In recent years, the treatment of some difficult-to-treat blood cancers has been revolutionized by therapies using engineered T cells. These use the patient’s own immune system to destroy cancer cells. But researchers have not had much success in developing the therapy, also known as CAR-T, against tumors, which make up the vast majority of cancer diagnoses – so far.
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Because new study results indicate that scientists are finally making progress with next-generation CAR-T therapies. Recently, the German biotechnology company BioNTech presented preliminary results of a clinical trial with a therapy called BNT211 at the European Society for Medical Oncology conference in Madrid.
The team had treated 44 patients with tumors, primarily ovarian and germ cell tumors, with different doses of CAR-T cells and, in some cases, with a vaccine to support the therapy. Of the 38 people for whom there was enough data to assess how well the treatment worked, 45 percent responded: their tumors shrank or disappeared completely. The presentation focused on another group of 27 participants who received a higher dose of treatment. The researchers found an even better response rate of almost 60 percent. However, more serious side effects also occurred here.
This is just one of the hundreds of CAR-T therapies in clinical trials. Researchers are working to make CAR-T more effective, precise and safe. “We’re learning, we’re making progress, and I think it’s starting to work in solid tumors,” says Marcela Maus, head of cellular immunotherapy at Massachusetts General Hospital Cancer Center. “I am very confident that this will be an extremely useful therapy.” According to Maus, there had long been pessimism regarding the prospects of CAR-T therapies against tumors.
“A living medicine”
T cells are immune cells that help the body fight infections by destroying diseased cells or recruiting other immune cells to attack. Unfortunately, they have a hard time detecting cancer cells. CAR-T treatments offer a remedy. For these therapies, T cells are taken from a patient’s blood. The cells are then genetically engineered to carry a receptor called a chimeric antigen receptor (CAR) that can bind to a protein on the surface of the cancer cell. These manipulated cells are then grown in the laboratory until their numbers reach into the millions. Finally, they are injected back into the body. When the cells encounter the protein they are supposed to recognize, they become activated and begin destroying the cancer cells. “They’re a living drug, so to speak,” says Andrew Jallouk, a hematologist and oncologist at Vanderbilt University.
One of the biggest challenges in using this approach against tumors was finding the right protein. “That’s what the whole field is really looking for. How do you find the right antigen?” says Travis Young, vice president of biologics at Calibr, an institute within Scripps Research in La Jolla, California, that is responsible for discovery and development of medication.
However, some of the proteins that would be most suitable as targets are also found in vital tissue. There is therefore a risk that T cells will also attack healthy cells when they should actually only be fighting a tumor. That’s exactly what happened in an experiment 15 years ago, when researchers engineered T cells to target HER-2, a surface protein found in many breast cancers. One patient experienced respiratory distress minutes after treatment and died five days later. The T cells had also detected small amounts of HER-2 molecules on their lung cells and also attacked the wrong target tissue.
Avoid collateral damage
BioNTech avoided this problem by targeting a unique protein called claudin-6, which is found only in fetal tissue and some cancers, but not in healthy adult tissue. Another way to prevent damage is to make T cells smarter. By developing T cells with multiple receptors, researchers can create cells that only become active when certain conditions are met – a kind of biological logic gate. Arsenal Bio is one of the companies taking this approach.
For example, researchers can create cells that are activated only when two different antigens are present (an “and” gate), or cells that are activated when either receptor is present (an “or” gate). “You can create multiple inputs for the cell, just like with a computer,” says Young from the Calibr Institute. The T cell can then use this logic to decide whether it is encountering a tumor cell or a normal cell.
This is also more in line with how T cells work naturally: They have multiple inputs and negative and positive feedback loops. Arsenal Bio launched a clinical trial testing a CAR-T therapy for ovarian cancer in January this year. This is usually recognized so late that patients only have a small chance of survival.
However, sometimes there is no unique protein or set of proteins to focus treatment on. In this case, if there are no tumor-specific targets, it might be possible to add them. For example, a team of researchers from Columbia University reported in the journal in mid-October Sciencethat they have developed a CAR-T therapy that uses engineered bacteria to mark tumors.
The researchers modified a strain of E. coli to carry the gene for a green fluorescent protein and injected the bacteria into mice. The bacteria accumulated in the animals’ tumors and formed the fluorescent dye together with an anchor protein. This duo then reaches the surface of the tumor cells and is anchored there. They then injected the mice with T cells that targeted the green protein. “We paint the tumors green, and the T cells can ‘see’ green,” says Rosa Vincent, a graduate student specializing in synthetic biology at Columbia University who was lead author of the study.
Bacteria make tumor cells vulnerable
It is not entirely clear why the bacteria only accumulate in the tumors. However, Vincent suspects it has to do with the tumor’s microenvironment. “Because the tumor is so immunosuppressed, it provides the bacteria with a perfect environment for their growth,” she says. “You only need one cell and it grows exponentially. However, if it settles in healthy tissue, the immune system immediately eliminates it.” This strategy is not yet ready for clinical trials, but the team is already thinking about how to advance the research. Humans are more sensitive than mice to toxins found on the surface of E. coli. “So the biggest risk is sepsis and toxic shock,” Vincent continues. “But there are so many technical strategies we can use to reduce the toxicity of the strains.”
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