Abstract
According to preliminary results from a phase I/II trial, cord blood–derived natural killer cells complexed with AFM13, a bispecific antibody, showed efficacy in patients with relapsed/refractory CD30+ lymphomas. Complete responses were seen, and treatment was extremely well tolerated.
A complex of cord blood–derived natural killer (NK) cells and AFM13 (Affimed), a bispecific antibody, has shown efficacy in patients with relapsed/refractory CD30+ lymphomas. Preliminary phase I/II trial results were presented during the American Association for Cancer Research Annual Meeting 2022 in New Orleans, LA, April 8–13.
The standard therapy for CD30+ malignancies, including classical Hodgkin and anaplastic large cell lymphomas, is brentuximab vedotin (Adcetris; Seagen). “It's effective, but most patients eventually relapse and have few other options, so there's a large unmet need,” said principal investigator Yago Nieto, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.
AFM13 is designed to engage CD16A on NK cells and CD30 on lymphoma cells, but “it's a well-confirmed observation by our group and others that endogenous NK cells, especially in Hodgkin patients, are dysfunctional,” Nieto said. “Their microenvironment is profoundly immunosuppressive, so they can't exert much antitumor activity. That's why AFM13 alone has limited efficacy.”
Yago Nieto, MD, PhD, discussed AFM13, a bispecific antibody designed to engage CD16A on NK cells and CD30 on lymphoma cells, during the AACR Annual Meeting 2022.
Instead, Nieto and colleagues utilized MD Anderson's cord blood bank as a source for donor NK cells, which were preactivated with cytokines, “inducing a memory phenotype and enhancing their cytotoxicity,” he said. Following expansion, the cells were incubated with AFM13 shortly before being infused as a complex into patients.
To date, 22 patients have been enrolled, all with disease progression on multiple prior regimens—not only brentuximab vedotin, but also PD-1 checkpoint inhibitors, stem cell transplants, and CD30-targeted chimeric antigen receptor T-cell therapy. After lymphodepletion, they received AFM13–NK at one of three doses and then three weekly infusions of AFM13 alone. Among 19 evaluable patients, the objective response rate was 89.5%, including 10 complete responses. At 9 months, median progression-free and overall survival rates were 52% and 81%, respectively.
“These were very sick patients,” Nieto noted, some with pronounced “B symptoms,” such as drenching night sweats, fevers, and unintentional weight loss. Yet “treatment was amazingly well tolerated,” with no cytokine release syndrome, neurotoxicity, or graft-versus-host disease, allowing investigators to select the highest dose of AFM13–NK, 100 million cells/kg, for the trial's phase II portion.
Jeffrey Miller, MD, of the University of Minnesota in Minneapolis and the study's invited discussant, observed that clinical benefit might be “tricky to separate out if you're giving AFM13 complexed with NK cells, and AFM13 on its own as well.”
The additional AFM13 infusions “ensured that NK cells stayed bound to the bispecific,” Nieto explained. “We already know AFM13 alone doesn't do much, at least in this population. In flow cytometry analyses, we also saw far greater AFM13 binding by donor rather than endogenous NK cells, and we think the complex is what's boosting efficacy.”
Costimulation with IL15 may be another way “to fix dysfunctional endogenous NK cells,” Miller suggested. With GT Biopharma, he's evaluating trispecific killer engagers, or TRiKEs, which feature an IL15 linker—“so you not only engage NK cells but spur their proliferation too, expanding the immune response in vivo.” (For more about trispecifics, see p. 1404 or Cancer Discov 2022;12:1404.)
That said, “there's an emerging concept in the field about functional expansion,” he added. “Perhaps there are disease-specific indications where endogenous NK cells are just too suppressed to ever function well, and we might do better by adding adoptive cell transfer.”
Overall, “it's early days yet,” Miller concluded of AFM13–NK, “but I do like the proof of concept and look forward to longer follow-up data from more patients.”
For Nieto, the next steps include “increasing from two to four treatment cycles for more curative potential,” and combining AFM13–NK with lenalidomide, which enhances NK cells’ effector capacity at low doses. “We want to build on responses that are already good and make them even better.” –Alissa Poh
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