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

Article

Treatment with a CD19-targeted CAR-natural killer–cell therapy led to a 73% objective response rate, including 7 complete responses, in patients with relapsed/refractory non-Hodgkin lymphoma and chronic lymphocytic leukemia.

Katy Rezvani, MD, PhD, a professor of stem cell transplantation and cellular therapy at The University of Texas MD Anderson Cancer Center

Katy Rezvani, MD, PhD, a professor of stem cell transplantation and cellular therapy at The University of Texas MD Anderson Cancer Center

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.
Recent Videos
Daniela van Eickels, MD, PhD, MPH, the vice president and head of medical affairs for Bristol Myers Squibb’s Cell Therapy Organization
Paul Melmeyer, MPP, the executive vice president of public policy & advocacy at MDA
Daniela van Eickels, MD, PhD, MPH, the vice president and head of medical affairs for Bristol Myers Squibb’s Cell Therapy Organization
Arun Upadhyay, PhD, the chief scientific officer and head of research, development, and Medical at Ocugen
Arun Upadhyay, PhD, the chief scientific officer and head of research, development, and Medical at Ocugen
John Brandsema, MD, a pediatric neurologist in the Division of Neurology at Children’s Hospital of Philadelphia
John Brandsema, MD, a pediatric neurologist in the Division of Neurology at Children’s Hospital of Philadelphia
Barry J. Byrne, MD, PhD, the chief medical advisor of Muscular Dystrophy Association (MDA) and a physician-scientist at the University of Florida
John Brandsema, MD, a pediatric neurologist in the Division of Neurology at Children’s Hospital of Philadelphia
© 2024 MJH Life Sciences

All rights reserved.