Abstract
The ability of cancer cells to evade the immune system is one of the most deadly characteristics of the majority of malignant tumours. Accordingly, the recent development of antibodies which target tumor cell evasion of immune checkpoints such as the cytotoxic T lymphocyte associated antigen-4 (CTLA-4) as well as the programmed cell death protein (PD-1) and the PD-1 ligand (PD-L1) has been a major and apparently highly effective approach in the treatment and/or eradication of a variety of highly malignant forms of cancers. The US Food and Drug Administration (FDA) has recently approved the application of lpilimumab (which targets CTLA-4) and pembrolizumab (targeting PD-1) for the treatment of advanced gastric cancer. Indeed, various checkpoint blockade antibodies have been approved or have been under clinical investigation. An indication of the renewed interest and importance of cancer immunotherapy is that James Allison was awarded the Lasker-DeBakey Clinical Research Award in 2015 for his discovery that antibody blockade of CTLA-4 enhances the immune response to cancer. Further, this discovery has stimulated the development of multiple immune checkpoint approaches to the treatment of cancer. In addition, a number of monoclonal antibodies (MAB) have been created to specifically target antigens on cancer cells and/or to selectively deliver radiotherapy to them. These immunotherapeutic approaches and advances will be reviewed in this article.
Cancer metastasis is responsible for most of the morbidity and mortality associated with cancer. Cancer metastatic progression is a multiple step process which includes enhanced cell proliferation, release of proteolytic enzymes, cell motility and invasion, angiogenesis and establishment of a supportive microenvironment at the sites of metastatic growth (1, 2).
Traditional cancer therapy has focused on removal or destruction of tumour cells by surgery, radiation and rather non-selective types of chemotherapy. Surgery and radiation are often effective with tumours which are localized and have not metastasized to multiple sites throughout the body. Chemotherapy appears to be most effective in the treatment of metastatic cancer; however, typical chemotherapeutic agents such as cisplatin, methotrexate, vincristine, 5-fluorouracil among many others, focus on rapidly growing tissues since cancer cells are relatively rapidly growing. Thus, cancer chemotherapy often results in a high incidence of unwanted and damaging side-effects in rapidly-dividing normal tissues, such as blood cells and cells lining gastrointestinal tract.
With a greater understanding of cellular chemistry and genomics during the past twenty years, cellular targets that are unique to cancer cells have been identified and chemotherapeutic agents which specifically bind to, destroy or otherwise inactivate these unique cellular targets have been developed. These agents which impede these unique or overexpressed cancer targets tend to be more selective, -thus more effective with fewer side-effects than traditional, non-selective chemotherapy. They target critical checkpoints which are often overexpressed on rapidly growing and malignant cancer cells, such as vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and tyrosine kinase. Therefore, cancer Immunotherapy is an exciting and relatively new method to selectively block critical checkpoints in the process of cancer development (3, 4).
Anticancer Immune Checkpoint Targeting
It is commonly known that cancer cells are resistant to the body's immune system; however, in the late 1800's William Coley and other clinical investigators observed that some solid tumors regressed or were totally eliminated in patients that suffered streptococcal skin infections or were injected with bacterial extracts (3, 5). Unfortunately Coley's work did not have adequate controls and other investigators of that period were unable to duplicate his observations. Thus, this concept was not actively studies or pursued for approximately the next fifty years. However, the encouraging results of Sherman and Allison have stimulated new enthusiasm for targeting critical checkpoints of the immune regulatory system in order to enhance immune responsiveness in tumours cells (4). Since Sharma and Allison (4) demonstrated that CTLA-4, which turns off the response to T-cells, could be targeted, and thereby enhance the killing of tumour cells, these observations led the way to the study and identification of several other pathways or checkpoints which were typically deactivated or activated in malignant tumors (6, 7). The main check point inhibitors used for the treatment of cancer included lipilimumab (which targets CTLA-4) and pembrolizumab (targeting PD-1) (8, 9). Indeed, antibodies from unique checkpoint targets were employed in immunohistochemical staining for determining cancer cells (10). In addition, novel checkpoint inhibitors and co-stimulators are currently under study such as LAG-3 (11), TIM-3 (12), VISTA (13), ICOS (14), OX40 (15) and 4-1BB (16). Further many of the checkpoint inhibitors are being developed and some of these are currently under clinical study (4). The FDA recently approved the first therapeutic vaccine for advanced prostate cancer (17).
Antitumor Monoclonal Antibodies (MABs)
Several of specially engineered humanized or chimeric MABs have been approved recently by the FDA. These MABs are used to target and kill cancer cells. The novel MABs include the following: (i) Alemtuzumab which is a humanized IgG1 which targets CD52 and is often overexpressed on malignant lymphocytes, granulocytes, macrophages and natural killer cells. This agent has been approved for therapy in patients with lymphocytic leukemia who have not responded to alkylating agents (18, 19); (ii) Bevacizumab which is also a humanized IgG1 MAB that binds to VEGF and blocks its binding to the VEFG receptor on cancer cells. This action inhibits the formation and growth of tumor blood vessels; thus, restricts the growth and metastatic development of tumor cells. It has been approved for the treatment of metastatic colon cancer and metastatic kidney cancer as well as non-small cell lung cancer and glioblastoma. Due to the antiangiogenic mechanism of this agent it may reduce wound healing and should not be used soon after surgery (20-22); (iii) Panitumumab which is a human IgG2 kappa MAB is used to eradicate metastatic colon cancer expressing epidermal growth factor receptor (EGFR) which has been unresponsive to traditional chemotherapy (23-25); (iv) Cetuximab a human/mouse chimeric MAB, which also binds to and inactivates the EGFR, is used in the treatment of EGFR-positive colon cancer and also for head and neck cancers (24-26); (v) Ofatumumab is a human IgG1 MAB used in patients with chronic lymphocytic leukemia who are unresponsive to chemotherapy (27-30); (vi) Trastuzumab is a humanized MAB that acts at extracellular HER-2/neu which impedes ERGR activity. This agent is used in patients with HER-2/neu-positive breast cancer and metastatic gastrointestinal (GI) cancers and in patients with other forms of cancer that express HER-2/neu (31-34); (vii) Rituximab is a human/murine MAB that has been approved for the treatment of non-Hodgkin's lymphoma and also lymphocytic leukemia. It may also be effective for the treatment of other tumours and autoimmune diseases such as lupus erythematosus (27, 35-38) .
In addition to the use of MABs in the direct treatment of various cancers, MABs are also used to deliver radioisotopes selectively to cancer cells. Examples of the delivery MABs include: (i) Arcitumomab which is a murine antibody fragment that is labeled with technetium 99m. This agent is administered to patients with metastatic colorectal cancer to view the extent of metastatic development (39-42); (ii) Ibritumomab tiuxetan is a murine MAB which is labeled with yttrium 90 or Indium 111. These radioactive agents are used for the treatment of patients with non-Hodgkin's lymphoma and often used together with Rituximab which was discussed above (43-45); (iii) Capromab pendetide, a murine MAB, targets prostate membranes and is used to diagnose prostate cancer or determine the extent of cancer eradication following prostatectomy (46-48); (iv) Tositumomab is a MAB labeled with iodine 131 and is used to treat patients with non-Hodgkin's lymphoma who are unresponsive to standard chemotherapy (49-52) .
The Future of MAB Immunotherapy
One of the major problems with the use of MAB treatment is that cancer cells are constantly mutating which often leads to resistance or complete lack of responsiveness to targeted therapy. However, as tumour cells mutate, they develop new antigens and checkpoint targets and the current system of rapid cancer genome sequencing can be employed to identify these novel targets for MAB immunotherapy. Accordingly, this process may lead to the expansion and development of new and more effective MABs' inhibitors (4, 53-55).
The relatively recent appreciation of the effectiveness of MAB immunotherapy has led to a major consideration of new therapeutic combinations that employ standard chemotherapy together with immunotherapy to provide a combination approach which may enhance therapeutic responsiveness while reducing adverse side effects (4, 56-59).
Footnotes
This article is freely accessible online.
- Received March 7, 2017.
- Revision received April 11, 2017.
- Accepted April 12, 2017.
- Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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