Cytokine-activated natural killer (NK) cells, combined with an investigational bispecific antibody targeting CD16a and CD30 (AFM13), showed potent anti-tumor activity against CD30+ lymphoma cells, according to a new study from researchers at The University of Texas MD Anderson Cancer Center.
“This preclinical work provided proof of principle for NK cells precomplexed with AFM13, suggesting that they can effectively eliminate lymphoma cells expressing CD30 and warrant further clinical testing,” said senior author Katy Rezani, M.D., Ph.D., professor of Stem Cell Transplantation and Cellular Therapy at MD Anderson.
The findings were published this week in Clinical Cancer Research. https://clincancerres.aacrjournals.org/content/early/2021/04/29/1078-0432.CCR-21-0164
The team’s results have spurred launch of a Phase I clinical trial to evaluate the combination—cord blood-derived NK cells (cbNK cells) with AFM13—as an experimental cell-based immunotherapy in patients with CD30+ lymphoma.
“These findings suggest that, in animal models, ex vivo pre-activated and expanded cord blood-derived NK cells complexed with AFM13 were able to safely eliminate CD30+ lymphoma cells,” Rezvani said. “We look forward to learning if this investigational therapy may provide benefits to patients with advanced lymphoma in the ongoing clinical trial.”
Rezvani presented interim results on three patients from the Phase I clinical trial at the virtual American Association for Cancer Research (AACR) 2021 Annual Meeting. The trial is ongoing.
NK cells are part of the innate immune system and act to eliminate cancer cells in the body. However, they have limited persistence on their own, and tumors can develop mechanisms to evade NK cells, which presents substantial barriers to the broad application of NK cell immunotherapy. Rezvani’s research team is working on approaches to enhance the anti-tumor efficacy of NK cells. Potential solutions include bispecific engagers that target NK cell activity via an NK activating receptor when simultaneously targeting a tumor-specific antigen, as well as enhancing functionality using IL-12/15/18 cytokine pre-activation.
Affimed’s AFM13 is a proprietary bispecific antibody designed to bind to CD16a on NK cells and CD30 on lymphoma cells. Initial studies on NK cells isolated from the blood of patients with Hodgkin lymphoma found that AFM13 formed a stable complex with NK cells and could induce NK cell-mediated killing of CD30+ cells. However, the activity of these cells was modest, leading the researchers to evaluate alternative NK cell sources.
In this study, the team assessed single-cell NK cell responses stimulated by the tetravalent bispecific antibody AFM13 that binds CD30 on leukemia/lymphoma targets and CD16A on various types of NK cells using mass cytometry and cytotoxicity assays. The combination of AFM13 and IL-12/15/18 pre-activation of blood and cord-blood-derived NK cells was investigated in vitro and in vivo, and they write that the treatment “exhibited enhanced responses to CD30+ lymphomas” in both settings.
In animal models, pre-activated and expanded cbNK cells complexed with AFM13 resulted in improved tumor control and survival relative to controls, with minimal side effects observed.
The researchers reported heterogeneity within AFM13-directed conventional blood NK cell (cNK) responses, as well as consistent AFM13-directed polyfunctional activation of mature NK cells across donors. The NK cell source also impacted the AFM13 response, with cNK cells from healthy donors showing better responses than those from Hodgkin lymphoma patients.
Further experiments suggested that cbNK cells, isolated from umbilical cord blood donations made to the MD Anderson Cord Blood Bank, displayed consistent and improved activity against lymphoma with AFM13 relative to other NK cell sources. The researchers were able to further stimulate the anti-tumor immune activity of cbNK cells by pre-activation with a combination of the cytokines IL-12/15/18.
