Kate Johnson

June 14, 2016

CHICAGO — Chimeric antigen receptor (CAR) T-cell therapies are causing a stir in leukemia and lymphoma circles, with impressive response rates and sustained remission in patients with advanced, chemorefractive disease.

With more than 20 American trials looking at the anti-CD19 CAR T-cell space, treatment toxicity is emerging as a major focus.

"There is no gain without pain, and the 'cytokine release syndrome' [CRS] does remain a problem, although multiple groups are looking at ways of preventing it," noted Catherine Bollard, MD, director of the program for emerging technologies in immune cell therapies at the Children's Research Institute in Washington, DC.

Dr Bollard acted as discussant for a series of three studies on CAR-CD19 T-cell therapy presented here at the American Society of Clinical Oncology 2016 Annual Meeting.

However, "there's definitely been a lot of progress even over the last year to try to balance efficacy and toxicity," she told Medscape Medical News.

Marked by high fevers, myalgia, and in some cases neurologic toxicity, CRS does appear to be "a testament to the potency of this therapy," said David L. Porter, MD, from the lymphoma program at the Abramson Cancer Center, University of Pennsylvania, in Philadelphia.

Indeed, while groups grapple with trying to identify patient and disease risk factors for the development of severe CRS, there is emerging evidence that it does seem to be linked to better response.

"Certainly, if you have bulky disease, it seems you will only respond if you have CRS, but having said that, the intensity of the CRS can be better managed and better controlled," said Dr Bollard. "And CRS doesn't tend to happen in patients with minimal residual disease, yet we heard a series today in which patients had a 100% rate of complete response."

Tinkering with various aspects of the complicated CAR-T cell regimen has offered various insights into ways to reduce or at least predict CRS.

In one study presented during the session, James Kochenderfer, MD, from the Experimental Transplantation and Immunology Branch of the National Cancer Institute, showed that lightening up on pretreatment conditioning chemotherapy can cut toxicity without sacrificing efficacy.

In a trial of 22 patients with advanced lymphoma, conditioning chemotherapy was given for 3 days (fludarabine 30 mg/m² and cyclophosphamide 300 to 500 mg/m² daily) before infusion of anti-CD19-CAR T-cells, with an overall response rate of 73% (complete response, 55%; partial response, 18%).

Compared with Dr Kochenderfer's previous experience with 100% toxicity, in this trial, 55% of patients had grade 3 or 4 neurologic toxicity, including confusion, dysphasia, encephalopathy, and gait disturbances — all of which resolved, usually in less than 2 weeks, he said.

Additionally, 18% had grade 3 or 4 hypotension, "which is in contrast to a lot of CAR T-cell trials in which acute lymphoblastic leukemia is treated, when symptoms such as hypotension, fever, and various other signs of what I would call the classic cytokine release syndrome are the most troublesome toxicities," he noted. "In our experience, it is actually the neurologic toxicities that are the most troublesome when we're treating lymphoma patients."

"Anti-CD19 CAR T-cells will probably become an important part of lymphoma therapy in the near future, " he predicted.

Playing with the T-cell dose was another idea from Dr Porter, which did not reduce toxicity as expected, but did offer insight into how to refine the therapy.

In a trial of relapsed refractory chronic lymphocytic leukemia, 24 patients were randomized to either high- or low-dose T-cells with no difference between groups in the development of CRS.

"We have not identified a dose–toxicity relationship, and I think that was somewhat anticipated," he said. "Since these cells can expand in vivo at very high levels, I think it has more to do with how many cells the patients end up with, rather than how many we infuse," he explained.

The higher dose was more efficacious, however, with 54% of high-dose patients responding to treatment, compared with 31% of low-dose patients.

On the basis of the findings, six more patients were enrolled in the high-dose group, which now has a complete response rate of 35% and a partial response rate of 18%.

Both Dr Porter and Shannon L. Maude, MD, PhD, from the Children's Hospital of Philadelphia, have had success managing CRS with the interleukin-6 receptor antagonist tocilizumab, which can rapidly reverse severe symptoms.

"We have also seen neurotoxicity similar to what others have reported. This ranges from confusion and delirium to frank encephalopathy and in some cases seizures," said Dr Maude, adding that most symptoms can resolve untreated, but seizures are managed with antiepileptics.

Researchers at her institution have developed a CRS prediction model based on cytokines measured in the 3 days prior to the development of severe CRS (Cancer Discov. 2016;6:664-679).

Updating her results with CAR-CD19 T-cell therapy, Dr Maude reported sustained remissions in 60 pediatric patients with acute lymphoblastic leukemia (median age, 11 years).

The 12- and 24-month relapse-free survival rates are 60% and 53%, respectively, with 24 patients in continuous remission for 1 year or more, 19 without further therapy, she said. Seven patients proceeded to stem cell therapy, and one to donor lymphocyte infusion, with two relapses. Overall survival in this cohort is 79% at 12 months and 61% at 24 months, she said.

"There's definitely been a lot of progress, even over the past year, to try to balance efficacy and toxicity," said Dr Bollard.

"If we do achieve long-term persistence and control toxicities in some settings, I think we can see a replacement for stem cell transplant for these patients with this therapy, and there is the absolute potential to combine this approach with other immunomodulatory therapies," she added.

"With the phase 1 data completed, we are now conducting larger trials, and partnership with industry has really broadened the applicability of this approach," she explained. "There are still issues other than cytokine release syndrome, such as what to do with patients with CD19-negative disease. Do we use this therapy upfront or only in the relapse setting? We still don't truly understand what makes CAR successful in terms of efficacy — whether it's the type of conditioning, whether it's the type of CAR, whether it's the viral vector, whether it's the type of cell that you're transfusing. All of those are variables that still need to be worked out," she said.

Dr Bollard and Dr Maude have disclosed no relevant financial relationships. Dr Porter reports relationships with Genentech, Roche, Novartis, Ocata Therapeutics, and Immunovative Therapies. Dr Kochenderfer reports relationships with Bluebird Bio (Inst), and Kite Pharma (Inst).

American Society of Clinical Oncology (ASCO) 2016 Annual Meeting: Abstracts LBA3010, 3009, and 3011. Presented June 6, 2016.


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