DRAMATIC RESPONSES WITH CARs IN B-CELL LEUKEMIA

More dramatic clinical results with engineered T-cell therapy have been reported, this time from a trial showing that 14 of 16 patients (88%) with advanced adult B-cell acute lymphoblastic leukemia (B-ALL) achieved complete remission (CR).

The findings were published in the February 19 issue of Science Translational Medicine.

"These extraordinary results demonstrate that cell therapy is a powerful treatment for patients who have exhausted all conventional therapies," said senior author Michel Sadelain, MD, PhD, director of the Center for Cell Engineering at the Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City. Their technology to modify T-cells has been licensed to Juno Therapeutics.

This novel approach to therapy involves extracting T-cells from the patient, subjecting the cells to chimeric antigen-receptor (CAR) cell engineering, and then infusing the engineered T-cells back into the patient. It was the talk of the show at the recent annual meeting of the American Society of Hematology (ASH), as reported by Medscape Medical News.

At the ASH meeting, dramatic clinical results were reported by teams from the National Cancer Institute, which has licensed the technology to Kite Pharmaceuticals, from 19 patients with B-cell lymphomas, and also by a team from the University of Pennsylvania, which has licensed it to Novartis, and reported on 32 adult patients with chronic lymphocytic leukemic and 22 pediatric patients with acute lymphocytic leukemia. However, while all the researchers emphasized the tremendous potential of this therapy, they also warned that it has adverse effects and that these are early data.

T-Cells "Re-educated"

In the current study, the MSKCC team report results from 16 patients with relapsed or refractory B-ALL (median age, 50 years). At this stage, the disease is highly chemotherapy resistant and progresses rapidly, and such patients usually have a poor prognosis, with an expected median survival of less than 6 months, the researchers write.

All of the patients underwent leukapheresis and received "physician's choice" salvage chemotherapy. This was followed, regardless of response, with cyclophosphamide conditioning chemotherapy and an infusion of modified T-cells (which had been "re-educated" to recognize the cancer CD19 protein).

The researchers report that the modified T-cells elicited an overall complete response rate of 88%, which is higher than has been seen historically with salvage chemotherapy alone (around 30%), they comment.

Of the 14 patients who had an overall complete response rate, 10 had complete remission (CR) and 4 had CR with incomplete count recovery (CRi). The median time to CR/Cri was 24.5 days.

These CR rates, obtained in a very poor prognostic patient population, far exceed expectations based on historical data, and are consistent with a profound antitumor effect mediated by the modified T-cells, the researchers comment.

"Furthermore, in patients wherein the malignant tumor clone could be monitored in bone marrow by deep sequencing, we found rapid elimination of the malignant B-ALL tumor clone" after the infusion, they add.

To date, 7 of the 16 patients (44%) have gone on to a have successful allo-stem cell transplant, which, at present, is the only therapeutic modality with curative potential, the researchers note. "This is especially meaningful when compared to the reported historically low frequency (5%) of relapsed or refractory adult B-ALL patients who ultimately transition to allo-SCT after salvage therapy."

There have been no relapses in all of these 7 patients (follow-up ranges from 2 to 24 months), although 2 patients have died from post-transplant complications.

Of the 9 patients who did not go on to transplant, 6 patients were ineligible (3 because of failure to achieve a CR and 3 because of pre-existing comorbidities). One is being evaluated for a transplant, and 2 were eligible but declined a transplant.

Learning More About the Adverse Effects

Some patients react to the infusion of modified T-cells with a clinical syndrome of fevers, hypotension, hypoxia, and neurological changes associated with marked elevations of serum cytokines, the researchers comment. This has been termed cytokine release syndrome (CRS), but because of the anecdotal nature of this phenomenon, it has "remained largely undefined."

Patients with evidence of CRS usually develop a fever about 24 hours after the infusion, but this fever is not always followed by the other symptoms, they note. They set out to monitor closely levels of cytokines to see if there was a way to differentiate between patients with fevers that would resolve spontaneously and those who would develop also the other symptoms and would need other therapeutic intervention.

The MSKCC team found that 2 cytokines, in particular, were hugely elevated (75-fold increase over baseline) in patients with severe (s)CRS who required intensive medical intervention. They suggest that this marker, in combination with clinical symptoms and persistent fever, could be used to identify patients with sCRS.

This is a clinically meaningful stratification, they say. Patients who develop sCRS may require intensive care with mechanical ventilation, vasoactive pressors, antiepileptics, and antipyretics. High-dose steroids are also used, and the interleukin-6-receptor blocking agent tocilizumab has been reported to result in a rapid resolution of sCRS. While the symptoms may be severe, they have, to date, been fully reversible, the researchers note.

Patients who develop sCRS have a hospital stay averaging 56.7 days, whereas the other patients who develop what they term nCRS tolerate the infusion and need only routine observation and management, and stay in hospital for an average of 15 days.

In their trial of 16 patients, 7 developed sCRS and 9 had mild or no CRS.

Further studies are now planned, which will explore this modified T-cell infusion in earlier stages of B-ALL and also in other cancer types.

This research was supported by grants from the National Cancer Institute and a number of American cancer foundations. Dr. Sadelain and a coauthor, Renier Brentjens, MD, PhD, from MSKCC, are coholders of a patent that covers the technology used to create the modified T-cells in this study, which has been licensed to Juno Therapeutics.

Sci Transl Med. 2014;6:224ra25. Abstract