New Phase 2 Study of Tri-Modal Immunotherapy for Indolent B-Cell Lymphoma Launches

An open-label, phase 2 study, ResQ215B, is being launched to evaluate a novel, chemotherapy-free immunotherapy combination for adult patients diagnosed with relapsed or refractory CD19+/CD20+ indolent B-cell non-Hodgkin lymphoma (iNHL). The patient population includes those with conditions such as Waldenström macroglobulinemia, which are currently considered incurable lymphomas.¹

The primary objective of this phase 2 trial is to determine if the addition of nogapendekin alfa inbakicept-pmln (Anktiva; formerly N-803) an interleukin-15 (IL-15) superagonist, to a combination of chimeric antigen receptor-natural killer (CAR-NK) cells and a monoclonal antibody can significantly enhance immune-mediated tumor control beyond existing standards of care.

Unlike traditional monotherapies, the ResQ215B study utilizes a tri-modal regimen designed to attack malignant cells through multiple, complementary biological mechanisms. This outpatient-friendly approach consists of 3 distinct components:

1. CD19 t-haNK (CAR NK cell therapy): An "off-the-shelf," allogeneic NK cell therapy derived from an NK-92 cell line. This therapy is dual engineered to express:
   • A CD19-specific CAR, which allows the cells to directly target and lyse malignant B cells expressing the CD19 protein.
   • A high-affinity CD16 receptor, engineered to enhance the cell's ability to mediate antibody-dependent cellular cytotoxicity .
2. Nogapendekin alfa inbakicept: An IL-15 superagonist acting as an immune enhancer to improve the depth and durability of the immune response.
3. Rituximab (Rituxan): A well-established monoclonal antibody that targets CD20+ B cells.

Distinguishing Features of Trial Design

The ResQ215B trial is notable for several departures from conventional cellular therapy protocols, particularly those involving CAR-T cells:

• Chemotherapy-free and lymphodepletion-free: The study design avoids the use of traditional chemotherapy and the intensive lymphodepletion regimens typically required for CAR-T cell engraftment.
• Off-the-shelf availability: Because the CAR NK cells are allogeneic and derived from a standardized cell line, the regimen does not require the lengthy and complex individualized cell manufacturing processes (vein-to-vein time) associated with autologous therapies.
• Outpatient administration: The safety profile and off-the-shelf nature of the components allow for an outpatient treatment model, potentially reducing the need for hospitalization and making the therapy more accessible to a broader patient base.

Clinical Foundation and Rationale

The new trial builds directly on the results of the phase 1 QUILT-106 study (NCT06334991), which evaluated CD19 t-haNK cells plus rituximab without nogapendekin alfa inbakicept.

In an initial cohort of 4 heavily pretreated patients with Waldenström macroglobulinemia, treated without chemotherapy or lymphodepletion, a 100% disease control rate was achieved. Two patients experienced rapid and durable complete remissions, which remain ongoing at 7 and 15 months of follow-up, respectively, without requiring further therapy.

The other 2 patients achieved stable disease, with 1 showing declining IgM levels.

A previously published phase 1 study (NCT02384954)² demonstrated that combining an IL-15 superagonist with rituximab resulted in a 78% complete response rate in patients with relapsed iNHL who had previously failed rituximab therapy. This data suggests that IL-15 agonists can help restore immune function in the face of antibody resistance.

Researchers believe that by integrating nogapendekin alfa inbakicept into this established regimen for phase 2, they can further enhance the proliferation and activation of the therapeutic NK cells. This synergy is intended to transform the treatment paradigm for iNHL by providing a potent, durable immune response without the toxicity and logistical burdens of current high-intensity treatments.¹

Future Directions

As a pivotal phase 2 trial, ResQ215B represents a significant step in the evolution of "chemo-free" oncology. By leveraging the innate power of NK cells through CAR engineering and cytokine superagonism, ImmunityBio aims to provide a patient-friendly alternative for those facing relapsed or refractory indolent B-cell lymphomas. If successful, this tri-modal approach could redefine the standard of care for Waldenström macroglobulinemia and other iNHLs.

“A therapy that does not require apheresis, individualized manufacturing, chemotherapy, or inpatient hospitalization would represent an important advance for patients with iNHL, who are regarded as having incurable lymphomas,” said Lennie Sender, MD, chief medical officer for Cell Therapy and Liquid Tumors at ImmunityBio, in a news release. “This could open the door to a more patient-friendly immunotherapy option for follicular lymphoma, Waldenström, and other indolent NHL subtypes that currently rely on more aggressive or continuous treatments. Indolent B-cell lymphomas, such as Waldenström macroglobulinemia, remain an area of high unmet medical need.”

REFERENCES

1.ImmunityBio launches phase 2 chemotherapy-free CAR-NK cell therapy trial with ANKTIVA (ResQ215B) in indolent lymphomas. News release. ImmunityBio. February 2, 2026. https://tinyurl.com/9nj2dcy6

2.QUILT-3.002: N-803 in patients with relapse/refractory iNHL in conjuction with rituximab. ClinicalTrials.gov. Updated July 3, 2024. Accessed February 2, 2026. https://clinicaltrials.gov/study/NCT02384954