CD19-Directed CAR-NK Cell Therapy Elicits Responses in Non-Hodgkin Lymphoma and CLL

Katy Rezvani, MD, PhD

Treatment with a CD19-targeted CAR-natural killer (NK)—cell therapy led to a 73% objective response rate (ORR), including 7 complete responses (CRs), in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), according to results of a small phase I/IIa study (NCT03056339) published in the New England Journal of Medicine.¹

At a median follow-up of 13.8 months, 8 of 11 patients who received treatment had a response. Of the 7 CRs, 4 were in patients with NHL and 3 occurred in patients with CLL. Additionally, 1 patient achieved remission of the Richter’s transformation component; however, their CLL was persistent. Responses were seen within 30 days after infusion at all dose levels, and the infused CAR-NK cells expanded and persisted at low levels for ≥12 months. Moreover, the maximum-tolerated dose was not reached.

“We are encouraged by the results of the clinical trial, which will launch further clinical studies to investigate allogeneic cord blood-derived CAR NK cells as a potential treatment option for patients in need,” corresponding study author Katy Rezvani, MD, PhD, a professor of stem cell transplantation and cellular therapy at The University of Texas MD Anderson Cancer Center stated in a press release.2

In the trial, researchers administered human leukocyte antigen (HLA)-mismatched anti-CD19 CAR-NK cells originated from cord blood. NK cells were transduced with a retroviral vector expressing genes that encode anti-CD19 CAR, interleukin-15, and inducible caspase 9. The cells were expanded ex vivo and administered in a single infusion at either 1 x 10⁵, 1 x 10⁶, or 1 x 10⁷ CAR-NK cells/kg of body weight after lymphodepleting chemotherapy.

Between June 2017 and February 2019, 15 patients were enrolled; 4 of them withdrew before treatment was administered. The median age was 60 years (range, 47-70), and all patients had received a median of 4 lines of prior therapy (range, 3-11). Five patients had CLL, including 2 who had Richter’s transformation or accelerated CLL, and high-risk genetic characteristics. The 6 patients with NHL comprised diffuse large B-cell lymphoma (n = 2) and follicular lymphoma (n = 4). Three of these patients had transformation to high-grade lymphoma. Four of the 6 patients with lymphoma had disease progression following autologous hematopoietic stem cell transplantation, and the remaining 2 had refractory disease.

Results also showed that, in all 8 patients, the response to treatment occurred during the first month after infusion.

Investigators utilized a quantitative real-time polymerase chain reaction assay to measure in vivo expansion of the treatment. Expansion of CAR-NK cells was observed as early as 3 days after infusion and CAR-NK cells persisted for ≥12 months. The peak CAR-NK copy number was measured 3 to 14 days after infusion and was found to be dose-dependent. After day 14, no dose-related differences were noted in the level of peripheral-blood transcripts or in the persistence of CAR-NK cells. Patients who responded to therapy had a significantly higher early expansion of CAR-NK cells compared with those who did not have a response at a median value of 31,744 and 903 copies/μg, respectively (P = .02).

In patients with available lymph node samples (n = 2), more CAR-NK cells were found in the lymph nodes than in the bone marrow or peripheral blood. Additionally, similar levels of CAR-NK cells were identified in the marrow and peripheral blood in those with available samples (n = 10). In those who did not achieve a response to therapy or had relapsed, CAR-NK cells were still detectable at low levels. Persistent CAR-NK cells, however, did not expand in vivo at the time of relapse.

After the infusion of CAR-NK cells, no symptoms of cytokine release syndrome, neurotoxicity, hemophagocytic lymphohistiocytosis, or graft-versus-host-disease were reported. Additionally, there were no increased levels from baseline of inflammatory cytokines, including interleukin-6. All patients had transient and reversible hematologic toxic events, which were mainly due to lymphodepleting chemotherapy. The most common adverse events were grade 4 neutropenia (n = 8) and grade 4 lymphopenia (n = 10).

“We have shown that it is possible to produce more than 100 doses of CAR-NK cells from a single cord-blood unit. This capability, together with the apparently minimal HLA-matching requirements between the donor of CAR-NK cells and the patient, may pave the way for a truly off-the-shelf product that could increase treatment accessibility for many more patients,” the authors concluded in the study.

The investigators also noted that no patients received cryopreserved and thawed CAR-NK cells, and the durability of the responses observed need to be examined with longer follow-up.

A pivotal clinical trial with the CD19-directed CAR-NK cell therapy TAK-007 will be initiated in 2021, according to the press release.

References

1. Liu E, Marin D, Banerjee P, et al. Use of CAR-transduced natural killer cells in CD-19-positive lymphoid tumors. N Eng J Med. 2020;382:545-553. doi: 10.1056/NEJMoa1910607.
2. CD19 CAR NK-cell therapy achieves 73% response rate in patients with leukemia and lymphoma [news release]: Houston, TX. The University of Texas MD Anderson Cancer Center. Published February 5, 2020. https://bit.ly/3bwJ5ip. Accessed February 5, 2020.