San Diego—In hematologic malignancies, chimeric antigen receptor (CAR)-modified T cells will be increasingly combined with other therapeutic strategies, according to multiple studies presented at the 2018 annual meeting of the American Society of Hematology (ASH).
Of many studies at ASH suggesting benefit from combination treatment, one tested pretreatment with a targeted therapy, another evaluated the effect of boosting CAR T-cell response with a checkpoint inhibitor, and a third tested the effectiveness of hematopoietic cell transplant (HCT) as a consolidation therapy.
The study evaluating pretreatment with a targeted therapy was conducted in patients with chronic lymphocytic leukemia (CLL). In a previous study by the same group, the absence of an IGH (immunoglobulin heavy chain) clone after CAR T-cell therapy was associated with 100% progression-free survival over a median 6.6 months of follow-up. However, the IGH malignant clone was eliminated in less than 60% of those who received CAR T-cell therapy.
In a new study presented at ASH, pretreatment with the BTK inhibitor ibrutinib (Imbruvica, Pharmacyclics) was associated with a deeper response (abstract 299). The investigators compared two cohorts of patients with relapsed/refractory CLL in the phase 1/2 study. In a 16-patient cohort, ibrutinib was initiated at least two weeks before leukapheresis and continued until three months after CAR T cells had been administered. A second cohort of 19 patients did not receive ibrutinib.
The study was based on the theory that ibrutinib pretreatment has the potential to prevent tumor progression, improve CAR T-cell function, and decrease cytokine release syndrome (CRS), according to investigator Jordan Gauthier, MD, from Fred Hutchinson Cancer Research Center’s Clinical Research Division, in Seattle.
Ibrutinib resulted in a deeper response, based on an improvement in the proportion of patients without malignant IGH sequences after CAR T cells were administered (83% vs. 60%). This reduction fell short of statistical significance (P=0.35), but the sample size was small and there were other promising trends, including a higher objective response rate (88% vs. 56%; P=0.06) and a lower rate of grade 3 or higher CRS (0% vs. 26%; P=0.05).
Overall, the findings encourage larger trials with the goal of documenting a clinical benefit in the form of a reduced risk for relapse, according to Dr. Gauthier. He said the strategy of adding ibrutinib to improve CAR T-cell activity was “well tolerated and feasible.”
Adding Checkpoint Inhibitors
As a combination strategy, the rationale for adding checkpoint inhibitors to CAR T cells is to address T-cell exhaustion. The approach was tested specifically in children with B-cell acute lymphoblastic leukemia (ALL) in another ASH presentation (abstract 556).
In a group of 15 children with ALL who had an inadequate response to CAR T cells, 13 received the checkpoint inhibitor pembrolizumab (Keytruda, Merck) and one received nivolumab (Opdivo, Bristol-Myers Squibb) 14 days after CAR T-cell infusion.
The addition of a checkpoint inhibitor resulted in a complete or partial response in all four of the patients who had bulky extramedullary disease and recovery of B-cell aplasia in three of six patients with inadequate B-cell recovery after CAR T-cell therapy alone, reported Amanda Li, MD, from the Division of Oncology at BC Children’s Hospital, in Vancouver, British Columbia.
Among those who did not respond were those with poor initial marrow response to CAR T-cell therapy, but the study provides “initial evidence that checkpoint inhibitors can be used effectively and safely with CAR T-cell therapy in children,” according to Dr. Li. She and her coinvestigators noted that the data also support the hypothesis that checkpoint inhibitors can counteract T-cell exhaustion.
The study of HCT as a consolidation therapy also was conducted in patients with ALL (abstract 967).
In this series of 50 evaluable ALL patients participating in a phase 1 trial of CAR T cells, 33 received HCT, and the investigators found evidence of activity in several subgroups.
Of multiple subgroups evaluated, particular attention was devoted to patients with short-duration B-cell aplasia, which previously was shown to be a predictor of early relapse. All six of those with this history who did not undergo HCT had recurrent disease versus only three of the nine who did undergo HCT, according to Corinne Summers, MD, a pediatric hematologist at Fred Hutchinson Cancer Research Center.
“We demonstrate a trend toward improved leukemia-free survival for subjects without a history of HCT who undergo a consolidative HCT following CD19 CAR T-cell therapy,” Dr. Summers reported. However, she noted that the benefit of a second HCT after CAR T-cell therapy is not clear.
Overall, it appears that HCT leads to a deeper response. According to Dr. Summers, late relapses after CAR T-cell therapy “have so far only occurred in those without consolidative HCT.” However, longer follow-up is needed to confirm that patients with a prolonged response after HCT are protected from disease recurrence.
Data Are Encouraging
It is too soon to know which of the combinations involving CAR T cells will emerge as a standard of care, according to Angela Duenn, PharmD, from the Department of Pharmacy Services at Karmanos Cancer Institute, in Detroit, but she said she is encouraged. “CAR T cells have changed the landscape of hematologic malignancies,” emphasized Dr. Duenn, citing significant responses in patients with advanced disease and few therapy alternatives. “I am interested in toxicities that may develop as survival is extended,” but this is information that will only emerge from more experience and more patients, and, at this point, “only time will tell what is to come ahead.”