A recent study found that CD19/22 CAR T cells were well-tolerated and effective among relapsed/refractory B-cell precursor acute lymphoblastic leukemia (ALL) patients, according to initial findings released at the 2020 AACR Virtual Annual Meeting (Abstract CT051).
The researchers developed a novel bivalent, bispecific CAR targeting both CD19 and CD22. “Our hypothesis was that by simultaneously targeting CD19 and CD22 we could diminish the risk of antigen loss,” noted lead author Haneen Shalabi, DO, Assistant Research Physician at the Pediatric Oncology Branch of the NCI.
This is a phase I dose-escalation study of anti-CD19/CD22 CAR T cells in children and young adults with recurrent or refractory B-cell malignancies. The primary objectives of the trial include safety and toxicity. Secondary objectives are efficacy, CAR expansion, and CAR persistence.
“Our bispecific CAR T cell is a 3+3 dose-escalation design utilizing the NCI construct,” Shalabi explained. “Eligibility criteria included ages 3 through 30 with CD19+/CD22+ ALL or non-Hodgkin lymphoma.”
The researchers manufactured CAR T cells on site utilizing a closed system device and ASTCT consensus guidelines were used for cytokine release syndrome (CRS) grading. The first patient was infused at the NCI in May 2018.
“Our subject demographics reflect a heavily immunotherapy pretreated population,” noted Shalabi, during her presentation. “To date, we have enrolled 15 patients and treated 13 at three different dose levels.”
The median age was 19.6 years old. Fifty-four percent of patients had prior transplants and approximately 70 percent were treated with prior CD19 targeted therapy, including CD19 CAR or blinatumomab. About 40 percent of patients had been treated with CD22 targeted therapy, including inotuzumab or CD22 CAR.
Shalabi reported that the CAR T cells were well-tolerated and toxicities were reversible in all patients with grade 3 CRS occurring in 15 percent of patients.
“Six of 13 patients developed CRS and four of six were grades 1 or 2,” she noted. “Two patients at dose level 2 had grade 3 CRS and received tocilizumab. One patient had neurotoxicity at dose level 3, and she received tocilizumab for CRS, followed by steroids administration for neurotoxicity.”
Of the 12 evaluable patients, five patients had complete responses all seen at dose level 2 or greater, according to Shalabi, who noted that all of these patients had MRD-negative complete remissions. Four of these patients were CAR-naïve.
The researchers observed discrepancies in marrow response versus extramedullary disease. “Six patients with ALL had multifocal extramedullary disease in addition to bone marrow disease,” Shalabi explained.
While CAR T-cell expansion was seen in all responders, Shalabi noted during her presentation that persistence has been limited.
“In the peripheral blood, the median peak percentage of CAR T cells was 7 percent, with the range of zero to 55 percent,” she said. “And in the bone marrow, at Day 28, the median peak was 1.3 percent CAR T cells with a range of zero to 22 percent. CAR persistence has been measured by flow cytometry thus far. In the peripheral blood, we can detect CAR T cells to a median of 45.6 days with a range of 13 to 87 days.”
To date, two of five patients have relapsed with CD19+/CD22+ disease, according to Shalabi.
“Three patients remain in remission at a median of 7 months post-infusion,” she said. “One who underwent a first consolidative transplant shortly thereafter their restaging studies, one who remains in a CR at 7 months without interval therapy, and our last patient who is 6 weeks post-infusion and currently awaiting a second transplant.”
Early experience with this novel bivalent, bispecific CAR demonstrates clinical activity with reversible CRS and limited neurotoxicity, Shalabi concluded.
“We have seen that higher burden disease is associated with higher grade CRS,” she outlined. “Responses were seen in all CAR-naive patients and responses were dose-dependent with increased CAR expansion and high-burden disease.
“Additionally, we have seen discrepant results between marrow and extramedullary disease suggesting potentially limited CAR T-cell trafficking to these sites of extramedullary disease.”
Treatment at higher dose levels may be needed to overcome this limitation as well as close monitoring and longer follow up, Shalabi noted, adding that researchers noticed that utilization of PET scans in monitoring extramedullary disease is essential.
Shalabi suggested that “limited CAR persistence is likely contributory to antigen positive relapses; longer follow up and a larger cohort is needed to assess the dual functionality of this CAR.”
There are a number of different areas that require additional research.
“Future directions include the incorporation of an additional dose level, intensification of lymphodepletion in a patient cohort who has received prior car treatments, and comparing CAR-T manufacturing via the automated Prodigy and a culture bag system,” noted Shalabi. “[Other areas to explore include] the evaluation of CAR T-cell products to better characterize functional properties of exhaustion and the consideration of the role of checkpoint blockade in augmenting CARs in those with extramedullary disease with limited CAR T-cell response.”
Catlin Nalley is a contributing writer.