Singe agent off-the-shelf CAR-NK (CD-19 t-haNK) cell therapy in combination with rituxumab Results in complete response in participants with waldenstrom's macroglobulinemia

Abstract

Abstract Background: Relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (NHL), including incurable Waldenström's macroglobulinemia (WM), remains challenging to treat, warranting novel immunotherapies. CD19 t-haNK (CAR-NK) is a targeted high-affinity natural killer (NK) cell therapy – an off-the-shelf, allogeneic NK cell line engineered to express a CD19-specific chimeric antigen receptor (CAR) and a high-affinity CD16 (FcγRIIIa 158V) receptor. This design enables dual anti-tumor mechanisms: direct CAR-mediated cytotoxicity and augmented antibody-dependent cellular cytotoxicity, when paired with anti-CD20 monoclonal antibody rituximab. Combining CD19 t-haNK cells with rituximab could thereby target CD19⁺/CD20⁺ lymphoma cells to enhance tumor cell killing. QUILT-106 is a first-in-human, phase 1 trial evaluating the safety and preliminary efficacy of CD19 t-haNK cell therapy alone and in combination with rituximab in patients with R/R CD19⁺CD20⁺ B-cell NHL. We report here the results in a rare tumor type of WM, with promising complete responses in late stage disease. Methods: This open-label phase 1 study (NCT05618925) is being conducted at 3 sites in South Africa. Eligible participants have R/R B-cell NHL expressing CD19 and CD20, with active disease after ≥2 chemotherapy-based lines. All patients receive a lead-in cycle of CD19 t-haNK cell monotherapy, followed by a 1-week safety observation pause, then a second cycle combining CD19 t-haNK with rituximab. Key endpoints include safety/tolerability and objective response rate (ORR) by standard criteria. As of August 3, 2025, 3 patients with WM have been enrolled. To date, two WM patients were evaluable with relapsed/refractory disease. Both had undergone multiple lines of standard therapy and had active disease. No chemo or lymphodepleting conditioning was used. Treatment was delivered on an outpatient basis. Disease responses were assessed by standard WM criteria. Safety: CD19 t-haNK cell therapy (alone and with rituximab) has been well tolerated to date. No dose-limiting toxicities, cytokine release syndrome, or unexpected immune adverse events have been observed in the first 12 treated patients. Results: Both WM patients tolerated the regimen with no significant toxicities. Notably, all infusions (including the CAR-NK cells) were administered as outpatients and no toxicities or cytokine-release syndrome occurred. Each patient had a significant tumor burden (90% bone marrow infiltration) and high IgM levels at baseline despite multiple prior therapies. After treatment, both patients achieved profound clinical responses. One patient attained a complete response (CR) after the first cycle of CD19 t-haNK cell monotherapy. The second patient, who received the full combination (CD19 t-haNK cells and rituximab in subsequent cycles), also achieved a deep remission, with a marked decline in IgM paraprotein and bone marrow clearance of disease, and remains in remission for 6 months at time of this report.These responses were rapid and durable: by the first post-treatment assessment, both patients showed >90% reduction in serum IgM, resolution of anemia and constitutional symptoms, and improvement in marrow pathology. Conclusion: In two heavily pretreated patients with WM, an entirely chemotherapy-free, outpatient immunotherapy regimen induced profound responses, including a complete remission achieved with CD19-targeted NK cells alone. These cases underscore the potential of NK cell-based combination therapy to overcome refractory WM using the patient's immune system rather than cytotoxic chemotherapy. Updated data to be presented. The biologic-only approach (incorporating CD-19 t-haNK with optional antibody therapy) was not only highly active against WM but very well tolerated, with outpatient administration and minimal side effects. This preliminary evidence suggests that such novel immunotherapy combinations can provide deep and durable remissions in WM even after multiple prior treatments. Further evaluation in larger studies is warranted to confirm the generalizability of these findings and to establish this chemo-free strategy as a viable treatment option for relapsed WM.