How to Turn our Bodies into Cancer-Fighting Machines
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In the early years of Xiuyan Wang’s career, she received a special request from a patient at the Memorial Sloan Kettering Cancer Center (MSKCC): he wanted to meet the person that would be making his cells.
Wang ventured to the patient’s room, away from the experimental lab where she usually spent her days, and met him face-to-face. “He said, oh, you’re the one making my cells!” she recounted. “Please make good cells.”
Wang did, indeed, make good cells. She has since become the Assistant Director of the Cell Therapy and Cell Engineering Facility at MSKCC, where innovative medical treatments are developed by scientists in spacesuit-like sterilization gear. Their treatments can’t be pressed into pills or drilled into bone; they’re made of living human cells, just as living as you or me, with some tweaks here and there to make them better at one thing: fighting cancer.
These cancer treatments mark an exciting shift away from the typical chemotherapy and surgery. A type of immunotherapy, they work with a patient’s immune system to give it the tools it needs to identify and attack cancerous tumor cells. In general, what Wang is working on goes a little something like this:
Harvest a patient’s blood.
Engineer their white blood cells to better fight cancer.
Return those new blood cells to the patient.
Over the course of Wang’s career, she’s watched her lab staff grow from her and one part-time technician to now almost 40 full-time faculty and seen the number of cell engineering facilities in the country skyrocket from seven to over 200. “It’s a very hot field right now,” she said. After decades of countless clinical trials and experimental treatments, in 2017 the first drugs for cell therapy were finally approved by the FDA to treat blood cancers. To understand how these treatments work, we need to take a trip back in time and revisit a few high school biology basics.
Tumors, and other foreign cells our body doesn’t want, have antigens on their surface. Antigens tell you what the cell is made of; a virus could have antigens that identify it as COVID-19, or a tumor could have antigens that identify it as brain cancer.
Our body takes care of these unwanted cells in a three-pronged attack system of T-cells, B-cells, and NK-cells (these are all types of white blood cells). T-cells identify antigens, so they let the immune system know what kind of response to give. B-cells make specific antibodies according to the signals they received from T-cells, marking the surfaces of unwanted cells with these antibodies. NK (natural killer) cells do the dirty work, killing foreign cells once they are identified and marked by their companions. NK cells can also find and kill foreign bodies without the help of T- and B-cells, but cancerous cells can sometimes evade their detection, and the other cells need to step in to finish the job.
Immunotherapy harnesses this process to enhance the immune system, personalizing it for whichever cancer the patient is suffering from. The five drugs that have been approved by the FDA use CAR T-cell therapy, or chimeric antigen receptor T-cells; this is also the type of therapy Wang and the technicians at the MSKCC specialize in.
In the fight against cancer, T-cells need to be able to properly identify tumor cells and distinguish them against healthy tissue. CAR T-cell therapy edits new genes into a patient’s T-cells to help them do this.
Let’s dissect the CAR. “Chimeric” refers to chimeric genes, new genes that are produced by combining different DNA sequences. “Antigen receptors” are what is being added to the T-cells to make them better at identifying cancer; essentially, scientists like Wang are adding receptors to the patient’s T-cells that are specially engineered to find their specific type of cancer antigens. The process looks like this:
The patient is connected to two IV lines, one removing their blood and the other returning it. Once removed, the blood is put through a machine to separate the white blood cells from the red. The red blood is returned through the second IV line.
The white blood cells are sent to a lab, where the T-cells are separated from B- and NK-cells using added chemicals and/or centrifuges.
The T-cells are ‘infected’ with an inactive virus that inserts the genes for the CAR, thus turning them into CAR T-cells.
These new, engineered cells are cultivated until there are enough of them to be able to survive and replicate inside the patient’s body.
The T-cells are returned to the patient’s body, where they bind to cancerous tumor cells, identifying them as such and recruiting the rest of the immune system to attack.
This therapy is best used for blood cancers, AKA “liquid tumors” (even though the tumor cells themselves aren’t liquid) and is the only cell therapy that has been approved by the FDA. They are used as a “third-line” treatment for patients close to their deathbed, only after two previous rounds of treatment, i.e. two rounds of chemo, fail to do the job. After CAR T-cell treatment, anywhere from 35-94% of patients, depending on the type of cancer and treatment used, achieved lasting remissions after their conventional treatments failed. The first FDA-approved drug, Kymriah, saw 62% of its patients in remission two years after their treatment.
But blood cancers only make up about 10% of adult cancer in the U.S.; the majority are classified as “solid tumors,” the abnormal masses of cells growing erroneously on livers, colons, or lungs you typically think of when imagining a tumor.
“For solid tumors there is still a big barrier,” Wang said, and there’s a lot she and her team are working to overcome. For starters, liquid tumors are a lot easier to identify than solid tumors. Blood cancer cells are marked with the antigen CD19, making them an easy target for the engineered CAR T-cells to identify. By contrast, solid tumor cells can’t always be easily differentiated from healthy cells.
Often, their antigens exist inside the cell, not on the outside, buried inside the dense tumor microenvironment and making them invisible to the CAR. Their antigens aren’t unique to cancerous cells; a marker for lung cancer could be the same antigen that identifies the lung itself, and telling the white blood cells to attack that marker could have devastating effects on the healthy organ tissue they want to preserve.
In addition to the findability of solid tumors, their solid mass creates a microenvironment that’s especially hostile to immune responses, and has very little blood flow, making it tricky for blood-based treatments like CAR T-cell therapy to be effective.
But all hope isn’t lost for solid-tumor patients. Wang described a promising clinical trial at MSK for mesothelioma, cancer in the chest cavity, where the cell therapy treatment is directly injected into the tumor through a catheter.
“We have 20 clinical trials going,” Wang said, and their schedule is so packed that they’ve had to turn down pharmaceutical companies wanting to use their lab in favor of MSK’s own patients. “Now our calendar is so full, and some technicians can’t even have a proper vacation,” she said. “We have one person, she recently moved two weeks ago. She hasn’t even had time to unpack yet.”
Rather than pumping out the same treatments they know will work, the Cell Therapy and Cell Engineering Facility is a research lab, exploring new approaches to cell therapy that build on previous findings.
“They want to do something that works, for the patient’s sake,” Wang said. “They also want to do something conceptually new, so we will be the first...so we’ll be the leading institute.”
This helps the facility get better grants and retain the talented scientists on their team. Wang has lost personnel to big pharmaceutical companies after years of intense training at MSKCC, a frustrating experience as each member of the facility contributes to their ongoing innovation.
“We want people who are really coming in with the pride of changing somebody’s life or family’s live to make a positive impact,” Wang said, “we need people to think that way. And to do the innovation part, rather than working at a company, going 9-5, and doing the same thing all over.”
Because the facility works mainly on clinical trials, they’re making small-scale batches of their therapies, and much of the processing is done by hand. It can take weeks of preparation before a treatment can be administered to a patient, a significant roadblock in the quest to make sure the roughly 2 million Americans diagnosed with cancer every year will be able to access immunotherapy.
The other barrier to this is the treatment itself; in autologous treatment, the cells are harvested from the patient themselves, so that person is the only one who can use them.
“One product is for one patient, so the lot is very limited,” Wang explained. A solution to this is allogeneic treatment, the opposite of autologous. Allogeneic treatment would harvest cells from one healthy donor, and use those to create treatments for hundreds, or even thousands, of patients. This could make an off-the-shelf product that’s ready to use as soon as the patient needs it, along with making manufacturing cheaper and quicker. But there’s a reason this approach is much farther behind than autologous.
“Manufacturing of allogeneic is still in its infancy because of how you have to dampen the host and the graft interactions,” Wang said. Host and donor cells won’t necessarily get along once the treatment is administered, making allogeneic therapies a much more dangerous territory as patients risk graft versus host disease and rejection.
Besides those biological barriers, there’s the actual manufacturing process to consider. Machines are being developed that can process several treatments simultaneously, a crucial piece in the puzzle as accessibility for the treatments, both in terms of availability and cost, become the biggest thing standing in the way of patients and long-lasting remission.
Automating the development of cellular therapies “will enable so much,” Wang said. “It will enable the throughput and will help standardize a certain way of making a product…. Access will be easier, and cost will go down, and that’s the ultimate goal. We don’t want to have a very promising therapy but only 20 people are going to be able to get it versus 2,000 people.”
While Wang and her team specialize in CAR T-cells, there’s a whole world of promising approaches to immunotherapy using different cells, different molecules, and different DNA sequences that could all play a part in eventually finding legitimate cures for cancer.
“I don’t think this one approach is the answer, one size fits all. I think it’s gonna be some combination.” Ideally, Wang said, “the cell product will be personalized, we can prescribe, if you need three of the NK cells, two of the T-cells, and one of microphages in that sense. We want to be able to get there. But it’s going to be a long journey.”
And Wang’s been on that journey for years, watching as treatments succeed and fail, learning as patients come and go, and feeling pressure from the scientific community to continue innovating every day. She remembers a day nearly two decades ago when she had just given birth to her first child during her postdoc training.
“I asked my mentor ‘can I stay a little bit longer to take care of my baby?’” Wang said. “And he said, ‘I can wait, Xiuyan, but science cannot.’”
