Cancer scientists have been working against the clock for decades to outsmart a disease that comes back more powerfully after treatment. Traditional treatments like chemotherapy, radiation, and even newer forms of immunotherapy seem to score an initial victory only to see the cancer reappear some months later. The culprit is often the same: the immune system's most powerful cancer-killing fighters, T cells, burn out or disappear too soon.
Now, a team of UCLA researchers has tried a new way to keep those front-line warriors much longer. In the first-ever clinical trial, scientists have combined two powerful approaches -- engineered T cells and gene-edited blood-forming stem cells -- to create what is basically an internal immune factory. The goal is simple but lofty: teach the body to create its own fresh new supply of cancer-hunting T cells for months, if not years, after treatment.
The phase-one trial was run by Dr. Theodore Scott Nowicki, along with Dr. Antoni Ribas, Dr. Owen Witte, Dr. Donald Kohn, Dr. Lili Yang, and Nobel Prize winner Dr. David Baltimore. The study has taken over ten years to develop in the lab, and while it's beginning, the technique potentially could one day change the way we treat some of the most challenging cancers to cure.
The new cancer immunotherapies have a tendency to start off well. Engineered T cells that are programmed to hunt down and destroy cancer cells can shrink tumors dramatically. But all too frequently the gains prove temporary. The T cells become exhausted or get eliminated, and the cancer adapts and spreads again.
Dr. Nowicki explained the challenge: "We're trying to address a problem that limits many current cancer immunotherapies for solid tumors. They often work at first, but the benefit doesn't last because the infused T cells eventually die or become exhausted. The idea was to create a system where the patient's body keeps generating cancer-fighting immune cells over time. It's kind of like installing a permanent immune upgrade."
And that's where the new technology comes in -- pairing T cells with gene-modified hematopoietic stem cells, or HSCs. They're the same bone marrow stem cells that produce all of a body's immune cells and blood. By engineering them to make a tumor-specific receptor, researchers hoped to create a self-renewing pool of cancer-censoring T cells. These would last long after the initial delivery.
In this research, the researchers aimed at a cancer marker called NY-ESO-1. A "cancer-testis antigen," NY-ESO-1 is found in various cancers like sarcoma and melanoma but not in normal adult tissues. So that makes it a safer target because there will be lesser likelihood of attacking healthy cells. Dr. Nowicki explained, "NY-ESO-1 is found in a range of cancers, like sarcoma and melanoma, but it's rarely found in healthy adult tissues, so it's a relatively safe target."
The scientists chose to start with sarcomas, tumors that are hard to treat and which grow back even after removal by surgery or chemotherapy. Some 80% of synovial sarcomas are NY-ESO-1 positive, which gives the researchers a good molecular target on which to base their therapeutic T cells.
The process starts with the collection of a patient's own blood-making stem cells. In the lab, scientists insert the gene map for an NY-ESO-1-reactive T cell receptor into the stem cells using gene therapy techniques. The receptor is a molecular compass guiding the resulting T cells straight to cancer cells bearing NY-ESO-1.
After the engineered stem cells are ready, patients undergo high-dose chemotherapy in order to clear their bone marrow. The modified stem cells are then infused back into the bloodstream and migrate to the bone marrow, where they become integrated. Later on, these stem cells begin to produce T cells that have been engineered with the tumor-homing receptor -- providing a constant internal supply of cancer-destroying cells.
UCLA's Dr. Ribas, director of the tumor immunology program, described how it works: "This is accomplished by putting the cancer-specific receptors into the stem cells through the means of gene therapy, and then subjecting a bone marrow transplant to insert the gene modified stem cells, which then produce the genetically-redirected anti-cancer combat immune cells inside the patient's body."
The pilot trial was small and primarily meant to assess safety and feasibility. But the early results were encouraging. One patient showed measurable tumor shrinkage and had continuing detectable levels of engineered T cells for months. Imaging also confirmed that the stem cells had engrafted well and were producing the target T cells.
"We really taught the body how to produce its own armory of cancer-fighting T cells," said Dr. Nowicki. "That's never been done in humans before.".
The designed T cells provided no sign of anergy (a form of immune paralysis) or exhaustion, two factors that have otherwise restricted the potential of earlier T cell therapies. This suggests that the approach could provide more durable cancer control than standard T cell infusions.
Even with promise, the therapy is now experimental and challenging. The procedure is complex, involving stem cell procurement, gene manipulation, and bone marrow conditioning. It requires skilled teams, advanced laboratory facilities, and strong patient health before treatment is started.
Dr. Nowicki compared it to bone marrow transplants in their early days. "Right now, it's definitely complex, but so were bone marrow transplants in their infancy," he said. Since this was a phase I trial, there weren't large numbers of patients, and long-term results are not known. The trials will have to be larger in size to confirm if this approach can reliably extend survival or stop cancer from coming back.
The uses go well beyond cancer. The same principle -- engineered stem cells to construct an ongoing immune barrier -- could be used for chronic infections like HIV or even autoimmune diseases, where reeducating the immune system could balance it out. "Our trial for cancer is a start, but the horizon is broader," said Dr. Nowicki.
This study is the result of over a decade of research and the labor of more than 30 scientists. Dr. Ribas noted, "It took a team of more than 30 dedicated academic researchers and more than a decade to bring to patients the concept of genetically engineering the human immune system to result in a renewable source of cancer-specific immune cells."
Although it's still not a cure, this trial opens the door to a future where cancer immunotherapy is more than a fleeting uppercut -- it can be a long-term bulwark.
Research findings are available online in the journal Nature Communications.