1. Fuerst, Mark L.

Article Content

SAN DIEGO-The first-in-human anti-CD22 chimeric antigen receptor (CAR) T-cell therapy is safe, feasible, and clinically active in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL) who have undergone prior CAR T-cell therapy, according to a presentation at the American Society of Hematology annual meeting (Abstract 650).

acute lymphoblastic ... - Click to enlarge in new windowacute lymphoblastic leukemia. acute lymphoblastic leukemia

The study gives a first glimpse into how patients who already received CAR-T therapy directed at a CD19 might fare when given a second immunotherapy.


Despite the success of anti-CD19 CAR therapy for relapsed/refractory ALL, "the loss of CD19 expression in a substantial number of patients may limit therapeutic benefit," said study co-author Terry J. Fry, MD, of the Center for Cancer Research, NCI, Bethesda, Md., at a press briefing.


To overcome this problem and test an alternative target, NCI researchers developed an anti-CD22 CAR. "CD22, a B-lineage leukemia restricted antigen, is a well-defined, promising target for immunotherapy based approaches," said Fry.


CD22 Studies

Fry and colleagues designed a phase I dose escalation study to determine the feasibility of producing anti-CD22 CAR cells and assess the safety of administering escalating doses of anti-CD22 CAR T-cells in children and young adults with relapsed or refractory CD22+ B-cell malignancies. Secondary objectives included determination of anti-leukemia effects, measurement of persistence of anti-CD22 CAR T cells, and evaluation of cytokine profiles.


He reported the interim results based on the first 16 enrolled patients, median age 19.5 years, with relapsed/refractory CD22+ ALL. All patients have previously undergone allogeneic hematopoietic stem cell transplant, and most of them had a high burden of disease, explained Fry.


All patients underwent autologous leukopheresis for peripheral blood mononuclear cells. Cells were then CD3+ enriched and cultured in the presence of anti-CD3/-CD28 beads followed by lentiviral vector supernatant containing the anti-CD22 CAR, with culture duration of 7-10 days.


The patients began lymphodepleting chemotherapy with fludarabine 25 mg/m2 on Days -4, -3, and -2 and cyclophosphamide 900 mg/m2 on day -2 followed by cell infusion on Day 0. Dose level 1 started at 3 x 105 transduced CAR T cells per kg, Dose Level 2 at 1 x 106 transduced CAR T cells per kg, and Dose Level 3 of 3 x 106 CAR T cells per kg.


Eleven patients had previously received treatment with anti-CD19 CAR T-cell therapy; nine of these 11 patients had a CD19 negative/dim antigen escape.


Dose escalation occurred in six patients treated at Dose Level 1 due to expansion; dose-limiting toxicity (DLT) was grade 3 diarrhea; three patients treated at Dose Level 2 without DLT; and two patients at Dose Level 3 with grade 4 hypoxia the DLT.


"An 80 percent complete remission rate was observed at Dose Level 2 or higher in patients with a maximum grade 2 cytokine release syndrome," said Fry. "A high remission rate was seen after they achieved a biologically active dose."


Response was associated with dose level. Anti-CD22 CAR cells were detected in the peripheral blood, cerebrospinal fluid, and bone marrow of all responders. More than half of the responding patients had failed CD19 CAR T-cell therapy, he noted. "Eight out of 10 patients in the top two dose levels were responders," said Fry.


Three patients show ongoing, sustained remissions at 3 months, 6 months, and 12 months. "We have been able to show that you can give a second CAR therapy that is directed against a different antigen and have it be safe and effective," said Fry.


Five patients relapsed, one patient with CAR cells loss at Dose Level 1, and four patients with changes in CD22 expression. Those changes in CD22 expression were due to decrease in site density in three patients and antigen loss in one patient.


Successful CAR Therapy

"This is the first successful salvage CAR therapy for CD19 negative, B-cell ALL," Fry explained. "The preliminary experience suggests comparable potency to anti-CD19 CAR therapy. We saw no severe or irreversible neurotoxicity. Relapses were associated with changes in CD22 expression level."


He noted minimal residual disease-negative complete remissions were seen in patients who were both CAR T-cell naive or had previously been treated with anti-CD19 CAR T cells and were CD19 negative.


Opportunities exist for bi-specific or multi-specific CAR targeting. "We are beginning to think about how to include CD22 T cells along with upfront CD19 T cells as treatment," said Fry. "We envision infusing both CAR T cells together on the same construct."


While the trial is continuing to accrue patients, these early results raise new questions about how anti-CD22 CAR T-cell therapy might best be used, that is, is it better to wait for relapse after initial CAR T-cell therapy or preempt it by co-treating it? Fry and colleagues plan to investigate the combined use of anti-CD19 and CD22 CAR T-cell targeting approaches with the hypothesis that this will increase the likelihood of sustained remission.


Mark L. Fuerst is a contributing writer.