The revolutionary chimeric antigen receptor (CAR) T-cell therapies that gained approval from the U.S. Food and Drug Administration in 2017 both target CD19; the success in targeting that antigen has prompted investigators to look for new targets.
Results from a small, phase I, dose-escalation trial published in Nature Medicine suggest that targeting CD22 led to clinical activity against B-cell acute lymphocytic leukemia (B-ALL), including leukemia that was resistant to anti-CD19 immunotherapy. Though the relapse rate with this therapy was high, “this study gives hope to the idea that there may be another similar, very potent treatment,” commented Crystal Mackall, MD, director of the Parker Institute for Cancer Immunotherapy at Stanford University and corresponding author of the study. “This is the first time that we’ve seen response rates anything like we achieved when we were first testing the CD19 CAR T-cell therapy.”
Terry J. Fry, MD, of the Pediatric Oncology Branch at the Center for Cancer Research at the National Institutes of Health’s National Cancer Institute, and co-authors evaluated the safety and potential efficacy of anti-CD22 CAR T-cell therapy in 21 pediatric and adult patients (median age = 19 years; range = 7-30 years) with relapsed or refractory B-ALL. All patients had undergone at least one prior hematopoietic cell transplantation (HCT), and two had received two prior HCTs. Most patients (n=17) had previously been treated with CD19-directed immunotherapy, including 15 patients who had received CD19-targeted CAR T-cell therapy.
Patients received one of three anti-CD22 CAR T-cell doses: 3×105 cells/kg (n=6), 1×106 cells/kg (n=7), and 3×106 cells/kg (n=8).
Sixteen patients experienced cytokine release syndrome (CRS; grade 1 in 9 patients and grade 2 in 7 patients), a common adverse event (AE) associated with CAR T-cell therapy. CRS coincided with CAR T-cell expansion and occurred after day five of treatment, the researchers noted. A dose-limiting toxicity (DLT; grade 3, self-limited, non-infectious diarrhea during CRS) occurred in one patient at the first dose level (3×105), which required a protocol-specific expansion of the first dose level to six patients. No other DLTs were observed in patients at the first or second dose level (1×106).
Two patients receiving dose level three (3×106) developed dose-limiting grade 4 hypoxia that was associated with rapid disease progression. Therefore, the researchers selected 1×106 anti-CD22 CAR T cells/kg as the recommended phase II dose; this dosing cohort was expanded to include 13 total patients.
In the first 16 patients with available, complete assessments, transient visual hallucinations (n=2), mild unresponsiveness (n=1), mild disorientation (n=1), and mild to moderate pain (n=2) were observed but returned to baseline levels by day 28 post-infusion. All patients who achieved remission reported B-cell aplasia, including those who were not previously B-cell aplastic.
Twelve of 21 patients (57%) achieved complete remission (CR), mostly patients at the 1×106 dose level (n=11; p<0.001). “The data provided no evidence to suggest that previous chemotherapy or CD19-based immunotherapy diminishes the likelihood of remission induction following administration of bioactive doses of CD22 CAR T cells,” the authors reported, with nine of 10 anti-CD19 CAR T-cell–treated patients experiencing CR.
The researchers detected anti-CD22 CAR T cells in the peripheral blood of 19 treated patients, which peaked by day 14 after infusion. The median peak expansion was 62 percent of circulating T cells expressing CD22 CAR (range = 1-91%), and the median number of circulating CAR T cells was 316 cells/µL (range = 1-3,593 cells/µL).
By day 28, CAR T cells remained detectable in the peripheral blood in 15 of 21 patients (72%), in the bone marrow in 15 of 19 patients (79%), and in the cerebrospinal fluid in 12 of 17 patients (71%). CAR T cells remained detectable in the blood of seven of nine patients evaluable at three months post-infusion, in two of three patients at six months, in one patient evaluable at nine months, and in one patient evaluable at 18 months.
Remission lasted for a median of six months (range not provided), with eight patients relapsing at 1.5 to 12 months after infusion. Most of those who relapsed had leukemia cells that had diminished CD22 surface expression (n=7). The researchers also found that 10 of the 15 patients previously treated with CD19-targeted CAR T-cell therapy no longer expressed any CD19, suggesting that antigen loss limits treatment efficacy.
“These results are the first to establish that CAR T cells targeting antigens other than CD19 can mediate similarly potent antineoplastic effects,” the authors concluded. The findings also “demonstrate that resistance to immunotherapy via antigen loss can be overcome by treatment with CAR T cells targeting an alternative antigen, opening the way for dual-targeted immunotherapeutics.”
This phase I study is limited by its small patient population. “Future studies are needed to determine whether the high response rates observed with CD22 CARs in B-ALL will translate into similarly sizeable response rates in diffuse large B-cell lymphoma, in which CD22 expression is common,” the authors noted.
Two of the authors are inventors on a patent for the CD22-directed CAR T-cell therapy.
- Fry TJ, Shah NN, Orentas RJ, et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med. 2017 November 20. [Epub ahead of print]
- Stanford Medicine press release, November 20, 2017.