With outstanding clinical results, a new cancer treatment attracting attention is cancer immunotherapy using bispecific antibodies. But is this treatment really the way forward?
Tumour recurrence and the development of drug resistance are just two factors which contribute to the difficulties of curing cancer. Regardless of the advancements achieved in treating cancer, the development of new treatments is critical for those patients who experience recurrence or drug resistance. One potentially powerful tool that has emerged is cancer immunotherapy using bispecific antibodies, a product of genetic engineering.
Our immune system can fight and destroy cancer cells, however, many cancer cells are able to hide from or disable the immune system to avoid being destroyed. Immunotherapy is a treatment employed which makes use of specific parts of a patient’s immune system to fight disease like cancer by either stimulating the immune system to work harder or smarter to attack cancer cells or by administering man-made immune system proteins to inhibit specific proteins expressed by cancer cells. A recent review published in the Journal of Hematology and Oncology by researchers in China evaluated the outcomes of clinical studies using bispecific antibodies to treat solid tumours and discussed the challenges associated with this clinical application.
Types of Cancer Immunotherapy
There are several different types of immunotherapy being used today to treat cancer including monoclonal antibodies, which are designed by scientists to attack a specific part of a cancer cell and cancer vaccines which can elicit an immune response to prevent or treat some cancers. Another type of immunotherapy is immune checkpoint inhibitors; drugs that essentially prevent cancer cells from “turning off” the immune system and in turn helps the immune system to recognise and attack cancer cells. Finally, non-specific immunotherapies are also used to boost the immune system in a general way to help attack cancer cells.
More recently, however, first proposed in the mid-1980s as a potential cancer treatment, a novel immunotherapy strategy being rigorously investigated today is bispecific antibodies. Antibodies are Y-shaped proteins recruited by the immune system to identify and neutralise harmful or foreign objects such as bacteria, viruses, or parasites. These foreign particles or bodies are known as antigens. Bispecific antibodies are unique as they can simultaneously bind to therapeutics such as effector cells (activated cells including T cells, macrophages, and monocytes, that defend the body in an immune response) and targets like tumour cells to enhance tumour killing. They are also able to simultaneously block two different oncogenic mediators, powerful molecules which regulate cell proliferation, differentiation, and apoptosis (programmed cell death) that have been shown to play a pivotal role in the formation of many cancers.
Using Bispecific Antibodies to Treat Cancer
An exciting breakthrough in cancer treatment has been treating malignancies which affect the blood and lymph systems with bispecific antibodies. More recent clinical trials have also shown promising outcomes using bispecific antibodies to treat patients with solid tumours.
Commonly investigated bispecific antibodies with more advanced formats developed are called triomabs and bispecific T cell engagers. These compounds can bind simultaneously to T cells, as the name suggests, and a surface antigen on tumour cells. In 2014, blinatumomab, a bispecific T cell engager, was approved by the FDA as a treatment for relapsed or resistant acute lymphoblastic leukemia (ALL). However, its clinical application has been hindered due to the short serum half-life of this antibody.
The interaction mediated by these bispecific antibodies linking T cells and tumour cells initiates the killing process, as different immune effector cells are recruited and activated to the tumour site to eliminate tumour cells by various immunological killing mechanisms. Numerous clinical studies are in progress to further investigate the use of bispecific antibodies for solid tumours as opposed to blood and lymphatic malignancies.
The first step for successful cancer immunotherapy is identifying specific targets for the antibody on cancer cells. Bispecific antibodies which target antigens commonly expressed on specific solid tumours that have been extensively investigated and show potential for cancer immunotherapy include epithelial cell adhesion molecule (EpCAM), human epidermal growth factor receptor (HER) family, carcinoembryonic antigen (CEA), and prostate-specific membrane antigen (PSMA). These antigens are expressed on certain carcinomas including ovarian cancer and lung cancer. For example, 86.5 % of non-small cell lung cancer patients show high expression of EpCAM. Furthermore, an attractive treatment for glioblastoma is bispecific antibodies which target the over-expressed antigens EGFR and HER2. Cancers which overexpress CEA include lung, breast, and pancreatic cancer, and as the name suggests, PSMA is expressed in all stages of prostate cancer.
The review found that despite preclinical studies using bispecific antibodies to treat solid tumours showing potent antitumour efficacy, the outcome of most of the clinical trials showed it as a surprisingly less effective potential cancer treatment due to a number of challenges associated with this approach.
Challenges of Treating Solid Tumours with Bispecific Antibodies
Ideally, the bispecific antibody target would be a tumour specific antigen homogenously expressed on the surface of the tumour cell and play a pivotal role in the production of tumours. However, given there are numerous antigens expressed in various tumour cells, efforts to seek out particular antigens and improve specificity remain challenging.
Another issue with treating solid tumours with bispecific antibodies is permeability. Despite some bispecific antibodies having smaller molecular masses, such as bispecific T cell engagers, which enable greater permeability, the consequence is a short serum half-life of the antibody. In order to overcome this limitation, a number of approaches developed by researchers include chemically coupling of the bispecific antibody to polyethylene glycol to help stabilise it and increase its half-life.
There are still several other challenges like reducing the toxicity to normal tissues which need to be overcome before bispecific antibodies can be used successfully to treat solid tumours. Continued research by scientists to find possible solutions to these challenges and find better approaches to employing bispecific antibodies as a cancer treatment for solid tumours is essential, particularly as the preclinical trials have shown such promising results.
Written by Lacey Hizartzidis, PhD
Yu S, Li A, Liu Q, Yuan X, Xu H, Jiao D, Pestell RG, Han X, Wu K. Recent advances of bispecific antibodies in solid tumors. J Hematol Oncol. 2017 Sep 20;10(1):155. doi: 10.1186/s13045-017-0522-z. Review.
Immunotherapy, Cancer Information. Canadian Cancer Society website http://www.cancer.ca/en/cancer-information/diagnosis-and-treatment/chemotherapy-and-other-drug-therapies/immunotherapy/?region=on. Accessed September 29th, 2017.