Reinfusion of CAR T Therapy Shows Promise in B-ALL

Long term survival was limited and all patients with B-cell acute lymphoblastic leukemia eventually relapsed.

This content originally appeared on our sister site, Targeted Oncology.

A retrospective review (NCT03827343) has revealed that young patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) that relapsed or had a suboptimal response after chimeric antigen receptor (CAR) T-cell therapy could benefit from reinfusion.

Findings from the review were published in Journal for ImmunoTherapy of Cancer. Investigators include corresponding author Nirali N. Shah, MD, MHSc, National Cancer Institute.

“Our study provides important insights into [second CAR T-cell infusion] outcomes, including with antigen targets beyond CD19,” Shah and colleagues wrote.

Although CAR T-cell therapy has demonstrated efficacy in many indications, unmet needs remain for patients who have residual disease or who relapse after CAR T-cell therapy. A second infusion with the same CAR T-cell product now looks to be a possible option.

READ MORE: Tisa-Cel Shows Durable Efficacy in Pediatric and Young Adult Patients With R/R B-Cell Acute Lymphoblastic Leukemia

Shah and colleagues analyzed data from patients with B-ALL who received a reinfusion in 1 of 3 phase 1 NCI-based clinical trials (NCT01593696, NCT02315612, NCT0344839). These patients originally received either an anti-CD19, anti-CD22, or an anti-CD19/CD22 agent. If the patients had relapse after complete remission (CR) or suboptimal response and CAR expansion, they were offered a second infusion (n = 18).

Investigators were primarily trying to evaluate CR rates of second infusions as well as incidence of adverse events (AEs). Secondary outcomes included characterizing CAR expansion and antigen expression as well as the impact of lymphodepletion intensity.

A total of 136 patients were treated across the 3 studies, but only 18 (13.2%) went on to receive a second infusion with the same CAR product. As of the time of the second infusion, the median age of patients was 19 (range, 8-31). A majority of the patients were male (88.9%), White (66.7%), and of non-Hispanic ethnicity (83.3%). As of the second infusion, 88.9% had active medullary disease, 22.2% had low marrow involvement, 66.7% had high disease burden, and 11.1% had isolated CNS disease.

Patients had received a median of 6 lines of prior therapy (range, 2-13), including prior hematopoietic stem cell transplantation (HSCT) in 77.8%, prior immunotherapy in 44.4%, and prior alternate CAR T-cell therapy in 50%.

Seven patients (38.7%) had a suboptimal response to the fi rst infusion of either partial response or stable disease, including 4 who did not have a CR from first infusion, and 11 patients (61.1%) had an antigen-positive relapse; all 18 patients had CAR expansion. The median time between the fi rst and second infusion was 116.5 days (range, 35-373), and 38.9% received therapy in between.

The second infusion was administered at the same dose for 15 patients (83.3%), at a lower dose in 2 patients (11.1%) and a higher dose in 1 (5.5%).

Seven patients (38.9%) achieved an objective marrow response to the second infusion, with 5 of these patients (71.4%) achieving a minimal residual disease (MRD) negative CR, and 6 (33.3%) had a morphologic CR.

Long-term survival with second CAR infusion was limited. All patients eventually relapsed—including 2 with CNS disease, 3 with medullary relapse, and 1 with both medullary and extramedullary relapse— and none were eligible for HSCT. The median duration of remission was 77 days (range, 54-292).

“Our results suggest that diminished CAR T-cell expansion alongside antigen downregulation and loss impeded robust responses to CART2. Further exploration of the mechanisms underlying CART2 response is needed,” Shah et al wrote.

Cytokine release syndrome (CRS) was observed in 83.3% of patients with fi rst infusion, including severe CRS of grade 3 or higher in 27.8%. Only 22.2% reported CRS with second infusion at a maximum severity of grade 1. Neurologic toxicity was reported with fi rst infusion in 22.2% and with second infusion in 11.1%.

Observed peripheral blood CAR T-cell expansion was higher with the fi rst infusion than the second (median, 24.05 vs 1.69 cells/mL, respectively; P = .03). Five patients (27.8%) showed no CAR expansion post second infusion. CAR expansion tended to be higher with the CD22-targeted agent than the other CAR T-cell products.

REFERENCE
Holland EM, Molina JC, Dede K, et al. Efficacy of second CAR-T (CART2) infusion limited by poor CART expansion and antigen modulation. J Immunother Cancer. 2022;10(5):e004483. doi:10.1136/jitc-2021-004483