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 viruses that are often, but not always, modified in order to 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