Now Presenting: Dendritic cells – a driving force for new anti-tumor vaccines

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“I’m sorry, but your recent labs have come back, and they indicate that you have cancer.” Although those words are something that no one wants to hear from his or her doctor, that phrase is the sad reality for millions of people every year. However, scientists today are making many groundbreaking discoveries regarding potential cancer treatments and therapeutics, which are helping patients live longer and healthier lives.

One such discovery was detailed in a recent paper published by Dr. Joshua Brody’s group from the Icahn School of Medicine at Mt. Sinai, which demonstrated how his team has developed a vaccine against an evasive cancer known as indolent non-Hodgkin’s Lymphoma (iNHL). Currently in clinical trials, this vaccine has shown the potential to lead to remission in patients with late-stage forms of the disease, which was previously thought to be incurable. This vaccine works in part by stimulating specific cells of the body’s immune system to recognize and attack the cells that cause this form of cancer. The team’s findings provide substantial promise in the field of cancer therapeutics and may lead to new insights into the factors needed to develop effective anti-cancer vaccines.

How do vaccines work?

At their core, vaccines contain weakened or inactive pieces of disease-causing microbes or cancers. These pieces can act as antigens, which are particles that can stimulate our immune systems to identify and eliminate potential dangers to human health.  Antigens delivered in vaccines are first taken up by specific immune cells called “antigen presenting cells,” or APCs. A specific type of APC, known as dendritic cells (DCs), have been shown to play critical roles in helping our immune system fend off potentially deadly diseases, particularly in the context of vaccination. DCs take up antigens, process them internally, and then present or display them on their surface as a sort of warning sign to other immune cells, alerting them to potential danger (Figure 1). One such immune cell is the T-cell, which, upon recognition of antigens on the surface of DCs, become activated. Some of these activated T cells become cytotoxic T-cells which, true to their name, release chemicals that directly kill any cells expressing the target antigen. This process of antigen presentation by DCs thus allows T cells to specifically identify and attack the foreign invaders that express antigens on their surface, should they ever come in contact with each other.

Figure 1: Antigen presentation. When DCs encounter disease-causing cells, like tumor cells, they can phagocytose (or engulf) the diseased cell. Following phagocytosis, the DC will break-down the engulfed cell and present disease-associated proteins on its own surface to alert other immune cells to the problem. In the case of cancer cells, TAAs can be presented by DCs and used to alert T-cells to the presence of cancer. Cytotoxic T-cells can then develop, which release chemicals that directly kill TAA-expressing cancer cells.

After your immune system has been exposed to a disease once, it almost always has the ability to “remember” it in the future, should you ever be re-exposed. After re-exposure, your immune system will rapidly eliminate the potential threat before it poses serious harm to your body. Vaccines act as your body’s “first exposure” to inactivated versions of  these diseases, which allows your immune system to generate these memory responses if you are ever re-exposed.

Although we traditionally think of vaccines as tools to protect us from infectious diseases, such as polio and hepatitis, they also have the potential to be used to help our immune systems recognize and eliminate cancerous cells. In recent years, the use of vaccines has gained traction in the development of new anti-cancer therapeutics

In order to help the immune system fight cancer, anti-cancer vaccines leverage molecules called tumor-associated antigens (TAAs), or altered versions of proteins that are not produced by healthy cells. These cancer cell-specific TAAs can help the immune system recognize cancer cells as abnormal and dangerous. Further, these TAAs can be incorporated into vaccines that kick-start the immune system, activating it and galvanizing immune cells against the TAA-expressing tumor cells.

How does the Brody lab’s vaccine work to protect against cancer?

Dr. Joshua Brody’s lab has taken this concept of antigen presentation of TAAs by DCs and co-opted it to generate a powerful new vaccine against iNHL. Using a mouse model, the group demonstrated that a specific type of DC, known as Batf3-dendritic cells (Batf3-DC) are critical for presenting TAAs to T cells, so that T cells can then attack cancerous cells. Additionally, the group showed that they could directly inject their vaccine into tumor lesions to stimulate Batf3-DC at these sites. In addition to stimulating Batf3-DC at these lesions, Dr. Brody’s team also treated the mice with tumor-localized radiation, which killed some of the cancer cells and led them to expose some of their unique TAAs. Once the Batf3-DC reached these radiation-treated lesions, they could process and present the TAAs to T cells, thereby activating them. These vaccine-activated T cells were better able to enter tumor sites and kill off cancerous cells, resulting in tumor regression and improved survival in the mice. When the group used this vaccine with another treatment to improve the T cells’ abilities to survive and remain active, they noted that the combination delayed tumor growth even more, and further prevented the cancer from spreading to other sites within the body.

Based on their astonishing results, the group then set out to try out their vaccine in a clinical trial with patients who suffered from advanced stage iNHL. In the study, 11 patients received multiple Batf3-DC-stimulating injections, 2 doses of localized radiation, and multiple T cell-stimulating injections into their tumor lesions. Most of the patients did not suffer any adverse effects from the treatment, with only one who developed a mild fever and minor flu-like symptoms. Following the trial, 8 of the patients saw complete regression of their treated tumors. Additionally, 3 of the trial participants found that after receiving the vaccine, even cancerous lesions that had spread to other areas of their body had regressed, allowing them to enter remission. These findings were particularly important, as this trial was the first to demonstrate that it is possible to achieve tumor regression for metastatic lesions by using a vaccine treatment that specifically acts to stimulate DCs. Further assessments of the patients’ lymph nodes after these treatments showed that their number of cancerous cells decreased, while their healthy cells increased. Furthermore, they had increased amounts of memory T cells, which are critical for vaccine effectiveness. These early findings are incredibly promising, and further testing of the vaccine will help determine its efficacy and whether it is safe enough to receive FDA approval for regular patient use against this disease.  

The group’s vaccine, which was designed to stimulate specific DCs to drive anti-tumor T cell responses, is the first of its kind in clinical trials and has provided researchers with novel insights for the future of cancer treatments. By gaining a deeper understanding of the role that these cells play in driving the regression of cancerous lesions, these scientists have broken ground in the generation of robust anti-tumor immunotherapeutics. Their findings may provide the basis for many targeted vaccines in the future and will hopefully provide more people with the tools they need to live cancer-free.

 

Cover image: “Take a shot at protecting yourself and others from the flu” by BC Gov Photos is licensed under CC BY-NC-ND 2.0 

3 comments

    • Hi Dr. Vigue! The work was actually done by Joshua Brody’s lab at Mt. Sinai! But it is definitely very promising for the future of anti-cancer vaccines!

      Like

  1. Over 50 years ago, my uncle who was a dermatologist, was convinced that the key to treating skin cancers and probably other cancers was using vaccines. The work of Dr. Brody at Mt. Sinai along with many others around the world will eventually reach the goal.

    Liked by 1 person

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