CD70 Emerges as Target to Overcome Treatment Resistance in MCL

A protein that helps mantle cell lymphoma (MCL) cells hide from the immune system could be used to treat patients whose disease no longer responds to Bruton tyrosine kinase (BTK) inhibitors or chimeric antigen receptor (CAR) T-cell therapy, according to preclinical findings published in Cancer Letters.

The study, from researchers at The University of Texas MD Anderson Cancer Center, found that CD70 expression rises steadily as MCL becomes resistant to treatment. A bispecific antibody directed at CD70 killed BTK inhibitor-resistant lymphoma cells in the laboratory and extended survival in mice. Michael Wang, MD, professor in the Department of Lymphoma and Myeloma at MD Anderson, is the paper’s senior author.

BTK inhibitors and CD19-directed CAR T-cell therapy have produced durable responses in relapsed/refractory (R/R) MCL. “Nevertheless, most patients ultimately relapse due to therapeutic resistance, immune escape, or failure of adoptive cell therapy, underscoring a critical unmet clinical need,” the authors write.

CD70 belongs to the tumor necrosis factor ligand superfamily and is the only ligand for the costimulatory receptor CD27. It is aberrantly expressed in aggressive MCL, especially SOX11-positive cases, they note. Tumor cells use the CD70-CD27 axis to escape immune surveillance by driving T-cell apoptosis and exhaustion and by expanding regulatory T cells, known as Tregs.

Rising CD70 With Resistance

The investigators used single-cell RNA sequencing on 28 MCL patient samples and on normal B cells from healthy donors. CD70 expression increased from BTK inhibitor-sensitive to BTK inhibitor-resistant to BTK inhibitor/CAR T dual-resistant specimens. The same pattern appeared in a separate group of CAR T-resistant samples. Flow cytometry of 11 primary specimens showed that CD70 protein was highest in blastoid MCL. Samples from relapsed patients also contained exhausted CD8+ T cells and Treg subsets, with lower cytotoxicity scores.

To test whether CD70 drives this immunosuppression, the team built a CD70-blocking single-chain variable fragment (CD70-scFv2). They tested it in a coculture system designed to mimic the tumor microenvironment. Exposure to CD70-positive MCL cells raised levels of the Treg activation marker CD25 and of the immunosuppressive cytokine IL-10, and blocking CD70 lowered both. CD70 blockade also restored CD27 on T cells and reduced the exhaustion markers PD-1 and TIGIT.

A Bispecific Approach

The researchers then engineered a CD70 × CD3 bispecific T-cell engager in a knob-into-hole IgG1 format. Along with activating T cells, the antibody pushed them toward less-differentiated, stem cell–like memory states, which the authors said are linked to longer persistence. The team tested it against 2 BTK inhibitor-resistant cell lines, JeKo-BTK KD and MAVER-1. The CD70-bispecific antibody increased interferon-γ, tumor necrosis factor-α, and granzyme B and killed a large share of tumor cells within 24 hours.

Next, mice were engrafted with MAVER-1 cells and given T cells from healthy donors. Both doses tested (10 and 100 μg/kg) significantly slowed tumor growth compared with controls, and the survival benefit grew with the dose. Two of 5 mice survived long term at the lower dose and 4 of 5 at the higher dose, while all control animals died of progressive disease.

“Together, these findings identify CD70 as a driver of immune evasion and a therapeutic actionable target, supporting the clinical development of CD70-directed T-cell-engaging therapies for patients with R/R MCL,” the authors wrote.

They noted that several CD70-directed treatments are already moving toward the clinic, including CAR T and CAR-NK cell therapies, antibody-drug conjugates, and bispecific antibodies. Still, they cautioned that the work is early.

“Although our findings demonstrate promising preclinical efficacy, it is limited to in vitro assays and immunodeficient mouse models that do not fully recapitulate the human immune system and tumor microenvironment,” they wrote.

They said studies in immune-competent and humanized mouse models are needed to show whether the strategy could work in patients.

Wang reports consulting fees, research support, and honoraria from multiple sources, including AstraZeneca, BeOne Medicines, Janssen, Kite Pharma, and Eli Lilly.

Reference
Yao Y, Liu Y, Yan F, et al. CD70-driven immunosuppression in mantle cell lymphoma identifies a vulnerability to CD70-directed bispecific antibody modalities. Cancer Lett. 2026;661:218855. doi:10.1016/j.canlet.2026.218855