Continuing the legacy of scientific advancement through sheer serendipity, a 78-year-old patient who had advanced chronic lymphocytic leukemia (CLL) is now cancer-free and a team of microbiologists and physicians from the University of Pennsylvania have a clue of how to improve an already promising cancer treatment, following what they describe as a “series of fortunate events”.
Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of certain blood cancers in the mere seven years since it was first tested in a human patient and is on track to be applied to numerous other aggressive cancers soon.
The technique, a personalized combination of gene therapy and immunotherapy, works by removing a patients’ own T-cells and inserting a gene encoding a surface receptor that has been specially engineered to complement a protein present on the patient’s cancerous cells but not their healthy cells. The modified T-cells are then cultured and infused back into the patients’ bloodstream, after which they bind to and subsequently kill cancer cells.
But, for unknown reasons, the transferred cells fail to take hold in the body of some individuals, and the treatment fails.
Currently, there are two CAR T-cell therapies approved for B-cell acute lymphoblastic leukemia and non-Hodgkin lymphoma, and past trials have shown that it can be effective against CLL.
The aforementioned patient was a participant in one of these trials; during which it initially appeared he belonged to the unlucky camp. After undergoing two CAR T-cell infusions, his bone marrow still showed extensive cancer cell infiltration. Unexpectedly, two months later, his CAR T-cells began to multiply and surged through his bloodstream.
Within six months, the patient showed no signs of leukemia. That was more than five years ago, and according to the case report published in Nature, each follow-up evaluation since has shown that the CAR T-cells remain in his system and he remains in full remission.
"It's the outcome we're always hoping for, but we know we can learn so much from every single patient no matter what,” co-senior author Dr Carl June said in a statement. “We brought this from the bedside back to the bench to understand as much as we could about what happened and why."
Upon analyzing the wave of modified T-cells responsible for the remarkable prognosis reversal, Dr June and his colleagues were amazed to find that 94 percent of the population arose from a single, original cell that had the antigen-encoding gene located within the sequence for a gene called TET2. During the creation of CAR T-cells, a non-pathogenic virus is used to insert the engineered gene into the T-cells' genome; where the sequence ends up is up to chance.
Normally, the protein made by the TET2 gene regulates the growth of blood cells such as T-cells and prevents their rapid expansion, but the insertion of the CAR gene on one chromosome reduced the amount of protein that could be made. And in a truly bizarre twist of fate, the patient just so happened to have a natural mutation in the other chromosome’s copy.
With TET2 crippled, the CAR T-cell with this unique genetic profile was able to rapidly multiply and destroy the CLL cells.
"It's a truly remarkable finding, and essentially tells us the minimum dose needed for CAR T cells to do their job is one," said lead author Joseph A. Fraietta.
Subsequent laboratory experiments with a different cell line confirmed that inhibiting TET2 can boost the efficacy and longevity of CAR T-cells, paving the way for higher success rates in future patients.
