Low-Dose Targeted Radioimmunotherapy (Iomab-ACT) Achieves Lymphocyte and Monocyte Depletion Prior to CD19-Targeted CAR T-Cell Therapy for Relapsed of Refractory B-Cell ALL or DLBCL with Minimal CRS and Icans
Transplantation and Cellular Therapy(2024)
Abstract
Background
CD19-targeted chimeric antigen receptor-modified T-cells (CAR-T) are effective in patients (pts) with (w/) relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL). However, severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) remain challenges. Host monocytes appear to be the major source of cytokines driving CRS/ICANS. Low doses of the CD45-targeted antibody radioconjugate 131-I apamistamab (4-20 mCi) achieve transient lymphodepletion; preclinical studies support potential for monocyte depletion as well while sparing stem cells. We hypothesized a nonmyeloablative dose of 131-I apamistamab (75 mCi, Iomab-ACT) would deplete host lymphocytes and monocytes, promote CAR-T expansion, and reduce risks of CRS/ICANS.
Methods
We are conducting a pilot study (NCT04512716) of Iomab-ACT (w/o chemotherapy) prior to 19-28z CAR-T (Park et al., NEJM, 2018) in up to 6 adults w/ R/R CD19+ DLBCL (de novo or transformed) or B-ALL. Active/prior CNS disease, prior CAR-T, and prior allogeneic transplant (alloHCT, if off T-cell suppressive therapy) are not exclusionary. Bridging therapy is at investigator discretion. Iomab-ACT is administered 5-7d (goal 6d) pre-CAR-T. 19-28z CAR-T is administered as single infusion (1x106/kg, B-ALL pts; 2x106/kg, DLBCL pts). Dose-limiting toxicities (DLTs) were defined per protocol; adverse events (AEs) were graded (G) by CTCAE v5.0.
Results
Treated pts summarized in Figure 1. Median (range) absolute monocyte lymphocyte counts were 0.2 (0.0-0.2k/mcL) and 0.1 (0.0-0.2k/mcL), respectively, on day of CAR-T. No pts developed ICANS; 1 pt developed isolated fever (G1 CRS) post-CAR-T. Non-hematologic toxicities possibly/probably/definitely related to therapy have been minimal (G3 febrile neutropenia, n=2; all other AEs G1). Pt #2 has heavily pre-treated Richter syndrome (RS) and experienced DLT (severe trilineage cytopenias requiring RBC/PLT transfusion support, G-CSF, and romiplostim w/o marrow hypoplasia and w/o other apparent neoplastic/drug-induced etiology, w/ eventual recovery by day 60). He achieved CR, though relapsed 8 months post-CAR-T. Pt #4 has refractory RS and achieved CR by PET CT at 4 weeks post-infusion. CAR-T was detectable post-infusion in all pts w/ persistence to date of up to 4 weeks. Lymphocyte subset levels are depicted in Figure 2.
Conclusions
Low-dose Iomab-ACT prior to 19-28z CAR-T depletes peripheral lymphocytes/monocytes and has minimal non-hematologic toxicity (including CRS/ICANS); cytopenias requiring blood product/growth factor support can occur in the weeks post-CAR-T. This pilot continues to enroll pts.
MoreTranslated text
AI Read Science
Must-Reading Tree
Example
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
Generate MRT to find the research sequence of this paper
Chat Paper
Summary is being generated by the instructions you defined