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Two CAR NK Cell Therapies Show Safety, Efficacy for AML, NHL

NKX101 and NKX019 have demonstrated preliminary signs of safety and efficacy in heavily pretreated patients with AML and NHL in 2 separate phase 1 studies.

Two allogeneic chimeric antigen receptor (CAR)-engineered natural killer (NK)–cell therapies, NKX101 and NKX019, have demonstrated preliminary signs of efficacy and promising safety in heavily pretreated patients with acute myeloid leukemia (AML) and non-Hodgkin lymphoma (NHL), according to findings from 2 separate dose-finding studies released by Nkarta, Inc, the company developing the cell therapies.

In the first study, 5 patients with relapsed/refractory (R/R) AML received a 3-dose regimen of NKX101, which consisted of 1 billion or 1.5 billion CAR NK cells per dose and was the highest administrated in the study. Following infusion of the therapy, which targets the NKG2D ligand, 60% of patients experienced a complete response (CR), with 2 of the 3 CRs testing negative for minimal residual disease (MRD). In the second study, the CD19-targeted therapy NKX019 elicited a response in 5 of 6 patients with R/R NHL, when given in a 3-dose regimen with 1 billion CAR+ NK cells per dose, which was the highest dose in the study. The CR rate in this trial was 50%.

No dose limiting toxicities were seen in the studies and there were no commonly observed adverse events (AEs) associated with CAR T-cell therapies. In both studies, there were no cases of cytokine release syndrome, neurotoxicity, or graft-vs-host disease reported following infusion of the CAR NK cells.

“We’re excited to see our CAR NK co-lead candidates, NKX101 and NKX019, show such striking early single-agent activity in heavily pretreated patient populations, with an exceptional safety profile without the side effects associated with CAR T cell therapies,” Paul J. Hastings, president and CEO of Nkarta, said in a statement. “These encouraging data across multiple indications further validate Nkarta’s best-in-class NK cell platform, as we seek to transform cancer treatment by bringing together the safety advantages of NK cells with an off-the-shelf modality designed to make the benefits of cell therapy accessible in a community setting.”

Both therapies are engineered from allogeneic NK cells derived from the peripheral blood of healthy donors. Following leukapheresis, the collected cells are engineered to express a CAR, either NKG2D for NKX101 or CD19 for NKX019. In addition to this tumor finding CAR, both therapies are also engineered with a membrane-bound form of the cytokine IL15, to support cell therapy persistence. After expansion, the finished products are cryopreserved until administration, allowing for "off-the-shelf" treatment.

NKX101 for AML

At the time of the data analysis, which took place April 21, 2022, there were 21 patients enrolled in the phase 1 study that explored NKX101 (NCT04623944). These patients include 17 with AML and 4 with high-risk myelodysplastic syndrome (MDS). Patient enrolled in the study had received a median of 3 prior lines of therapy (range, 1-12), including prior venetoclax (Venclexta) for those with AML. At baseline, blast cells were present in a median of 27% of bone marrow samples (range, 3% to 85%). Treatment was administered at either 2 doses (days 0 and 7) or 3 doses (days 0, 7, and 14) and all patients received fludarabine/cyclophosphamide lymphodepletion prior to the first dose of NKX101.

In the 2-dose group, the highest dose consisted of 1.5 billion cells per infusion. This group enrolled 3 patients with AML, and there were no responses observed at this dose level. The second group in the 2-dose cohort received 150 to 450 million cells per infusion. There were 3 patients with AML and 2 with MDS in this group. In those with AML, the overall response rate (ORR) was 33% and there was no response observed in patients with MDS.

In the 3-dose arm, the highest dose patients received was 1.0 billion to 1.5 billion CAR+ NK cells per infusion. This group contained 5 patients with AML and 2 with MDS. There were no responses observed in those with MDS and the ORR was 60% for those with AML, all of which were CRs. A lower dose of 100 million to 300 million was also given in the 3-dose cohort. Six patients with AML received this dose, with a response seen in 4 (ORR, 67%). There were no CRs. No patients with MDS were treated with this dose. Across all dose sizes in the 3-dose group, the ORR was 47% for those with AML (8 of 17) with a CR rate of 18% (3 of 17).

The most common adverse events (AE) were those associated with lymphodepletion, the most common grade ≥3 AEs were thrombocytopenia (48%), febrile neutropenia (38%), neutropenia (33%), and anemia (29%). Two patients experienced a grade 2 infusion reaction.

“Relapsed/refractory acute myeloid leukemia is a historically hard-to-treat disease, and given the lack of effective treatments, people with cancer and those who treat them are faced with few options,” investigator in the NKX101 clinical trial Marcello Rotta, MD, Colorado Blood Cancer Institute (CBCI), a part of the Sarah Cannon Cancer Institute at Presbyterian/St. Luke’s Medical Center, said in a statement. “Complete responses with corresponding MRD negativity in R/R AML using engineered NK cells, as seen in these preliminary findings, is encouraging. We look forward to leading further investigation to better understand the full potential of a CAR NK approach.”

NKX019 for B-Cell Malignancies

At the April 21, 2022, data analyses, there were 13 patients enrolled in the phase 1 study exploring NKX019 (NCT05020678). The histologies enrolled included 5 with aggressive large B-cell lymphoma (LBCL), 3 with B-cell acute lymphoblastic leukemia (B-ALL), 3 with follicular lymphoma, 1 with mantle cell lymphoma (MCL), and 1 with marginal zone lymphoma (MZL). Patient enrolled in the study had received a median of 4 prior lines of therapy (range, 2-7). The study enrolled those with extensive disease in both the United States (n = 3) and Australia (n = 10). Three doses of NKX019 were administered at either 300 million cells per dose or 1 billion cells per dose on days 0, 7, and 14. Additionally, all patients received fludarabine and cyclophosphamide lymphodepletion prior to the first dose of NKX101.

Across all NHL subtypes, the ORR was 50% at the 300 million dose and 83% at the 1 billion cell dose. The CR rate was 25% and 50% in these groups, respectively. In those with B-ALL, there were no responses. In the 300 million dose group, there were no patients treated with MCL or MZL. Of those with LBCL treated at this dose (n = 3), there was 1 partial response (33%). There was 1 patient with follicular lymphoma treated at this dose with a CR.

Two patients with LBCL received 3 doses of NKX019 at 1 billion cells each, with a CR experienced by 1 (50%). There was 1 patient each with MCL and MZL treated at this dose level, each experienced a CR. There were 2 patients with follicular lymphoma treated at this dose level, with an ORR of 100% that consisted entirely of partial responses.

The AEs were similar in this study, with toxicities observed that are commonly associated with lymphodepletion. The most common grade ≥3 AEs were neutropenia (69%), thrombocytopenia (38%), febrile neutropenia (23%), and anemia (15%). One patient experienced a grade 1 infusion site reaction.

“The curative potential of CAR T-cell therapy is truly remarkable, but many eligible patients are still not cured, and the safety and logistical challenges of approved autologous CAR T therapy are barriers,” investigator in the NKX019 trial Michael Dickinson, MD, Lead, Aggressive Lymphoma disease group, Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, said in a statement. “The NKX019 trial exemplifies the continued progress of our field. NKX019 showed clear activity, in patients with a range of NHL histologies, without the sort of toxicities expected of other cellular therapies, supporting continued exploration of this CAR NK candidate.”

Findings from both interim analyses are being prepared for presentation at a future medical meeting, according to Nkarta. Additionally, both studies continue to enroll participants at the highest dose levels. The findings that are presented will include additional follow-up from the high-dose levels, the company noted.

Nkarta announces positive preliminary dose finding data for two lead engineered natural killer cell programs. Nkarta, Inc. April 25, 2022. https://ir.nkartatx.com/news-releases/news-release-details/nkarta-announces-positive-preliminary-dose-finding-data-two-lead