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Dec 08 2015

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Latest Findings Add Insight Into Targeted Cancer Immunotherapy

cancerResearchers at The Children’s Hospital of Philadelphia reported their latest results from their studies of an investigational personalized cell therapy for a highly aggressive form of acute lymphoblastic leukemia (ALL). Developed by researchers at the University of Pennsylvania and CHOP, the therapy is made from patients’ own immune T cells, which are extracted and bioengineered into CTL019 cells that potentially seek and destroy leukemia cells.

Among the findings, the team reported that 93 percent of pediatric patients reached remission after receiving the therapy for relapsed/refractory ALL. ALL is the most common childhood cancer, with limited effective treatment options for the approximately 10 to15 percent of patients who relapse after standard therapies.

The research team presented these results and more at the American Society of Hematology (ASH) annual meeting in Orlando. They reflect the CHOP-Penn team’s continued process of discovery about the investigational therapy, which is now part of clinical trials active at 15 sites globally, including CHOP.

Reporting Long-Term Remissions After CTL019

In a presentation by study leader Stephan A. Grupp, MD, PhD, a pediatric oncologist at CHOP and professor of Pediatrics at the Perelman School of Medicine at Penn, the team reported that among the first 59 children with relapsed/refractory ALL treated in their clinical trial, 55 patients (93 percent) experienced complete remission, with a one-year overall survival rate of 79 percent. They reported that 18 patients had continuous remissions for more than one year, and nine patients for more than two years. Relapse-free survival at one year was 55 percent.

“The patients who participated in these trials had relapsed as many as four times, including many whose cancers came back even after stem cell transplants,” Dr. Grupp said. “The durable responses we have observed with CTL019 therapy are unprecedented.”

Most (88 percent) of the patients experienced cytokine release syndrome (CRS), a condition which may include fever and muscle pain in milder forms, to hallucinations, delirium, and life-threatening complications in more severe cases. All patients in the trial who experienced CRS recovered from it.

Predicting a Common Side Effect of CTL019

In the largest and most comprehensive profiling of the clinical and laboratory manifestations of CRS in patients receiving the investigational therapy, the CHOP and Penn research teams described multiple patterns of cytokine activation, several of which they reported to have predictive value for later development of CRS or severe CRS. Their study included clinical, laboratory, and biomarker data of 39 children and 12 adults with relapsed/refractory ALL treated in CTL019 trials.

“These represent the first data that can accurately predict which patients treated with this therapy have a high probability of becoming critically ill,” said study leader David T. Teachey, MD, a pediatric hematologist/oncologist at CHOP and assistant professor of Pediatrics at Penn. “These data are directly relevant to efforts to improve the safety of this therapy.”

CTL019 for CNS Relapse

Not all leukemia relapses are the same; some children experience an ALL relapse involving the central nervous system (CNS). Susan R. Rheingold, MD, an associate professor of Pediatrics at Penn, reported on the safety and efficacy of CTL019 for the subgroup of children in the trial with a prior CNS relapse of ALL.

Of 53 pediatric patients in the CTL019 clinical trial, 12 patients had leukemia involving the CNS in the year preceding their CTL019 treatment. All achieved complete remission in the bone marrow and CNS, and eight of these 12 patients (67 percent) remained in remission at a median of eight months past their infusion. Four of the 12 patients relapsed with cancer cells in their bone marrow but not detectable in the CNS.

The team reported that none of the 53 patients in the trial had a subsequent CNS relapse after receiving CTL019 therapy. The CTL019 cells also appeared to reach the cerebrospinal fluid (CSF) in almost all patients; evidence of the bioengineered cells was present in 46 of 47 patients whose CSF was evaluated.

Encephalopathy, a known side effect of CTL019, occurred in three of 12 patients with prior CNS relapse (25 percent), a similar rate to that among patients without CNS relapse (12 of 41, or 29 percent).

Due to this preliminary data, the team has established a clinical trial cohort for patients with CNS-relapsed ALL to further test the safety and efficacy of CTL019 in this group.

“We were excited to see such potent and durable responses to CTL019 immunotherapy in patients with CNS involvement in their leukemia,” Dr. Rheingold said. “In addition, the unexpected trafficking and persistence of bioengineered cells into CSF raises the possibility that in the future this type of cell therapy could be used for other types of cancers affecting the CNS.”

Seeking Methods to Address Relapse After CTL019

To improve upon the high long-term remission rates after CTL019, the research team is investigating treatment variations for patients whose CTL019 cells show limited lasting potential as well as patients who relapse.

Shannon L. Maude, MD, PhD, a pediatric oncologist at CHOP and assistant professor of Pediatrics at Penn, reported that repeat infusion of CTL019 cells may prolong response to therapy in some of these patients. Among 15 patients receiving the repeat infusion, responses varied across subgroups based on the indication for reinfusion. Six out of seven patients whose CTL019 cells had become undetectable did not see their B cells return, suggesting continued function of CTL019 (which is intended to destroy those B cells with the protein CD19 on their surface), for up to 18 months after the reinfusion.

Responses to reinfusion were lower in patients whose B cells had returned within six months of receiving CTL019 (three of six later relapsed), and in patients with low-level residual CD19+ leukemia after receiving CTL019 (two of two later relapsed). Patients receiving repeat infusion showed minimal toxicities, including fever and fatigue.

Study leader Dr. Maude further reported on early results of a Phase 1 clinical trial testing safety of another version of the bioengineered cells the team anticipates may reduce the risk of treatment failures. The new cells, designated CTL119, use a “humanized” version of CTL019.

The team developed CTL119 cells on the hypothesis that some patients’ relapses may be caused by their immune systems rejecting certain mouse-derived portions of proteins on CTL019 cells. Three of six children receiving the investigational humanized CTL119 cells (after relapsing following prior cellular immunotherapy) showed response to the CTL119. Only the three responding patients experienced CRS, but none was severe.

“These early results suggest that immune-mediated rejection may be an important mechanism of resistance in the subset of patients who rapidly lose the bioengineered cells after infusion,” Dr. Maude said. “More research into these rejection mechanisms will be vital to improve durable remission rates in patients prone to this form of relapse.”

Permanent link to this article: http://blog.research.chop.edu/latest-findings-add-insight-into-targeted-cancer-immunotherapy/