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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 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.

Featured Scientist
Priya Darshinee Issuree, Ph.D.
New York University Medical Center
Postdoctoral Fellow  |  2015
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Colorectal Cancer Statistics
3rd
Most common cancer in the United States
7
Types of immunotherapy clinical trials
Over 95%
Of colorectal cancers are adenocarcinomas

Clinical Trials for Colorectal Cancer

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

Therapies
  • Checkpoint Inhibitors and Immune Modulators
  • Monoclonal Antibodies
  • Cancer Vaccines
  • Adoptive Cell Therapy
  • Oncolytic Virus Therapy
  • Adjuvant Immunotherapies
  • Cytokines

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:

Pembrolizumab (Keytruda®): An Anti-PD-1 Antibody
  • A phase II study for patients with microsatellite unstable (MSI) tumors, including colorectal cancer (NCT01876511).
  • A stage II trial combining pembrolizumab and radiotherapy for patient with colorectal cancer (NCT02437071)
  • Two phase I/II studies for patients with advanced cancer and advanced genitourinary cancer, including colorectal cancer (NCT02318901NCT02268825).
  • A phase I trial for patients with metastatic or advanced epithelial cancers, including colorectal cancer, in combination with enadenotucirev, an oncolytic virus (NCT02636036).
  • A phase I study for patients with microsatellite unstable (MSI) colorectal cancer, in combination with a JAK inhibitor, INCB039110, or a PI3K-delta inhibitor, INCB050465 (NCT02646748).
  • A phase I trial for patients with microsatellite stable colorectal cancer (NCT02512172).
  • A phase I study for patients with solid tumors, including colorectal cancer (NCT02298959).
Nivolumab (Opdivo®): An Anti-PD-1 Antibody
  • A phase I/II trial for patients with recurrent and metastatic colon cancer, +/- ipilimumab (Yervoy®), an anti-CTLA-4 antibody (NCT02060188).
  • A phase I/II trial for patients with solid tumors, including colorectal cancer, in combination with varlilumab (CDX-1127), an anti-CD27 antibody (NCT02335918).
  • A phase I/II trial for patients with advanced cancer, including colorectal cancer, with epacadostat (INCB024360), an IDO inhibitor (NCT02327078). IDO is expressed by a number of tumor types and correlates with poor prognosis.
  • A phase I trial for patients with advanced cancer, including colorectal cancer, in combination with FPA008, an antibody that inhibits colony stimulating factor-1 receptor (CSF1R), which targets immune cells (NCT02526017).
  • A phase I/II trial for patients with advanced cancer, including colorectal cancer (NCT02423954).
Ipilimumab (Yervoy®): An Anti-CTLA-4 Antibody
  • A phase I/II trial for patients with recurrent and metastatic colon cancer, in combination with nivolumab (Opdivo®) (NCT02060188).
  • A phase I/II trial for patients with advanced solid tumors which have spread to the liver, lung, or adrenal gland (NCT02239900).
  • A phase I study of ipilimumab for patients with NY-ESO-1-positive tumors, in combination with T cells genetically engineered to target NY-ESO-1 (NCT02070406).
Durvalumab (MEDI4736): An Anti-PD-L1 Antibody
  • A phase II trial for patients with colorectal cancer (NCT02227667).
  • A phase II trial for patients with brain metastasis from epithelial-derived cancers, including colorectal cancer (NCT02669914).
  • A phase I trial for patients with advanced solid tumors, including colorectal cancer, in combination with tremelimumab, an anti-CTLA-4 antibody (NCT01975831). This trial is sponsored by Ludwig Cancer Research in partnership with the Cancer Research Institute.
Tremelimumab: An Anti-CTLA-4 Antibody
  • A phase I trial for patients with advanced solid tumors, including colorectal cancer, in combination with durvalumab (MEDI4736) (NCT01975831). This trial is sponsored by Ludwig Cancer Research in partnership with the Cancer Research Institute.
Atezolizumab (MPDL3280A): An Anti-PD-L1 Antibody
  • A phase I trial testing CPI-444, an oral small molecule targeting a receptor on immune cells, alone and in combination with atezolizumab for patients with advanced cancers, including colorectal cancers (NCT02655822).
Varlilumab (CDX-1127): An Anti-CD27 Antibody
  • A phase I/II trial for patients with solid tumors, including colorectal cancer, in combination with nivolumab (Opdivo®) (NCT02335918).

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 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 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)
  • A phase I study of OMP-131R10, an anti-RSPO3 antibody, in patients with previously treated metastatic colorectal cancer (NCT02482441)

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, and NY-ESO-1. Several clinical studies of cancer vaccines for colorectal cancer are open, including: 

  • A phase II study of a dendritic cell vaccine for patients with chemo-refractory metastatic colorectal cancer (NCT02615574).
  • A phase II trial of a dendritic cell-based vaccine using the NY-ESO-1 cancer antigen, given in combination with T cells genetically engineered to target the cancer-specific antigen NY-ESO-1 (NCT01697527).
  • 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 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).
  • A phase I study of a NY-ESO-1 vaccine, T cells genetically engineered to target NY-ESO-1, and the checkpoint inhibitor ipilimumab (Yervoy®) (NCT02070406).
  • A pilot studu testing the GVAX vaccine in patients with colorectal cancer (NCT01966289).

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 II trial of T cells genetically engineered to target the cancer-specific antigen NY-ESO-1, given in combination with a dendritic cell-based vaccine using the NY-ESO-1 cancer antigen (NCT01697527).
  • A phase II study of T cells genetically reengineered to target the NY-ESO-1 antigen in patients with NY-ESO-1-positive cancers (NCT01967823).
  • 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/II trial of chimeric antigen receptor (CAR) T cells in patients with a MUC1-positive solid tumor, including colorectal cancer (NCT02617134).
  • A phase I study of T cells genetically engineered to target NY-ESO-1 in combination with the checkpoint inhibitor ipilimumab (Yervoy®) (NCT02070406).
  • 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 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 KRAS-mutant metastatic colorectal cancer (NCT01274624).
  • A phase I trial of enadenotucirev, an oncolytic virus, for patients with metastatic or advanced epithelial cancers, including colorectal cancer, in combination with pembrolizumab (Keytruda®) (NCT02636036).

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 epacadostat (INCB024360), an IDO inhibitor, in combination with nivolumab (Opdivo®), a PD-1 checkpoint inhibitor, in patients with advanced cancer, including colorectal cancer (NCT02327078). IDO is expressed by a number of tumor types and correlates with poor prognosis.
  • 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 are messenger molecules that help control the growth and activity of immune system cells.

  • A phase I trial to test interleukin 12 (IL-12) in patients with epithelial 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 2016, National Comprehensive Cancer Network (NCCN) Guidelines for Patients, ClinicalTrials.gov, GLOBOCAN 2012, CRI grantee progress reports and other grantee documents

Updated March 2016

*Immunotherapy results may vary from patient to patient.

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