Dr Mehta-Shah on Novel CTCL Target Research

There’s probably multiple clones that a single patient has in cutaneous lymphomas, represented at different frequencies over the course of someone’s disease — and we think different clones respond differently to different targets of therapy. That’s been a little bit of our philosophy of how we treat patients.

It was about a decade ago that the discovery of CCR4 overexpression in cutaneous T-cell lymphoma led to an international trial and the FDA approval of mogamulizumab. That speed is now the template for a broader hunt. Neha Mehta-Shah, MD, MSCI, of the Division of Oncology at Washington University School of Medicine, says the field is “at the precipice of a lot of change” as new targets in CTCL come into focus.

At the 6th World Congress of Cutaneous Lymphoma (WCCL), Mehta-Shah surveyed where novel-target discovery in CTCL stands: the genomics, the protein-expression work, and the agents now being built around newly identified targets. She discussed the practical and future implications of that work in a second part of this discussion.

Several targets are advancing at once, Mehta-Shah noted. CD94 antibodies were presented at the meeting in a first-in-human study in certain rare cytotoxic T-cell lymphomas, and the role of TNF-α and soluble TNF-α receptor inhibition has emerged as another area the field is only now learning to harness.

The throughline is a shift from repurposing agents developed elsewhere toward therapies built around the biology of CTCL itself.

A central theme of her own work is that a single patient harbors multiple malignant clones, present at different frequencies as the disease evolves. Those clones can respond differently to different targeted therapies. That insight, Mehta-Shah said, shapes how her group approaches treatment, rather than assuming one target defines a patient’s disease.

Her translational data have pointed to specific opportunities. The work showed recurrent overexpression of STAT-pathway genes, along with copy-number changes in chromosomal regions tied to STAT expression and to EZH2 — not necessarily EZH2 overexpression, but copy-number alterations in EZH2-dependent domains.

That finding led her group to launch a study of EZH2 inhibitors in cutaneous lymphomas, which recently completed accrual; she hopes to share the data soon, while noting the approach is tempered by caution given recently evaluated risks of EZH2 inhibitors. The broader importance of JAK-STAT signaling in CTCL — and how best to harness it — remains an ongoing focus of her research.