New cell therapy research from the MHRA is evaluating immunostimulating cancer therapies to reduce side effects for patients

The report “Antibody Conjugates for Targeted Delivery of Toll-like Receptor 9 Agonist to Tumor Tissue”published in the journal PLOS ONE, highlights MHRA research that has shown that genetic engineering of antibodies used to activate and support the immune system against cancer leads to improvements in their reliability and effectiveness.

Antibodies provide the human body with a natural defense mechanism, activating the immune system to fight disease and infection. Monoclonal antibodies (MAb) are developed in the laboratory to produce multiple copies of these natural antibodies and reproduce their properties.

MAbs are an example of immunotherapy and can in some cases support the immune response against cancer. Because tumors grow from normal cells in the body, immune cells may not always recognize them as harmful. Mabs are being developed that can specifically recognize cancer cells and when found, they send a signal to initiate a targeted immune response against them.

Researchers and healthcare professionals have also successfully harnessed the immune system to target tumor cells in other ways using toll-like receptor (TLR) agonists.

TLR agonists activate proteins in immune cells that detect signs of infection, triggering a systemic and widespread immune response.

These have been used effectively in the treatment of skin and bladder cancer, but only when the treatment is applied directly to the tumor so that an immune response is triggered at the tumor site.

However, not all cancers can be treated directly and if these treatments are given by a method such as infusion, the immune response occurs throughout the body leading to side effects for patients. By combining these TLR agonists with cancer-specific mAbs, they can more directly target tumor sites, contain the immune response and reduce side effects.

However, the ability of this combination to effectively target tumor sites may be inconsistent, reducing treatment efficacy. The MHRA researchers aimed to investigate whether specifying the site on the surface of the MAb where it binds to the TLR agonist could improve the reliability of this combination for targeting cancer cells.

They combined a TLR9 agonist with the MAb “trastuzumab”, which is currently used to treat certain types of breast, esophageal and stomach cancer.

The researchers then compared the immune response resulting from random and site-specific binding of the TLR9 agonist with trastuzumab.

The random method resulted in the TLR9 agonist occasionally binding to trastuzumab near its antigen-binding sites, which are used to bind to cancer cell proteins and signal an immune response. This prevented the MAb from binding to cancer cell proteins, reducing the risk of triggering an effective immune response.

In contrast, genetically modifying the MAb so that the TLR9 agonist bound farther from the antigen-binding sites leaves the antibody’s ability to bind to cancer cell-specific proteins intact.

The results showed that an effective immune response was more consistent in site-specific testing than in random testing.

This indicates that engineering the site to which MAbs and TLR agonists bind increases the effectiveness of this type of treatment, making it more reliable and more likely to cause fewer side effects for patients.

Dr. Sandra S. Diebold, Senior Immunotherapy and Biotherapy Scientist at MHRA, said:

Cancer patients often undergo painful treatments that can have a serious impact on their quality of life. Finding ways to more reliably activate the immune system to detect and target cancer cells is a critical step in ensuring patients receive more effective treatments with fewer side effects.

Although more research is needed to demonstrate the benefits of a site-specific approach, this study shows promise in achieving this goal for patients.

By adding to the body of evidence regarding methods of combining mAbs with TLR agonists, we hope to further support the development of safer and more effective cancer treatments.

Will Quince, Minister of Health and Secondary Care said:

More targeted treatments could mean better outcomes for patients, which is why we invest in cutting-edge cancer research for patients and work with scientists to develop effective treatment with fewer side effects.

We have also partnered with some of the best and brightest minds who have created Covid vaccines to try to develop new cancer vaccines and are investing record sums in exciting trials to better treat cancer.

Dr Henry Stennett, head of research information at Cancer Research UK, said:

This study shows the power of precisely re-engineering the immune system to unleash its ability to fight cancer.

Although more work is needed to translate these findings into the clinic, we are excited to see scientists developing more effective and gentler treatment options for people with cancer.

New, innovative therapies based on research findings are essential to overcoming this disease.

Read it full report

Notes to Editors

1. The Medicines and Healthcare products Regulatory Agency (MHRA) is responsible for regulating all medicines and medical devices in the UK ensuring that they work and are of acceptable safety. All of our work is backed by sound, evidence-based judgments to ensure that the benefits justify all the risks.
2. The MHRA is an executive agency of the Department of Health and Social Care.