Protective Coating Enables Universal CAR-T Cell Therapy

In a new study, a team of scientists from Peking University in China has developed a cancer therapy that has the potential to make lifesaving treatments accessible to patients everywhere. This new cancer therapy could expand access to advanced treatments. The study was published in the journal Cell.

CAR-T cell therapy is one of the most exciting breakthroughs in cancer treatment. It works by extracting a patient's own immune cells, genetically engineering them to recognize cancer cells, and then reintroducing them to attack the disease. Many patients with blood cancers such as leukemia and lymphoma have experienced remarkable recovery thanks to this approach.

However, this cell therapy faces three major challenges: each patient's treatment requires weeks to prepare, is extremely expensive, and some critically ill patients lack access to healthy cells. The scientific community has long hoped to develop an "off-the-shelf," universal CAR-T therapy using healthy donor cells, making it readily available. The challenge is that the body often rejects the donor cells, or the cells attack the patient's body, posing a safety risk.

The team successfully overcame this barrier. By knocking out a single gene, they gave the donor CAR-T cells a protective, armor-like coating. This coating helps the cells evade the patient's immune system and avoid elimination, thereby prolonging their survival. In laboratory tests and early clinical trials, these modified cells demonstrated comparable cancer cell-killing efficacy to conventional CAR-T cells. Importantly, they persisted in patients for months without causing dangerous side effects.

Specifically, the team discovered that knocking out signal peptide peptidase-like 3 (SPPL3) enabled glycan-mediated immune escape in primary T cells. SPPL3 deficiency altered the T cell glycan profile, limiting ligand accessibility and reducing allogeneic immune responses without compromising the function of the anti-CD19 CAR molecule.

Figure 1. SPPL3 deletion modifies glycosylation on primary T cells, reducing allogeneic immune responses without impairing tumor control by anti-CD19 allogeneic CAR-T cells. (Wu Z, et al., 2025)

In a Phase I clinical trial, SPPL3-deficient, T cell receptor (TCR)-deficient, anti-CD19 allogeneic CAR-T cells met their primary safety endpoint. Grade 3 or higher cytokine release syndrome (CRS) was observed in three of nine patients with relapsed/refractory B-cell non-Hodgkin's lymphoma (B-NHL). Reverse translation studies revealed the critical role of the TCR in maintaining T cell persistence.

Thus, the safety of SPPL3-deficient, TCR-retaining CAR-T therapy was evaluated under compassionate use in three patients with lymphoma or leukemia, and no clinical signs of graft-versus-host disease were observed. These findings suggest that glycan shielding achieved through SPPL3 deletion is an important approach for optimizing universal CAR-T therapy.

This study demonstrates the feasibility of safe and effective universal CAR-T cell therapy. If subsequent trials are successful, cancer patients may have access to faster, more affordable, and more accessible off-the-shelf treatment options, offering new hope to patients who were previously untreatable.

Reference

Wu Z, et al. Glycan shielding enables TCR-sufficient allogeneic CAR-T therapy. Cell, 2025.