TwoStep Therapeutic: Treating a Cancerous Metastatic Lymoma using Dendritic-cell Targeting Drugs Coupled with a Molecule
It is a challenge to establish immunity assays. But he and others think that intratumoural injections could soon be avoidable. The solution, they say, is to chemically link dendritic-cell-targeting drugs to antibodies or other molecular partners that accumulate inside tumours after being given systemically.
Such drug conjugates are in widespread development. Levy and his colleagues completed work that demonstrated that a drug combined with a molecule could be used to shrink tumors in mice, without causing any serious adverse effects. “It avoids the whole logistical difficulty of tumour injection,” he says. TwoStep Therapeutic in San Carlos, California, was founded in Fall of 2003 to develop the conjugates that were so compelling.
Called in situ vaccination (ISV), it involves delivering a combination of drugs to stimulate immune cells along with an intervention that kills cancer cells, such as radiotherapy, directly to an individual’s primary tumour.
Morrison needed to enter the second trial more quickly. His lymphoma had become more aggressive, unchecked by chemotherapy. This trial — for which Morrison finished treatment in January 2021 — included a third drug. Most participants did not see a lot of benefit, but for him, it worked out well. He went into complete remission. Although he is still nervous prior to his check-up scans, he’s in good shape today.
The results of the clinical trial were Emboldened by them. 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 remission, three had partial regressions and the disease stabilized in two more. A 2012 trial that focused on a different cancer type yielded similar results6.
The drugs have to be delivered directly into the tumours to limit systemic toxicity. This makes treatment for easily accessible tumours such as breast cancer more complex and variable, due to the constraints on the use of ISV.
Only irradiated cancers were eliminated in Demaria’s control mice. But in mice that had received the drug to stimulate the production of extra dendritic cells, metastatic tumours in non-irradiated parts of the body also shrank.
The goal is to make the dying cancer cells release their cargo of unique antigens. The stimulated immune cells then mop up these antigens and trigger a body-wide immune response. Just as with mRNA vaccines, recipients are immunized against their own cancers — it just happens through a different route. Brody says, “a vaccine is whatever educates your immune system.” “We are making the vaccine at the site of the tumour.”
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. When it comes to cancer therapy, it’s important that cytotoxic T cells are stimulated by the use of dendritic cells.
Vaccines for cancer against themselves do not always solve the cancer recognition problem, but do they prevent cancer regression? A case study of Bill Morrison
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.
Second, she says, not knowing which specific antigens are driving immunity makes it difficult to directly test whether ISV induces a T-cell response. 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. Moreover, if clinical benefits are absent, researchers will be uncertain of whether the vaccination failed or whether something downstream prevented tumour regression.
The immune system’s ability to destroy tumors is one of the main reasons for cancer immunotherapy. All the time this happens it stops cancer from developing. There are two ways in which cancer becomes established: by preventing the immune system from learning to recognize them or by stopping immune cells from attacking them. The cancer vaccine hopes to solve the recognition problem.
Morrison had been looking for a lymphoma specialist, and one of his sons had found an oncologist at the Mount Sinai Hospital in New York City. Over the course of 20 years, a vaccine was being studied for people with cancer who have their own tumours.
In 2017, Bill Morrison was working hard and feeling fine. He began to feel a lot of swelling on his neck. “It didn’t hurt but it was kind of puffed out on one side,” he says. It seemed a little odd.
Source: Turning tumours against themselves
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But, overcoming the challenge of selling this approach to industry partners is arguably the most important next step for ISV to progress towards routine clinical care.
Cancer kills almost ten million people annually. A study claims that this disease is going to cost the world 25 trillion international dollars in the next 30 years, an artificial currency used to compare economies. JAMA Oncol. 9, 465–472; 2023). The US declared a war on cancer more than 50 years ago and many believed that it would be defeated. 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 on their way.
By combining medical tasks, theranostics — a combination of therapy and diagnostics — is scoring impressive results. The idea is to send radioactive particles into the body to identify and locate cancer, and then follow up with a different class of emitters that can deal the cancer cells a death blow. Artificial intelligence is being explored to help figure out which therapy is good 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.
We are pleased to acknowledge grant funding from MSD and the financial support of Pfizer in producing this Outlook. Nature retains sole responsibility for all editorial content.