Innate Cell Engager AFM13 Combined with Preactivated and Expanded Cord Blood-Derived NK Cells for Patients with Double Refractory CD30+ Lymphoma

Patients with multiple relapsed or refractory (R/R) Hodgkin lymphoma (HL) and other CD30+ lymphoma have few effective therapies available and targeted adoptive natural killer (NK) cell immunotherapy is an active area of investigation. Transfer of non-targeted NK cells has shown limited clinical benefit as target recognition of cancers by NK cells remains a substantial barrier. The innate cell engager (ICE®) construct, AFM13, is a first-in-class CD30/CD16A bispecific antibody construct that induces specific and selective killing of CD30+ tumor cells by engaging and activating NK cells. As a single agent, AFM13 has limited clinical activity against HL, likely due to the reduced effector function of autologous NK cells in these patients, which provides the rationale for the combination of AFM13 with allogeneic NK cells. Our prior preclinical work identified a promising combination of cord blood (CB)-derived NK cells that were first IL-12/IL-15/IL-18-preactivated followed by expansion (P+E) with engineered K562 feeder cells expressing membrane-bound IL-21, 4-1BB ligand and CD48 ex vivo, and subsequently complexed with AFM13 just prior to infusion (Kerbauy et al, Clin Cancer Res 2021; 27:3744-56). These cytokine-induced memory-like CB-derived NK cells precomplexed with AFM13 (AFM13-NK) presented chimeric antigen receptor (CAR)-NK cell-like features and showed an increased in vitro and in vivo antitumor activity compared to either P+E NK or AFM13 alone. Building on this work we wished to clinically study adoptive AFM13-NK cell therapy in pts with R/R CD30+ lymphomas.

METHODS: This single-center phase I-II trial (NCT04074746) evaluates the safety and activity of AFM13-NK, followed by AFM13 monotherapy. Patients aged 15-75 years with R/R CD30+ lymphomas refractory to brentuximab vedotin are enrolled. The trial goals are to identify the recommended phase 2 dose (RP2D) of AFM13-NK cells, estimate the overall (ORR) and complete response (CR) rates, event-free (EFS) and overall survival (OS) rates, and studies of NK cell activation and persistence. Each treatment cycle consisted of fludarabine/cyclophosphamide (days −5 to −3), followed by infusion of the AFM13-NK cells, cultured for 14 days as described above (day 0), and three weekly IV infusions of AFM13 (200 mg, days 7, 14 and 21). Two cycles were administered to patients 1-19 and 4 cycles were given starting with patient 20. Response was evaluated on day 28 of each cycle. Patients were enrolled at 3 dose levels: DL1 (10⁶ NK/Kg), DL2 (10⁷NK/Kg) and DL3 (10⁸ NK/Kg). Each patient received the same NK dose in all cycles.

RESULTS: As of 7/31/22, 30 pts have been enrolled and treated (Table) at DL1 (N=3), DL2 (N=3) and DL3 (N=24), with 1 (N=1), 2 (N=24), 3 (N=3) or 4 cycles (N=3). All patients had active progressive disease at enrollment and no bridging therapy was given. The cords used for each of the 69 cycles were selected with no consideration for HLA match, which was 0/6 (N=31), 1/6 (N=31), 2/6 (N=5), 3/6 (N=1) and 4/6 (N=1). The product infused consisted of >99% NK cells (expanded >2,700 fold), with only 0.02% T cells. The NK cells were >98% viable and 92% of them were bound to AFM13. The products were infused fresh.

There were no infusion-related reactions (IRR) after infusing AFM13-NK and 11 IRR in 182 infusions of AFM13 alone (6%) (1 grade 3, 10 grade 2). We saw no cases of CRS, ICANS or GVHD of any grade. DL3 (10⁸ NK/Kg) was established as the RP2D. The ORR in the entire study is 97% with 63% CRs. All 24 patients treated at the RP2D responded (100% ORR) with 70.8% (17/24) CRs. Five patients had a response consolidated with a SCT. At median follow-up of 8 (range 1-23) months, the EFS and OS rates of all 30 patients are 57% and 83%, respectively.

AFM-NK cells were detected in serum from day 1 post infusion and persisted for 3-4 weeks. Donor NK levels followed similar patterns after each cycle, which argues against a sensitization effect in the patient after the first NK infusion. Donor NK cells showed by CyTOF increased binding to AFM13 and expression of activation markers.

CONCLUSIONS: This is the first clinical trial to date using an ICE® construct precomplexed with cytokine-induced memory-like CB-NK cells to treat patients with CD30+ R/R HL and NHL. Our preliminary results indicate that this ICE® precomplexed CB-NK cell therapy has an excellent tolerability profile and is highly active in patients with heavily pretreated R/R CD30+ lymphomas and warrants further investigation.

Nieto:Affimed: Other: Scientific advisory Board, Research Funding; Secura Bio: Research Funding; Astra Zeneca: Research Funding. Banerjee:Takeda: Research Funding; MD Anderson: Other: Management and Monitoring Plan. Srour:Orca Bio: Research Funding. Ahmed:Tessa Therapeutics: Consultancy, Research Funding; Seagen: Research Funding; Merck: Research Funding; Xencor: Research Funding; Chimagen: Consultancy, Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Myeloid Therapeutics: Consultancy. Emig:Affimed: Current Employment. Harstrick:Affimed: Current Employment. Shpall:Bayer: Honoraria; Takeda: Patents & Royalties; NY blood center: Consultancy; Navan: Consultancy; Fibroblasts and FibroBiologics: Consultancy; adaptimmune: Consultancy; axio: Consultancy; Affimed: Other: License agreement. Rezvani:Navan Technologies: Other: Participates on the Scientific Advisory Board ; Bayer: Other: Participates on the Scientific Advisory Board ; GSK: Other: Participates on the Scientific Advisory Board ; Virogin Biotech: Other: Participates on the Scientific Advisory Board ; AvengeBio: Other: Participates on the Scientific Advisory Board ; GemoAb: Other: Participates on the Scientific Advisory Board ; Takeda: Patents & Royalties, Research Funding; Affimed: Research Funding; Caribou Biosciences: Other: Participates on the Scientific Advisory Board .

AFM13 is not FDA approved.