Refined CAR-T cell therapy achieves cancer remission without chemotherapy

A new type of CAR-T cell therapy has achieved complete remission in patients with blood cancers, using lower cell doses and without the need for chemotherapy preconditioning.

An international team led by researchers in Germany and the USA have developed a new type of CAR-T therapy made from stem cell memory T cells (TSCM cells). These immune cells are believed to survive longer and proliferate more effectively than other T cells, potentially improving treatment persistence while reducing side effects.

'We have shown that a more defined, stem-like cell product can perform effectively at lower doses,' said Professor Luca Gattinoni from the Leibniz Institute for Immunotherapy, Regensburg, Germany and first author of the study published in Cell. '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.'

CAR-T therapy works by collecting T cells (immune cells that recognise and destroy infected or cancerous cells) from the patient or a donor, and editing them to recognise and attack cancer cells more effectively. Existing CAR-T treatments have transformed care for some blood cancers (see BioNews 1292 and 1323), but they often require chemotherapy before the CAR-T cells are infused. This chemotherapy preconditioning wipes out existing immune cells that might attack the CAR-T cells and helps the new cells engraft. However, it can also severely weaken the immune system, which may exclude frailer patients from receiving treatment.

The Phase 1 clinical trial enrolled patients with B-cell malignancies for whom a donor stem cell transplant had been unsuccessful in achieving lasting remission. Such patients have limited therapeutic options.

The first 20 patients received conventional donor-derived CAR-T cells produced using a standard manufacturing process. A second group of 11 patients received TSCM-enriched CAR-T cells in escalating doses. Neither group received chemotherapy before treatment, so the team could assess how the infused CAR-T cells expanded (multiplied) and functioned without additional immune suppression.

The TSCM-enriched therapy showed greater expansion and persistence in the body despite being given at substantially lower doses than conventional CAR-T therapy. It also appeared safer than conventional CAR-T therapies: cytokine release syndrome, a potentially dangerous inflammatory reaction linked to CAR-T treatment, was mostly low-grade and manageable. Even when TSCM-treated patients showed levels of CAR-T expansion associated with severe toxicity in the standard treatment group, side effects remained mild.

Not all patients responded to the new treatment, but researchers found that failures were linked mainly to external factors rather than defects in the engineered T cells themselves. These included low levels of target protein on tumour cells, immunosuppressive signals, and immune responses directed against the therapy.

The researchers said future trials with larger, randomised patient cohorts will test whether receiving chemotherapy preconditioning could further improve outcomes. They also hope to investigate whether the approach could be extended to other cancers, including solid tumours, where limited T-cell persistence has been a major barrier to successful CAR-T therapy.