Novel Approach Using Off-the-Shelf Preactivated NK Cells Shows Efficacy in CD-30 Positive Lymphoma

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Natural killer (NK) cells derived from donated umbilical cord blood and activated with a novel bispecific antibody known as AFM13 (which targets CD16A and CD30) were shown to be effective in patients with pretreated and refractory CD30-positive lymphoma. The overall response rate was 89% in patients with relapsed or refractory CD30-positive lymphoma, according to results from an investigator-initiated phase I/II trial reported by Nieto et al at the American Association for Cancer Research (AACR) Annual Meeting 2022 (Abstract CT003). All patients treated at the recommended dose for phase II responded, for an overall response rate of 100%. Tolerability was excellent, with none of the treatment-related adverse events associated with chimeric antigen receptor (CAR) T-cell therapy.

“This is the first clinical trial using off-the-shelf cord blood–derived cytokine-induced memory-like ex vivo expanded NK cells precomplexed with the innate cell engager AFM13 construct to treat patients with CD30-positive relapsed/refractory Hodgkin and non-Hodgkin lymphoma. Our preliminary results show an excellent tolerability profile, with no instances of cytokine-release syndrome, neurotoxicity, or graft-vs-host syndrome. Tolerability was very encouraging in heavily pretreated patients. This approach warrants further investigation for treatment of CD30-positive lymphomas,” stated presenter Yago Nieto, MD, PhD, Professor of Medicine, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston.

The novel approach uses NK cells from multiple donors, as distinct from autologous CAR T-cell therapy, which utilizes a patient’s own T cells in the manufacturing process, although off-the-shelf CAR T-cell therapies are being developed.

NK cells are white blood cells that monitor the body for virus-infected and cancerous cells. The technology to isolate and expand NK cells from umbilical cord blood was developed at MD Anderson. AFM13 is a proprietary first-in-class bispecific antibody construct designed to bind to CD16A on NK cells and CD30 on lymphoma cells, acting as a bridge between the two cell types that allows the NK cells to destroy the cancer cells. The NK cells are activated with cytokines, expanded in the presence of artificial antigen-presenting cells, and finally complexed with AFM13.

Study Details

The study utilized NK cells separated from banked umbilical cord blood and manufactured over a 2-week period. The cells were expanded and precomplexed with AFM13. Patients received chemotherapy with fludarabine/cyclophosphamide and then were infused with AFM13 CAR-like NK cells over a 3-week period. Response was assessed at 28 days. Patients were treated for two cycles. Three different dose levels of the expanded, precomplexed NK cells were evaluated, and the recommended dose carried forward for phase II was identified as 1 × 108/kg, which was the highest dose.

The study enrolled 22 patients with a median age of 40 years. Two-thirds were male. Twenty had Hodgkin lymphoma, and two had T-cell non-Hodgkin lymphoma. The median number of prior lines of therapy was seven (range = 1–14). All 22 patients were treated with prior brentuximab vedotin, 21 patients received prior anti–PD-1 therapy, 14 patients had prior stem call transplantation, and 2 had received prior CAR T-cell therapy. The median number of prior relapses was six, and all 22 patients experienced progressive disease immediately after prior therapy.

“The treatment was shown to be safe, with no cases of cytokine-release syndrome, neurotoxicity, or graft-vs-host disease,” Dr. Nieto said. There was no dose-limiting toxicity identified, and dose level 3 was established as the recommended phase II dose going forward.

Dr. Nieto explained that the preactivated NK cells are detected in serum for up to 3 weeks. “The expansion and persistence of NK cells at cycle 2 is the same as after cycle 1. This is a big difference from autologous CAR T cells in that the patients are not desensitized after each cycle of NK therapy,” he said.

The trial was originally designed to assess durability of response to two cycles. An amendment has been approved by the U.S. Food and Drug Administration to increase the length of treatment from two to four cycles, enabling longer follow-up of patients

“These data suggest that this new therapeutic option, either used as a bridge to stem cell transplantation or perhaps even as a curative treatment, offers an effective treatment option for patients with CD30-positive lymphoma,” Dr. Nieto said. “We are excited about these findings and the possibility of bringing this treatment to this patient population with a large unmet need.”

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