This article is more than 5 years old. Information may no longer be current.
Anti–CD22 CAR T-cell therapy induces responses in relapsed, refractory ALL
Click Here to Manage Email Alerts
SAN DIEGO — Anti–CD22 chimeric antigen receptor T-cell therapy appeared active and safe for children and young adults with relapsed or refractory acute lymphoblastic leukemia, according to interim results of a first-in-human study presented at the ASH Annual Meeting and Exposition.
Researchers reported an 80% complete remission rate among patients treated at the two highest dose levels. Those responses occurred in patients who were naive to chimeric antigen receptor (CAR) therapy, as well as those who underwent prior treatment with anti–CD19 CAR therapy and achieved CD19–negative status.
“This is the first successful salvage CAR therapy for CD19–negative B-ALL, and our preliminary experience suggests a potency that is at least comparable to the phase 1 experience with CD19 at the same dose level,” Terry J. Fry, MD, head of the hematologic malignancies section of the pediatric oncology branch at NCI’s Center for Cancer Research, said during a press conference.
Anti–CD19 CAR therapy has been highly effective for patients with relapsed or refractory ALL, inducing complete remission rates between 80% and 90% in clinical trials. However, some patients do not respond. Also, loss of CD19 expression occurs in a substantial number of patients, potentially limiting the therapeutic benefit.
CD22 — widely expressed on B-lineage leukemia and lymphomas — is a well-defined alternative target in B-ALL, Fry said.
Fry and colleagues developed an anti–CD22 CAR, and then evaluated the safety of administering escalating doses of these cells to children and young adults with relapsed or refractory CD22–positive B-cell malignancies.
The regimen’s antileukemia effects, a measurement of persistence of anti–CD22 CAR T cells and an evaluation of cytokine profiles served as secondary objectives.
Study participants underwent lymphodepleting chemotherapy on days –4, –3 and –2. The regimen consisted of three doses of fludarabine 25 mg/m2 and one dose of cyclophosphamide 900 mg/m2.
Cell infusion began on day 0. Researchers established three dose levels: 3 x 105 transduced T cells/kg (n = 6), 1 x 106 transduced T cells/kg (n = 9), and 3 x 106 transduced T cells/kg (n = 2).
Fry presented results from 16 patients (median age, 19.5 years; range, 7-30; male, n = 9), all of whom had relapsed or refractory ALL and had undergone at least one prior allogeneic hematopoietic stem cell transplant.
Eleven of these patients had undergone prior treatment with anti–CD19 CAR T-cell therapy and five had undergone treatment with blinatumomab (Blincyto, Amgen), a bispecific T-cell engaging antibody construct that links CD3–positive T cells with CD19–positive B cells. At the conclusion of these prior treatments, nine patients either were CD19 negative or had reduced CD19 expression.
Results of the anti–CD22 CAR therapy analysis showed one of six patients treated at the lowest dose attained remission. Eight of 10 participants treated at one of the higher dose levels — comparable to those used by CD19 CAR T-cell programs — achieved complete remission with no evidence of residual disease at 1 month after infusion.
Six of nine patients who achieved remission later relapsed, primarily due to declines in CD22 expression on the cells. At the time of reporting, three patients remained in remission, including one who had been in remission for more than 1 year.
Thirteen patients experienced cytokine release syndrome; however, all cases were mild and none exceeded grade 2. Fever and low blood pressure also were common. One patient died of sepsis that occurred after resolution of cytokine release syndrome.
Trial accrual is ongoing.
The results raise the question about whether anti–CD22 therapy is best used after relapse of initial CAR therapy, or if combined use of anti–CD19 and anti–CD22 CAR targeting approaches could be more effective.
“This may not be best used as a salvage therapy,” Fry said. “We are beginning to think about how this could potentially be included with CD19 in upfront CAR treatment.” – by Mark Leiser
Reference: Shah NN, et al. Abstract 650. Presented at: ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.
Disclosure: The NCI funded this study. Fry reports no relevant financial disclosures. Other researchers report honoraria from and patents/royalties with Juno; equity ownership in Unum Therapeutics; and board/advisory committee roles with Adaptimmune, GlaxoSmithKline, Pfizer-Servier, Roche, Unum Therapeutics and Vor Pharmaceuticals.
Perspective
Back to Top
Frederick Locke, MD
There is tremendous excitement surrounding anti-CD19 chimeric antigen receptors (CARs) for B-cell malignancies, with 50% to 80% of patients with relapsed/refractory acute lymphoblastic leukemia achieving complete remission following this therapy. Unfortunately, patients may relapse with decreased CD19 expression or loss of the CAR binding epitope via exon switching. CAR T cells targeting alternate, non-CD19, B-cell surface antigens could be utilized in conjunction or sequence to increase outcomes for these patients. CD22 is one such target expressed on the surface B cells.
Shah and colleagues conducted a cell dose–finding phase 1 clinical trial utilizing an anti-CD22 CAR for relapsed/refractory ALL pediatric and young adult patients. Median age was 19.5 years (range 7-30). Two thirds of the patients had received prior anti-CD19 CAR therapy and one third received prior anti-CD19 directed bispecific antibody therapy. These patients had active ALL disease with a large majority having heavy marrow burden and/or extramedullary disease. All patients had received a prior allogeneic transplant.
The toxicity profile in this limited set appears consistent with that seen anti-CD19 CARs. A total of 16 patients were treated on the study, which was designed to test safety and feasibility of the CARs at different cell dose levels. Following dose escalation and de-escalation a dose of 1 million anti-CD22 CARs per kg was selected and explored with an expanded cohort of patients. One patient died of treatment related multi-organ dysfunction in the setting of sepsis, although cytokine release syndrome (CRS) was relatively mild, with no grade 3 to grade 4 CRS per Lee criteria reported. The underlying pathophysiology of neurological toxicities observed on anti-CD19 CAR trials remains a mystery, so it is difficult to speculate if this anti-CD22 CAR would be expected to have the same degree of neurologic toxicities. In this study, no severe or irreversible neurologic toxicity was reported.
Nine of the 16 patients were able to achieve complete remission, which was most frequent in patients treated with at least 1 million anti-CD22 CARs per kg. Importantly, over 50% of the 16 patients treated on the trial were CD19 negative or dim, and five of these patients achieved a complete remission, demonstrating the first successful salvage CAR therapy for CD19-negative ALL patients.
Five patients relapsed after achievement of complete remission, one with CAR cell loss and the other four with a decreased expression in CD22. Extensive evaluation of the nature of CD22 down regulation, including testing with alternate antibodies, should be done to evaluate whether mechanisms of CD22 loss are similar to that seen with CD19 epitope loss.
These results are very exciting; however, targeting multiple antigens is several steps into the future, so we must consider the study in the context of the current landscape. First, these were young patients likely to have increased toxicity tolerability compared with older adults preventing extrapolation of safety data onto an older population. Second, all patients treated received a prior allogeneic hematopoietic stem cell transplant. Evidence suggests that graft-versus-host disease precipitated by CAR therapy in such patients is unlikely; however, donor chimerism and sequela of transplant were not reported. Testing of the therapy in non-allogeneic transplant patients should be prioritized in a larger study. Finally, the safety and efficacy for a uniform population of adults with ALL with anti-CD19 CAR T cells remains unclear, with several deaths due to cerebral edema being reported in non-peer reviewed forums. Results from pivotal studies testing anti-CD19 CARs for ALL and other B-cell malignancies must be reported and analyzed before the therapies are FDA approved.
Current timelines suggest approval for some indications could occur in 2017. As CAR T-cell therapies are rolled out to multiple centers, it must be done in a careful and measured manner. Centers with significant hematopoietic stem cell transplant or cellular immunotherapy experience, and those currently conducting CAR T-cell clinical trials, are best poised to manage the logistics of cell collection and administration as well as recognize and treat the unique toxicities. Considering the rapid pace of multicenter anti-CD19 CAR T-cell clinical trials, we likely will not need to wait long before anti-CD22 CAR T cells are similarly tested in larger studies aimed at FDA approval.
Click Here to Manage Email Alerts