Blood cancers

Decade-long CLL remissions achieved with CAR T cell therapy

Professor J. Joseph Melenhorst

The first patients with chronic lymphocytic leukaemia to be treated with CAR T-cell therapy are showing sustained remissions after ten years with persistence of CD4+ CAR T cells, according to US clinicians.

Two CLL patients who achieved a complete remission in 2010 have since shown long-lasting CD19-redirected CAR T cells, according to a report by clinicians at the University of Pennsylvania

Published in Nature, the article by Professor J. Joseph Melenhorst and colleagues at the Center for Cellular Immunotherapies, Perelman School of Medicine, reports an evolution of the CAR T cells over time, with a highly activated CD4+ cell population emerging and becoming dominant in both patients.

The long-persisting CD4+ CAR T cells continued to exhibit cytotoxic characteristics along with ongoing functional activation and proliferation, their analysis found.

“This transition was reflected in the stabilisation of the clonal make-up of CAR T cells with a repertoire dominated by a small number of clones,” they wrote.

Long term observations also revealed a population of gamma delta CAR T cells that prominently expanded in one patient concomitant with CD8+ CAR T cells during the initial response phase, they said.

The researchers said there appeared to be two distinct phases of CAR T-cell therapy responses in the patients, with an initial phase dominated by killer T cells, and long-term remission controlled by CD4+ T cells.

In one patient, CD4+ cells made up 97.5% of CAR T cells at year 1.4 and then more than 99.6% from year 3.4 to the latest time point (9.3 years) after infusion. In the second patient, CD4+ cells made up 97.6% of CAR T cells 7.2 years after infusion.

This surprising finding of CD4+ cell dominance led researchers to rethink the possibility that CD4+ T cells may be primarily responsible for distinguishing T-helper from T-cytotoxic cells, a statement from the University of Pennsylvania noted.

“Our identification and characterisation of these unexpected CAR T cell populations provide novel insight into the CAR T cell characteristics associated with anti-cancer response and long-term remission in leukaemia,” the authors concluded.

“This long-term remission is remarkable, and witnessing patients living cancer-free is a testament to the tremendous potency of this “living drug” that works effectively against cancer cells,” commented Professor Melenhorst.

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