CAR-Targeting CD22 an Effective Salvage Therapy in Relapsed Pediatric Acute Lymphoblastic Leukemia
San Diego, CA—Chimeric antigen receptor (CAR)-targeting CD22 therapy induced clinical responses and a high rate of complete remission in children and young adults with relapsed or refractory acute lymphoblastic leukemia (ALL), including patients who had received anti-CD19 CAR T-cell therapy, said Terry J. Fry, MD, Hematologic Malignancies Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute (NCI), at the 2016 American Society of Hematology meeting. These findings create the opportunity for bispecific or multispecific CAR T-cell targeting.
Anti-CD19 CAR T-cell therapy is very effective in precursor B-cell ALL, but a limitation of this treatment approach is the loss of CD19 expression in a substantial number of patients, according to Dr Fry.
“CD22 is a well-defined alternative target in B-cell ALL, and there are existing monoclonal antibody toxin conjugates that have shown efficacy in B-cell ALL, so based on this, a number of years ago within the NCI, we developed a CD22 targeted chimeric antigen receptor,” he said. The anti-CD22 CAR T-cell therapy was introduced in a phase 1 dose-escalation clinical trial, the results of which Dr Fry reported during the meeting.
In this clinical trial, 16 patients received anti-CD22 CAR T-cell therapy. All patients received a preparative regimen that included fludarabine 25 mg/m2 daily for 3 days and cyclophosphamide 900 mg/m2 daily for 1 day. All patients had undergone allogeneic hematopoietic stem-cell transplantation, 11 patients received anti-CD19 CAR T-cell therapy, and 9 patients were CD19-negative.
There were no dose-limiting toxicities at dose level 2 (ie, 1 × 106 transduced CAR T-cells/kg). One patient who received dose level 3 anti-CD22 CAR T-cell therapy (ie, 3 × 106 transduced CAR T-cells/kg) had grade 4 hypoxia that rapidly reversed with the use of steroid treatment. One patient had grade 5 multiorgan failure that occurred after the resolution of cytokine release syndrome.
Response was associated with the CAR T-cell therapy dose level. Compared with the doses used by current anti-CD19 CAR T-cell programs, 8 of the 10 patients who received anti-CD22 CAR T-cell therapy dose levels 2 or 3 achieved complete remission, with maximum grade 2 cytokine release syndrome. Of these 8 patients, 3 had ongoing remission at follow-up—1 for more than 1 year, 1 at 6 months, and 1 at 3 months. Of the 9 patients who achieved remission at dose levels 1, 2, and 3, 6 had disease relapse, the majority of which was attributed to reductions in CD22 antigen expression levels. Only 1 of 6 patients who were treated at dose level 1 attained complete remission.
These preliminary results suggest that the potency of anti-CD22 CAR T-cell therapy is at least comparable to the phase 1 experience with anti-CD19 CAR T-cell therapy at the same dose level, said Dr Fry. No severe or irreversible neurotoxicity occurred with anti—CD22 CAR T-cell therapy.
“This is the first successful salvage CAR T-cell therapy for CD19-negative B-cell ALL,” said Dr Fry. “Our bias is that this may not be best used as a salvage therapy, but we’re beginning to think how this could potentially be included with CD19 in the upfront CAR T-cell treatment,” he added.
One possibility is to introduce a gene construct that has a CD22 CAR and a CD19 CAR, with a cleavable link in between, and transduce the cells to obtain a one-to-one expression of both CARs on the surface of the T-cell, he said.