Small CAR T Cell Subset May Be Key To Treating Childhood Leukemia

Small CAR T Cell Subset May Be Key To Treating Childhood Leukemia
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University College London (UCL) and Great Ormond Street Hospital (GOSH) researchers and clinicians say they have discovered a small subset of T-cells that may play a key role in whether chimeric antigen receptor (CAR) T cell therapies will be successful against leukemia in children. The team, which assessed and compared CAR T-cells in patients receiving treatment as part of a Phase I study, say the results indicated that stem cell memory T cells (Tscm) appear to be critical for both destroying the cancer at the outset, and for long term immune surveillance. They suggest that exploiting this quality could improve the design and performance of CAR T therapies.

Martin Pule, Ph.D., who develops CAR T therapies at his lab at UCL Cancer Institute, said, “This research opens up new avenues to improve CAR design and manufacture, improving the performance of CAR T-cell therapy, to achieve a combination of early tumor clearance and long-term protection from relapses in patients with B cell leukemia.” Pule is co-author of the team’s published paper in Nature Cancer, which is titled, “Clonal expansion of T memory stem cells determines early anti-leukemic responses and long-term CAR T cell persistence in patients.”

CAR T therapy is a form of adoptive T cell transfer, as part of which immune cells (T-cells) are genetically engineered to contain a chimeric antigen receptor on their surface, which can specifically recognize cancerous cells. And while such therapeutic approaches demonstrate potential for treating different diseases, there are still gaps in our knowledge, the investigators noted. “Adoptive T cell transfer shows great promise for the treatment of both viral infections and cancer but much remains to be learnt about the optimal phenotype of T cell products, their clonal dynamics once infused and the origin of both early responding T cells that mediate initial responses as well as long-term-persisting T cells that provide immunological surveillance.”

With respect to the use of CAR T cell treatment for pediatric leukemia, Luca Biasco, PhD, at UCL Great Ormond Street Institute of Child Health, pointed out, “During clinical trials we have seen some very encouraging results in young patients with leukemia, however it’s still not clear why CAR T-cells continue to be present in the long-term for some patients, stopping the cancer from returning, while others remain at a high risk of relapse. To ensure that a leukemia treatment works any CAR T cell therapy must have a prolonged effect on the way that the body recognizes and removes cancer cells.”

For their newly reported study, the researchers assessed the CAR T cells of patients involved in the CARPALL Phase I study that evaluated a new CAR molecule known as CAT-19—which has been developed by UCL Cancer Institute and UCL Great Ormond Street Institute of Child Health—for treating children with acute lymphoblastic leukemia (ALL). Using a technique called ‘insertion site barcoding’, they were able to study the fate of different types of CAR T cells given to patients. “In this study we tried to find the origin and nature of the T-cells that control these long-term responses,” Biasco noted.

The investigators compared the CAR T cells in patients who still had CAR T cells detectable in their blood more than two years after their treatment, with individuals who had lost their CAR T-cells in the one to two months post treatment. Corresponding author Persis Amrolia, M.D., based at UCL Great Ormond Street Institute of Child Health and Consultant in Bone Marrow Transplant at GOSH, explained, “Using this barcoding technique, we were able to see ‘stem cell memory T-cells’ play a central role both during the early anti-leukemic response and in later immune surveillance, where the body recognizes and destroys cancer cells. This suggests that this small sub-group of T-cells are critical to the long-term success of the therapy.”

The team further noted, “… our data provide evidence for the first time, to our knowledge, of the critical role of TSCM cells in mediating both early anti-leukemic responses and long-term persistence of CAR T cells after infusion … By combining immunophenotyping and molecular tracking we have gained important insights into the nature and dynamics of both early expanding CAR T cells that mediate initial responses as well as long-term-surviving CAR T cells providing immune surveillance against leukemic relapse in two patients up to 3 yr after infusion …”

Researchers say the work indicates that clinicians could measure the types of CAR T-cells present after patients have had their anti-leukemia therapy, as an indication of whether they will be able to preserve their CAR T-cells into the future, and avoid relapse. Amrolia stated, “This new insight may help us to improve our CAR T-cell therapy and work out which patients are at a higher risk of relapse and may benefit from a stem cell transplant after CAR T-cell therapy.”

Biasco commented, “It was extremely rewarding to see how the application of our new barcoding technology to study CAR T-cells is unveiling such important information about what happens to these cells after they are given to patients. We now plan to expand the technology we established at UCL and validate these findings in larger groups of patients.”

And in conclusion, the authors wrote, “Our data may help identify patients at risk of early loss of CAR T cells and highlight the critical role of T memory stem cells both in mediating early anti-leukemic responses and in long-term surveillance by CAR T cells … Future efforts will focus on validating these findings in larger patient cohorts and improvement of CAR design and manufacturing methodology to preserve TSCM and TCM cells in the infused cell product.”