'Deep Remissions' of 4 Years Make CAR T-cells Unique in CLL

Nick Mulcahy

September 17, 2015

More than 4 years — that's the length of time two patients with poor-prognosis chronic lymphocytic leukemia (CLL) have been in remission after achieving a complete response (CR) with the one-time personalized cellular therapy known as CTL019, according to a new study.

These are "deep and sustained" remissions that provide evidence that "sets this treatment approach apart from other targeted agents, such ibrutinib and idelalisib," say the researchers, led by David L. Porter, MD, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia.

However, longer-term follow-up is needed to determine whether the therapy, which employs chimeric antigen receptor (CAR)-modified T-cells, will "result in complete eradication of CLL," they write in a research article published in the September 2 issue of Science Translational Medicine.

Allogenic stem cell transplantation can cure some patients with CLL, but the morbidity and mortality related to the procedure limit its use.

New targeted therapies such as ibrutinib (Imbruvica, Pharmacyclics/Janssen) have "exciting activity," write the researchers, but CRs are "unusual" with these drugs. In short, CLL remains "incurable with conventional therapies," they say.

There is, therefore, a need for newer and more potent targeted therapies, they explain.

Paul Barr, MD, from the Wilmot Cancer Center at the University of Rochester in New York, agrees that new treatments are needed, but he prefers not to view the range of options hierarchically. "I see these different therapies as being complementary," he told Medscape Medical News.

"Some patients may benefit long-term from CAR T-cells, while others may do well with ibrutinib or idelalisib," Dr Barr said, adding that personalized therapy strategies should eventually emerge from clinical data.

Dr Porter and his team pioneered the use of CAR-modified T-cells in cancer, and previously reported, with great acclaim, results that showed "durable" responses in CLL, acute lymphoblastic leukemia, and non-Hodgkin's lymphoma.

In their study, they  describe the now-completed 14-patient pilot trial of CTL019 for refractory/relapsed CLL, which began in 2010. These longer-term results reveal that the earlier reported durable responses, in some cases, have emerged as deep remissions.

Four of the patients (29%) achieved a CR with the immune therapy. The 10 patients who did not either progressed or died within 10 months, which is "a testament to the advanced stage and high-risk nature of these patients," the researchers explain.

Remission in the first two patients who achieved a CR is now 53 and 52 months, and in another patient  is now 28 months. The fourth patient who achieved a CR was in remission for 21 months when he died because of an infection that occurred after removal of a basal cell carcinoma on his leg.

 
The durability of the remissions...is remarkable.
 

"The durability of the remissions we have observed in this study is remarkable," Dr Porter said in a press statement. He called the patients "pioneers."

Four other patients achieved a partial response (median, 7 months), so the overall response rate was 57%.

All patients who received the experimental therapy, which is made from their own immune cells, were heavily pretreated, and only a few were eligible for bone marrow transplantation. Overall, the study participants were very ill. "We attempted to identify patients for enrollment who were at high risk of death from CLL without effective treatment," the researchers report.

Notably, all eight patients who responded to the T-cell therapy developed cytokine release syndrome (CRS), with symptoms ranging from mild to severe.

CRS symptoms included fever, myalgia, and nausea; in severe cases, these escalated to hypotension, capillary leak, and hypoxia. But the Penn team has developed a management strategy to treat CRS that includes the interleukin-6 antibody tocilizumab; it was used in four patients and all recovered from their CRS.

Cytokine release and other adverse events, such as neurologic symptoms and prolonged B-cell aplasia, are "fairly unique" to CAR T-cells, Dr Barr pointed out. Time will tell how well they are managed by clinicians elsewhere. "Multicenter studies are just now starting," he said.

Dr Porter and his colleagues note that treatment responses were associated with high levels of CTL019 cell expansion and persistence. In other words, when there is a response, some T-cells modified with CAR persist in the body for a long time to fight the cancer.

"Importantly, our tests of patients who experienced complete remissions showed that the modified cells remain in patients' bodies for years after their infusions, with no sign of cancerous or normal B-cells," said senior researcher Carl June, MD, PhD. "This suggests that at least some of the CTL019 cells retain their ability to hunt for cancerous cells for long periods of time."

We hope to continue to prolong patient remission and, as the group at Penn suggests, possibly even cure patients," Dr Barr added.

This study was funded by Novartis, the Leukemia and Lymphoma Society, and the National Institutes of Health. Some of the study authors report financial relationships with Novartis. Dr Barr reports financial ties with AbbVie, Pharmacyclics, Gilead, TG Therapeutics, and Genentech.

Sci Transl Med. 2015;7:303ra139. Abstract

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