Results from a Phase I clinical trial show promise for a CAR T therapy using a population of stem cell memory T cells (TSCM), achieving complete remission at low doses and lowering the risk of serious adverse effects including cytokine-release syndrome. The study was published in Cell today.
“Seeing patients achieve complete responses at doses as low as 250,000 cells per kilogram, without chemotherapy preconditioning, validates years of preclinical work and opens a new chapter in CAR T-cell design,” says Luca Gattinoni, MD, head of the research division for functional immune cell modulation at the Leibniz Institute for Immunotherapy (LIT) and lead author of the study.
While CAR T therapy has significantly improved treatment of blood cancers, many patients still struggle to experience lasting benefits. One potential cause for this is that the infused CAR T cells can often fail to expand and persist within the body over time. To overcome this challenge, Gattinoni’s team treated patients using a TSCM population with strong self-renewal and proliferation capacity.
“Today’s CAR T-cell products are heterogeneous, and that variability is reflected in the range of clinical responses and toxicity profiles we see in patients,” explains Gabriele Inchingolo, PhD candidate in Gattinoni’s team and a lead author of the study. “To address this, we developed a highly homogeneous CD8+ CAR T-cell product selectively enriched for TSCM cells and compared its performance to conventional CAR T cells.”
The first-in-human trial recruited patients with relapsed or refractory CD19 B-cell malignancies who had previously received a hematopoietic stem cell transplantation (HSCT), a patient population with very limited therapeutic options. Whether they received conventional CAR T cells or a TSCM-enriched product, no patients received chemotherapy preconditioning, which is typically used before infusing CAR T cells to help the cells engraft.
Compared to standard CAR T cells, the CAR TSCM cells showed greater expansion and persistence, allowing them to achieve complete responses even at low doses.
“We have shown that a more defined, stem-like cell product can perform effectively at lower doses. By employing a highly homogeneous TSCM population, we can potentially achieve more consistent engraftment and persistence, paving the way for more predictable outcomes and more rationally designed clinical trials,” says Gattinoni.
In addition, the TSCM cells showed a more favorable safety profile. Even at expansion levels that caused severe cytokine-release syndrome in patients treated with conventional CAR T cells, patients treated with the TSCM cells only experienced mild side effects.
“We observed less cytokine-release syndrome in this study compared to most other CAR clinical trials that I have participated in,” adds James Kochenderfer, MD, senior investigator at the surgery branch of the National Cancer Institute (NCI). “The TSCM platform yielded higher CAR T-cell levels on a per cell basis—and across many CAR T-cell studies, high blood CAR T-cell levels have been one of the strongest predictors of clinical efficacy.”
While not every patient responded to the CAR TSCM cell therapy, results showed that treatment failure was driven by external factors such as low levels of the target CD19 protein on tumor cells, immunosuppressive signals such as IL-10, and immune responses against the CAR construct. Future studies in larger cohorts will evaluate the addition of chemotherapy preconditioning and CD4 T cells to potentially continue improving patient outcomes, as well as expanding this approach into other forms of cancer, including solid tumors.
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