Innovative cancer therapies can help you cope with cancer
TLR9-activating drugs to destroy metastatic lymphoma: A groundbreaking clinical trial for a cancer vaccine using the human immune system
ISV is still in early investigational studies, with various research groups assessing which drug combinations achieve the strongest vaccinal responses1. Furthermore, the current need to inject drugs directly into tumours — to avoid dangerously activating the entire immune system — limits which hospitals offer it and precludes treating inaccessible tumours.
Drug conjugates are in high demand. In 2022, Levy and his colleagues completed work that showed that a TLR9-activating drug coupled to a peptide travelled to tumours in mice and shrank these cancers without systemic side effects13. “It avoids the whole logistical difficulty of tumour injection,” he says. So compelling were the results, a start-up company — TwoStep Therapeutics in San Carlos, California — was founded in 2023 to develop such conjugates.
The cost and complexity of producing a custom vaccine for each person makes it difficult for them to progress through large clinical trials. It is sounding almost peculiar but Brody is using a different approach that uses pre-made components and personalized immune responses to destroy a patient’s cancer.
Adding drugs that increase the function of T-cell might be an important addition to the cancer vaccine. (Notably, most ongoing mRNA vaccine trials include checkpoint blockade, too.) Levy has now added an antibody drug — anti-OX40 — to his TLR9-based ISV approach that directly stimulates T cells. Levy thinks the results of human trials have run into difficulties because most OX40 antibodies for human T cells do not yet work well. In the experiments in which mice with breast cancer were treated with anti-OX40, more than 30% lived until the end of the six-month experiment compared to less than two months for the mice who weren’t treated. Adding a checkpoint inhibitor increased the chances of survival. The practice of leaving the trained immune system behind would be great for people with operable primary tumours who need to have surgery. He says so.
Emboldened by these results, Levy and Brody launched a clinical trial. The results were published in 2010. The trial tested the effect of radiotherapy and TLR9 activation on metastatic lymphoma in 15 people5. One participant entered complete eradication, four had partial regressions, and the disease was stable in two more. A 2012 trial that focused on a different cancer type yielded similar results6.
The drugs need to be delivered directly to the tumours to limit toxicity. This constrains the use of ISV to treating easily accessible tumours such as breast cancer and lymphoma — and makes treatment more complicated and probably more variable than administering drugs systemically.
Dendritic cells contain numerous receptors that alert them to infections and inflammation, including toll-like receptors (TLRs). Stimulated TLRs propel dendritic cells into an activated state that is required for efficient antigen presentation. The drug Levy’s group chose acted on TLR9. The combination again caused tumours that were far away from the irradiated site to regress.
The goal is to cause dying cancer cells to release their cargo of unique antigens. The body’s immune response is triggered by the stimulated immune cells. The same goes for immunized recipients against their owncancers, just through a different route. A vaccine can educate your immune system. The vaccine is being made at the location of the tumours.
Modulating dendritic cells — a class of antigen-presenting cell — lies at the heart of ISV. These cells move through the body, ingesting antigens wherever they encounter them, before travelling to lymph nodes and presenting the antigens to cytotoxic T cells — which, when activated, can bind to and destroy cancer cells bearing the relevant antigens. For cancer therapy, it is crucial that dendritic cells stimulate cytotoxic T cells — which, when activated, can bind to and destroy cancer cells bearing the relevant antigens.
Bill Morrison’s cancer went unnoticed after he discovered a B-cell lymphoma in his father, a New York City man
Initial blood tests led to scans, which led to a biopsy, and finally to the revelation that Morrison had a B-cell lymphoma that had spread throughout his body. “It just came out of nowhere,” Morrison says.
She says it’s difficult to directly test the T-cell response when you don’t know which specific antigens are driving immunity. Without such assays, trials will have to rely solely on clinical outcomes — and not surrogate endpoints such as the development of immunity — meaning they will probably take longer. There is a chance that the vaccine failed or something prevented the regression of the cancer if clinical benefits are not present.
Cancer immunotherapy, in all its variations, is predicated on the immune system’s natural ability to destroy cancerous cells. This happens so often that it stops full blown cancer from developing. Cancers that do become established are those that have acquired mechanisms to escape the immune system — either by preventing the immune system from learning to recognize them or by stopping immune cells from attacking them. Therapeutic cancer vaccines aim to solve the recognition problem.
Morrison’s son searched for a lymphoma specialist and found someone in New York City who was 80 kilometres away from his home on Long Island. For the past 20 years, he’s studied the possibility of immunizing people who have cancer.
In 2017, Bill Morrison was working hard and feeling fine. Swelling on his neck got to him. He says it was pretty puffed out on one side. It seemed a little strange.
Source: Turning tumours against themselves
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Ten million people are killed annually by cancer. According to one study, this disease, in all its many forms, will cost the world a whopping 25 trillion international dollars — an artificial currency used to compare economies — over the next 30 years (S. Chen et al. JAMA Oncol. 9, 465–472; 2023). More than 50 years after the US declaration of a war on cancer, many hoped that the disease would be closer to defeat than these statistics suggest. People diagnosed with cancer today often still contend with the dismal side effects and highly uncertain outcomes associated with the decades-old therapeutic gauntlet of radiation, surgery and chemotherapy. New treatments for cancer are needed to turn the tide decisively — and they are rapidly arriving.
Theranostics consists of a combination of therapies anddiagnostics and is performing well. Sending radioactive particles to the body is a way to locate cancer and then send different types of emitters that can destroy the cancer cells. Researchers are also exploring the use of artificial intelligence to help work out which therapy is best for an individual. With new treatments emerging from labs so rapidly, it might be time to rethink the clinical-trial system lest people be deprived of the most effective treatments available.
The grant funding from MSD and the financial support from Pfizer are acknowledged by us. As always, Nature retains sole responsibility for all editorial content.
Researchers have shown that an antibody, anti-OX40, directly stimulates T cells, which are the body’s immune system’s attack centres, to destroy cancer tumours. It is the first time that a TLR9-activating drug has been used in a human clinical trial to treat a tumour in mice, they added. They further found that the antibody was also active in the cells of breast cancer.