SAN DIEGO – When one CAR stops one working, try another: chimeric antigen receptor (CAR) T-cell therapy for children and young adults with acute lymphoblastic leukemia is driving forward with a novel anti-CD22 target that in an early dose-finding trial has induced complete remissions in some patients with relapsed or refractory disease, including patients previously treated with anti-CD19 CAR-T therapy.
In the first-in-humans trial, CAR T-cell therapy directed against CD22 was shown to be safe and was associated with minimal residual disease (MRD)-negative complete remissions in eight of 10 children and young adults with relapsed/refractory B-precursor acute lymphoblastic leukemia treated at the highest dose level.
Dr. Terry J. Fry
“This is the first successful salvage CAR therapy for CD19-negative B-[lineage] ALL,” said co-principal investigator Terry J. Fry, MD, from the Center for Cancer Research at the National Cancer Institute in Bethesda, Md.
Preliminary experience with anti-CD22 immunotherapy suggests that it is comparable in potency to anti-CD19 CAR, and investigators are exploring the possibility that the two chimeric antigen targets could be combined for greater efficacy, he said during a briefing at the annual meeting of the American Society of Hematology.
Tough target
As reported previously from the 2013 ASH annual meeting, anti-CD19 CAR T cells induced complete responses in 10 of 16 children and young adults with relapsed/refractory ALL, and in a second study, CD19-targeted T cells induced complete molecular responses in 12 of 16 adults with B-lineage ALL refractory to chemotherapy.
In current phase 2 trials, anti-CD19 CAR-T therapy is associated with complete remission rates of 80% to 90% of those treated.
However, “we’re learning now that one of the limitations of this approach is the loss of CD19 expression occurring in a substantial number of patients, although it has not been systematically analyzed,” Dr. Fry said.
CD22, an antigen restricted to B-lineage cells, is a promising alternative to CD19 as a target, but finding just the right anti-CD22 CAR was tricky, Dr. Fry said in an interview. The investigators found that many candidate antigens bound well to T cells but had no efficacy, and it took several years of trying before they identified the current version of the antigen
In the phase I trial, the investigators enrolled 16 children and young adults (ages 7 to 22 years) with relapsed/refractory CD22-positive hematologic malignancies. All patients had previously undergone at least one allogeneic stem cell transplant, 11 had previously received anti-CD19 CAR-T cell therapy, and 9 were CD19-negative or had reduced CD19 expression on ALL cells.
The patients underwent peripheral blood mononuclear cells (PBMCs) collected through autologous leukapheresis. The cells were then enriched and expanded, and transduced with a lentiviral vector containing an anti-CD22 CAR for 7 to 10 days, allowing the cells to identify and bind to CD22 expressed on ALL blasts.
The patients then underwent lymphodepletion with fludarabine, and cyclophosphamide, and received infusions of the transduced T-cells at one of three dose levels, starting at 3 x 105 transduced T-cells per recipient weight in kilograms (DL-1), 1 x 106/kg (DL-2), and 3 x 106/kg (DL-3).
The complete remission rate at DL-2 and -3 combined was 80%, with the cytokine-release syndrome (CRS) at a maximum of grade 2.
As noted before, three of the remissions were comparatively durable, with one lasting more than a year.
There were no dose-limiting toxicities at DL-2, and grade 4 hypoxia at DL-3 was seen in one patient.There was one death from sepsis and multi-organ failure in one patient in an expansion cohort. There have been no cases of severe neurotoxicity thus far.
In five patients who experienced relapse, one treated at DL-1 had a loss of CAR cells, and four had changes in CD22 expression, primarily a decrease in site density that may cause the CD22 expression to fall below the threshold for CAR activity, Dr. Fry said.
“At least in our eyes, this may not be best used as a salvage therapy, but we’re beginning to think about how this should be included with CD19 in the upfront CAR treatment,” he said.
The study was funded by the National Institutes of Health with support from Lentigen and Juno Therapeutics. Dr. Fry reported no relevant disclosures.