The addition of a novel bispecific antibody to preactivated and expanded natural killer (NK) cells may represent an effective therapy for pretreated patients with relapsed or refractory CD30-positive lymphoma, according to preliminary findings from a phase 1/2 clinical trial presented during the 2022 American Association for Cancer Research Annual Meeting.
“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 or refractory Hodgkin and non-Hodgkin lymphoma,” said Yago Nieto, MD, PhD, Professor, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, who presented the results at the meeting. “We saw very encouraging activity in this population of heavily pretreated patients.”
NK cells are white blood cells that monitor the body for virus-infected and cancerous cells. 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 2 cell types, allowing 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.
The novel approach in this study used banked NK cells. By contrast, CAR T-cell therapy typically utilizes a patient’s own T-cells in the manufacturing process, although off-the-shelf CAR T-cell therapies are being developed. The manufacturing process is much simpler for preactivated NK cells than for CAR T-cells.
Study Details
The phase 1/2 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 plus cyclophosphamide, and then were infused with AFM13 CAR T-cell–like NK cells over a 3-week period. Response was assessed at 28 days. Patients were treated at 3 different dose levels for 2 cycles in phase 1 of the study. The highest dose was recommended for phase 2 (ie, 1 × 108/kg).
To be eligible for enrollment, patients had to have relapsed or refractory CD30-positive lymphoma, be between the ages of 15 and 75 years, and have an Eastern Cooperative Oncology Group performance status of 2 or lower. The study enrolled 22 patients with a median age of 40 years; 66% were male; 20 had Hodgkin lymphoma; and 2 had T-cell non-Hodgkin lymphoma.
These were very heavily pretreated patients. The median number of previous lines of therapy was 7 (range, 1-14). All 22 patients were previously treated with brentuximab vedotin (Adcetris), and 21 had received previous anti–PD-1 therapy. Fourteen patients had received previous stem-cell transplantation, and 2 had received previous CAR T-cell therapy. The median number of previous relapses was 6, and all 22 patients had progressive disease immediately after previous therapy.
Results
In 19 evaluable patients, the overall response rate was 89.3%, and it was 100% for all 13 patients treated at the recommended phase 2 dose. At a median follow-up of 11 months, the progression-free survival and overall survival rates across all 3 dose levels were 52% and 81%, respectively.
“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.”
The safety profile was quite promising, with no evidence of the treatment-related adverse events associated with CAR T-cell therapy.
“Our preliminary results show an excellent tolerability profile, with no instances of cytokine release syndrome, neurotoxicity, or graft-versus-host syndrome. Tolerability was very encouraging in heavily pretreated patients. This approach warrants further investigation for treatment of CD30-positive lymphomas,” Dr Nieto told attendees.
“These are pretty staggering results. We do not usually see results like this in a phase 1 trial. Nearly every patient responded, and on the flip side, there was no toxicity. We are moving away from chemotherapy and CAR T-cell therapy, although these results apply to a specific population of the CD30-positive patients. This is potentially practice-changing for a specific molecularly selected group of patients,” stated Timothy Yap, MBBS, PhD, FRCP, AACR Clinical Trials Committee Co-Chair, and Medical Director, Institute for Applied Cancer Science, and Professor, Department for Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston.