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Patients retain remission for 10+ years after CAR T-cell therapy

It’s 10 years since the first CLL patients were treated with CAR T-cell therapy and they are still in remission, as reported in Nature by U.S. clinicians at the University of Pennsylvania. 

CAR (chimeric antigen receptor) T-cell therapy is a revolutionary form of immunotherapy that reengineers immune cells to become cancer-killing cells, and there are suggestions that it could be a ‘cure’ for certain blood cancers. 

Deborah Henderson was one of the first Australians to have CAR T-cell therapy for CLL – read her story 

While trials in CAR T-cell therapy have been extraordinarily successful, putting some patients into remission when they had no further treatment options, the long-term effects had not been extensively studied. 

Back in 2010, two CLL patients achieved a complete remission within months of treatment. And since then, long-lasting CD19-redirected CAR T-cells have remained detectable for more than a decade after infusion, and both patients have sustained remission. 

In the journal article, Professor J. Joseph Melenhorst, and his colleagues, including Professor Carl June, at the Center for Cellular Immunotherapies explained that the CAR T-cells evolved over time, with the emergence of a highly activated CD4+ cell population that became dominant in both patients. 

They also found that the CD4+ CAR T-cells continued to show cytotoxic characteristics along with ongoing functional activation and proliferation. 

“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,” as reported in the Nature paper. 

They also said long-term observations revealed a population of gamma delta CAR T-cells that prominently expanded in one patient and occurred with CD8+ CAR T-cells during the initial response phase. 

The researchers said these two patients seemed to have two distinct phases of CAR T-cell therapy responses – an initial phase dominated by killer T-cells, then long-term remission controlled by CD4+ T-cells. 

At year 1.4 after infusion, one patient’s CD4+ cells made up 97.5% of CAR T-cells, 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 at 7.2 years. 

The CD4+ cell dominance was a surprising finding which led the researchers to rethink the possibility that CD4+ T-cells may be primarily responsible for distinguishing T-helper from T-cytotoxic cells. 

They concluded that, “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”. 

“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,” according to Prof. Melenhorst. 

The Director of the UCL Cancer Institute CAR T-cell program, Professor Martin Pule described this research as a landmark paper. 

“A decade ago, CAR T-cell therapy was a therapeutic approach explored by a very small number of scientists and was considered a fringe approach and unlikely to work,” said Prof. Pule. 

“This paper shows us that CAR T-cells can give patients with cancers, which no longer respond to chemotherapy, remission which lasts a decade.” 

Another University of Pennsylvania scientist involved in the research, Professor David Porter said the team had been unprepared for how successful the findings were. 

“Cancer doctors don’t use words like ‘cure’ lightly. But we now have patients who haven’t relapsed, and we really believe that we can start to use the word cure,” he said.  

Expert Series interview: Australia’s Associate Professor Michael Dickinson discusses CAR T-cell therapy – read this article 

Acknowledgment: This article has been collated based on stories published in the limbic and the Guardian.