13%.

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 (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 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 colorectal 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 colorectal cancer

Current immunotherapies for colorectal cancer fall into seven broad categories: monoclonal antibodies, checkpoint inhibitors and immune modulators, cancer vaccines, adoptive cell therapy, oncolytic virus therapy, cytokines, and adjuvant immunotherapies. 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.

Monoclonal Antibodies

Monoclonal antibodies are molecules, generated in the lab, that target specific antigens on tumors. Several monoclonal antibodies are currently being tested in clinical trials:

  • A phase II trial of RO5520985, a bispecific anti-ANG-2/anti-VEGF-A antibody, in patients with untreated metastatic colorectal cancer (NCT02141295).
  • A phase II trial of Sym004, an antibody targeting the cancer antigen EGFR (epidermal growth factor receptor), in patients with metastatic colorectal cancer (NCT02083653).
  • A phase I/II trial testing IMMU-132, an antibody-drug conjugate targeting Τrop-2, in patients with epithelial cancers (NCT01631552).
  • A phase I/II trial of IMMU-130, an antibody-drug conjugate targeting CEACAM5, which is expressed on the surface of a majority of solid tumors, in patients with metastatic colorectal cancer (NCT01605318).
  • A phase I/II trial of ensituximab (NPC-1C), an antibody against a MUC5AC-related antigen, in patients with recurrent, locally advanced colorectal cancer after standard therapy (NCT01040000).
  • A phase I trial of bavituximab, an antibody that targets an immune-suppressing molecule in tumors, in patients with rectal cancer (NCT01634685).
  • A phase I trial of MORAb-066, targeting tissue factor (TF), an antigen overexpressed in tumor cells and tumor endothelial cells, in patients with TF-expressing cancers, including colorectal cancer (NCT01761240).
  • A phase I trial of the anti-MIF antibody, which targets macrophage migration inhibitory factor, in patients with colorectal cancer (NCT01765790).
  • A phase I study of MGD007, a dual-affinity re-targeting (DART) protein designed to target the glycoprotein A33 antigen, which is found on 95% of colorectal cancers, in patients with metastatic colorectal cancer (NCT02248805).

Checkpoint Inhibitors and Immune Modulators

A promising avenue of clinical research in colorectal cancer is the use of immune checkpoint inhibitors. These treatments work by targeting molecules that serve as checks and balances on immune responses. By blocking these inhibitory molecules or, alternatively, activating stimulatory molecules, these treatments are designed to unleash or enhance pre-existing anti-cancer immune responses. The following trials are currently recruiting patients:

  • A phase II study of pembrolizumab (Keytruda®, MK-3475), a PD-1 antibody made by Merck, for patients with microsatellite unstable (MSI) tumors, including colorectal cancer (NCT01876511).
  • A phase I/II trial of MEDI4736, an anti-PD-L1 checkpoint inhibitor made by MedImmune/AstraZeneca, in patients with solid tumors (NCT01693562).
  • A phase I/II trial of MEDI6469, an anti-OX40 agonist antibody, alone or with tremelimumab, an anti-CTLA-4 antibody, and/or MEDI4736 (NCT02205333).
  • A phase I/II trial of nivolumab (Opdivo®), an anti-PD-1 antibody, +/- ipilimumab (Yervoy®), an anti-CTLA-4 antibody, in patients with recurrent and metastatic colon cancer (NCT02060188).
  • A phase I/II trial of ipilimumab in patients with advanced solid tumors which have spread to the liver, lung, or adrenal gland (NCT02239900).
  • A phase I/II trial of urelumab (BMS-663513), an anti-4-1BB/CD137 antibody made by Bristol-Myers Squibb, tested in combination with nivolumab (anti-PD-1) in patients with solid tumors (NCT02253992).
  • A phase Ib trial to test pembrolizumab (Keytruda®, MK-3475), an anti-PD-1 antibody, in patients with advanced, biomarker-positive solid tumors (NCT02054806).
  • A phase I trial of tremelimumab (anti-CTLA-4) and MEDI4736 (anti-PD-L1) in patients with advanced solid tumors, including colorectal cancer (NCT01975831). This trial is sponsored by Ludwig Cancer Research in partnership with the Cancer Research Institute. Another phase I trial of tremelimumab and MEDI4736 is for patients with solid tumors (NCT02261220).
  • A phase I trial of MEDI6383, an anti-OX40 antibody, for patients with advanced solid tumors (NCT02221960).
  • A phase I trial of MEDI0680 (AMP-514), an anti-PD-1 antibody, and MEDI4736 in patients with advanced cancers (NCT02118337).
  • A phase I trial of MEDI0680 (AMP-514) in patients with advanced cancer (NCT02013804),
  • Two phase I trials to test MPDL3280A, an anti-PD-L1 antibody being developed by Roche/Genentech, in patients with several cancers (NCT01375842, NCT01633970).
  • A phase I study of MSB0010718C, an anti-PD-L1 antibody being developed by EMD Serono, in solid tumors (NCT01772004).
  • A phase I trial with urelumab, an anti-4-1BB/CD137 antibody developed by Bristol-Myers Squibb, in patients with colorectal cancer (NCT02110082).
  • A phase I trial testing urelumab, an anti-4-1BB/CD137 antibody, in patients with advanced cancers (NCT01471210).
  • A phase I trial to test PF-05082566, an anti-4-1BB/CD137 antibody developed by Pfizer, in patients with solid tumors (NCT01307267).
  • A phase I trial of PF-05082566 and pembrolizumab (Keytruda, MK-3475) in patients with advanced cancer (NCT02179918).
  • A phase I trial to test varlilumab (CDX-1127), an anti-CD27 antibody made by Celldex, in patients with several cancers, including colorectal cancer (NCT01460134).
  • A phase I trial of varlilumab (CDX-1127) and nivolumab (Opdivo) in patients with advanced solid tumors, including colorectal cancer (NCT02335918).
  • A phase I trial of MOXR0916, an anti-OX40 antibody being developed by Roche/Genentech, in patients with advanced cancer (NCT02219724).
  • A phase I trial to test BMS-986016, a LAG-3 antibody, with or without nivolumab (anti-PD-1), in patients with solid tumors (NCT01968109).
  • A phase I study of lirilumab, an anti-KIR antibody being developed by Bristol-Myers Squibb, in combination with nivolumab (anti-PD-1) in patients with advanced solid tumors (NCT01714739).
  • A phase I trial of TRX518, an anti-GITR antibody, in patients with advanced cancer (NCT01239134). This trial is sponsored jointly by the CRI/Ludwig Clinical Trials Network.
  • A phase I trial of MK-4166, an anti-GITR antibody, in patients with advanced cancer (NCT02132754).

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 trial of a vaccine that targets the NY-ESO-1 protein in patients with advanced cancer whose cancers express NY-ESO-1 (NCT01697527).
  • A phase I/II trial of DCVax, being developed by Northwest Biotherapeutics, in patients with solid tumors (NCT01882946).
  • A phase I trial of FANG in patients with advanced cancer (NCT01061840).
  • A phase I trial to test AVX701, which targets the CEA antigen that has been found to be associated with colorectal cancers, in patients with stage 3 colorectal cancer (NCT01890213).
  • A phase I study to test a vaccine targeting brachyury, which helps drive cancer metastasis, in patients with advanced cancer, including colorectal cancer (NCT02179515).
  • A phase I study of vaccine therapy with or without sirolimus in treating patients with NY-ESO-1 expressing solid tumors (NCT01522820).
  • A phase I trial of a vaccine that targets the HER2 antigen in patients with metastatic cancer, including colorectal cancer (NCT01376505).
  • A phase I study of a HER2 vaccine in patients with HER2-expressing tumors (NCT01730118).

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 II trial using tumor-infiltrating lymphocytes (TILs) in metastatic digestive tract cancers (NCT01174121).
  • A phase I/II trial of T cells engineered to target VEGFR in patients with metastatic cancer (NCT01218867).
  • A phase I/II trial of T cells engineered to target MAGE-A3 in patients with metastatic cancer that expresses MAGE-A3, including colorectal cancer (NCT02111850).
  • A phase I trial of T cells targeting EGFR in patients with advanced cancer, including colorectal cancer (NCT01081808).
  • A phase I trial to test natural killer (NK) cells, important innate immune cells, in patients with advanced cancer, including colorectal cancer (NCT00720785).

Oncolytic Virus Therapies

Oncolytic virus therapy uses a modified virus that can cause tumor cells to self-destruct and generate a greater immune response against the cancer.

  • A phase II trial to test Reolysin, a virus that is able to replicate specifically in cancer cells bearing an activated RAS pathway, in patients with metastatic colorectal cancer (NCT01622543).

Adjuvant Immunotherapies

Adjuvants are substances that are either used alone or combined with other immunotherapies to boost the immune response. Some adjuvant immunotherapies use ligands—molecules that bind to proteins such as receptors—to help control the immune response. These ligands can be either stimulating (agonists) or blocking (antagonists).

  • A phase I/II trial of tumor necrosis factor and rintatolimod, which binds to Toll-like receptor 3 (TLR3), in patients with recurrent resectable colorectal cancer (NCT01545141).

Cytokines

Cytokines are messenger molecules that help control the growth and activity of immune system cells.

  • A phase I trial of AM0010, a recombinant human interleukin 10 (IL-10), in patients with advanced solid tumors (NCT02009449).
  • A phase I trial testing interleukin 15 (IL-15) in patients with advanced cancer (NCT01572493).
  • A phase I trial to test interleukin 12 (IL-12) in patients with solid tumors (NCT01417546).
     

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 better outcomes in colon cancer. This study 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 CVC Trials Network at the University of Heidelberg in Germany, is also working to elucidate how immune parameters correlate with prognosis in colorectal cancer. He has published several studies demonstrating that T cell infiltrates at the invasive margin of liver metastases from colorectal cancer predict response versus no response to chemotherapy, and represent the strongest independent prognostic factor in metastatic colorectal cancer. 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.,, 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 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.
  • April Price, Ph.D., a CRI postdoctoral fellow at the University of California, Berkeley, is working to understand how Toll-like receptors (TLR), a type of receptor that recognizes molecules that are broadly shared by pathogens, contribute to colorectal cancer. She has developed a model that will allow her to track the expression of TLRs within cells and determine whether TLR expression is modulated during inflammation, injury, and colorectal cancer. If TLRs are linked to the development of disease, then it may be possible to dampen inflammation promoted by TLRs, which would lessen the risk of developing inflammatory bowel disease and colorectal cancer.

Sources: National Cancer Institute Physician Data Query (PDQ), American Cancer Society Facts & Figures 2015, National Comprehensive Cancer Network (NCCN) Guidelines for Patients, ClinicalTrials.gov, GLOBOCAN 2012, CRI grantee progress reports and other grantee documents

Updated February 2015


[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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