Extension of the Life of Immune System Means Live Longer

A new mechanism that slows down and may even prevent the natural ageing of immune cells – one of the ninehallmarks of ageing’* – has been identified by an international team led by UCL scientists.

Published in Nature Cell Biology, researchers say the discovery in-vitro (cells) and validated in mice was ‘unexpected’ and believe harnessing the mechanism could extend the life of the immune system, allowing people to live healthier and longer, and would also have clinical utility for diseases such as cancer and dementia.

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Personalized cancer vaccines

Therapeutic cancer vaccines were first developed 100 years ago and have remained broadly ineffective to date. Before tangible results can be achieved, two major obstacles must be overcome. Firstly, since tumor mutations are unique to each patient, cancer cell antigens must be targeted extremely precisely, which is very hard to achieve. Secondly, a safe system is needed to deliver the vaccine to the right location and achieve a strong and specific immune response.

Li Tang’s team at EPFL’s School of Engineering in Switzerland is coming up with a solution to the delivery problem. The researchers have used a polymerization technique called polycondensation to develop a prototype vaccine that can travel automatically to the desired location and activate immune cells there. The patented technique has been successfully tested in mice and is the topic of a paper appearing in ACS Central Science. Li Tang has also co-founded a startup called PepGene, with partners that are working on an algorithm for quickly and accurately predicting mutated tumor antigens. Together, the two techniques should result in a new and better cancer vaccine in the next several years.

Helping the body to defend itself

Most vaccines – against measles and tetanus for example – are preventive. Healthy individuals are inoculated with weakened or inactivated parts of a virus, which prompt their immune systems to produce antibodies. This prepares the body to defend itself against future infection.

However, the aim of a therapeutic cancer vaccine is not to prevent the disease, but to help the body defend itself against a disease that is already present. “There are various sorts of immunotherapies other than vaccines, but some patients don’t respond well to them. The vaccine could be combined with those immunotherapies to obtain the best possible immune response,” explains Li Tang. Another advantage is that vaccines should reduce the risk of relapse.

Delivering a cancer vaccine to the immune system involves various stages. First, the patient is inoculated with the vaccine subcutaneously. The vaccine will thus travel to the lymph nodes, where there are lots of immune cells. Once there, the vaccine is expected to penetrate dendritic cells, which act as a kind of alert mechanism. If the vaccine stimulates them correctly, the dendritic cells present specific antigens to cancer-fighting T-cells, a process that activates and trains the T-cells to attack them.

The procedure appears simple, but is extremely hard to put into practice. Because they are very small, the components of a vaccine tend to disperse or be absorbed in the blood stream before reaching the lymph nodes.

To overcome that obstacle, Li Tang has developed a system that chemically binds the vaccine’s parts together to form a larger entity. The new vaccine, named Polycondensate Neoepitope (PNE), consists of neoantigens (mutated antigens specific to the tumor to be attacked) and an adjuvant. When combined within a solvent, the components naturally bind together, forming an entity that is too large to be absorbed by blood vessels and that travels naturally to the lymph nodes.

Source: https://actu.epfl.ch/news/

How To Turn Tumors Into Cancer Vaccine Factories

Researchers at Mount Sinai have developed last year a novel approach to cancer immunotherapy, injecting immune stimulants directly into a tumor to teach the immune system to destroy it and other tumor cells throughout the body.
The “in situ vaccination” worked so well in patients with advanced-stage lymphoma that it is also undergoing trials in breast and head and neck cancer patients, according to a study published in Nature Medicine in April.
The treatment consists of administering a series of immune stimulants directly into one tumor site. The first stimulant recruits important immune cells called dendritic cells that act like generals of the immune army. The second stimulant activates the dendritic cells, which then instruct T cells, the immune system’s soldiers, to kill cancer cells and spare non-cancer cells. This immune army learns to recognize features of the tumor cells so it can seek them out and destroy them throughout the body, essentially turning the tumor into a cancer vaccine factory.

The in situ vaccine approach has broad implications for multiple types of cancer,” said lead author Joshua Brody, MD, Director of the Lymphoma Immunotherapy Program at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai. “This method could also increase the success of other immunotherapies such as checkpoint blockade.”

After testing the lymphoma vaccine in the lab, it was tested in 11 patients in a clinical trial. Some patients had full remission from months to years. In lab tests in mice, the vaccine drastically increased the success of checkpoint blockade immunotherapy, the type of immunotherapy responsible for the complete remission of former President Jimmy Carter’s cancer and the focus of the 2018 Nobel Prize in Medicine.

Source: https://www.mountsinai.org/

Blood Vessels Can Contribute To Tumor Suppression

A study from the Institute of Pharmacology and Structural Biology in Toulouse (France) has introduced a novel concept in cancer biology : Blood vessels in human tumors are not all the same and some types of blood vessels found in the tumor microenvironment (i. e. HEVs) can contribute to tumor suppression rather than tumor growth(Cancer Res 2011).

 A better understanding of HEVs at the molecular level, which is one of the major objectives of the research team, may have an important impact for cancer therapy.

Dendritic cells, which are well known for their role as antigen-presenting cells, play an unexpected and important role in the maintenance of HEV blood vessels in lymph nodes (Nature 2011). In addition, the scientists discovered the frequent presence of HEVs in human solid tumors, and their association with cytotoxic lymphocyte infiltration and favourable clinical outcome in breast cancer. They also showed that IL-33 is a chromatin-associated cytokine (PNAS 2007, 453 citations) that function as an alarm signal (alarmin) released upon cellular damage (PNAS 2009, 312 citations). Inflammatory proteases can generate truncated forms of IL-33 that are 30-fold more potent than the full length protein for activation of group 2 innate lymphoid cells (PNAS 2012, 133 citations, PNAS 2014).

An important objective  is now to further characterize IL-33 regulation and mechanisms of action in vivo, through the use of multidisciplinary approaches.

Source: http://www.ipbs.fr/