Anti-CD19 chimeric antigen receptor natural killer (CAR NK) cells, derived from donor umbilical cord blood, produced a 73% objective response rate in 11 patients with lymphoid tumors who received just 1 dose of the infused therapy, with no occurrences of cytokine release syndrome or neurotoxicity, in preliminary study results out of MD Anderson. Seven patients had a complete remission.
Using positive results from a preclinical lymphoma model of mice that showed chimeric antigen receptor natural killer (CAR NK) cell antitumor activity, investigators at The University of Texas MD Anderson Cancer Center initiated a phase 1/2A trial of the treatment in human subjects. Their results will appear tomorrow in The New England Journal of Medicine (NEJM).
“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,” stated corresponding author Katy Rezvani, MD, PhD, professor of stem cell transplantation and cellular therapy.
Despite CAR T cells showing remarkable results in patients, they do have significant adverse effects that include cytokine release syndrome (CRS), neurotoxicity, seizures, and brain swelling. In addition, their manufacturing process is complex and can take several weeks. The authors of the present study believe that anti-CD19 CAR NK cells can overcome these roadblocks and make the treatment more accessible to more patients.
Instead of CAR T cells, which are autologous, the anti-CD19 CAR NK cells in the present study were allogeneic, coming from donor umbilical cord blood. They also were human leukocyte antigen (HLA)—mismatched. The treatment course consisted of a single infusion of 1 of 3 doses: 1 × 105, 1 × 106, or 1×107 CAR NK cells/kg of body weight. The maximum tolerated dose was not reached. In addition, the cells were “transduced with a retroviral vector expressing genes that encode anti-CD19 CAR, interleukin-15, and inducible caspase 9 as a safety switch,” the authors noted.
Prior to receiving the infusion, the 11 patients being studied received lymphodepleting chemotherapy with fludarabine and cyclophosphamide. Their median age was 60 years (range, 47-70), and all had a median of 4 previous lines of therapy (range, 3-11).
Preliminary results on these 11 patients—5 with chronic lymphocytic leukemia (CLL) and 6 with non-Hodgkin lymphoma (NHL)—show a 73% objective response rate, with 7 achieving complete remission (CR) at the median 13.8-month follow-up. An eighth patient with CLL with Richter’s transformation had a CR but also experienced ongoing cytopenia and CLL bone marrow infiltration. None of the patients experienced symptoms related to CRS, neurotoxicity, hemophagocytic lymphohistiocytosis, or graft-versus-host disease. All responses were noted within 30 days, irrespective of dose level.
“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,” they concluded. “Our preliminary results show that CAR NK cells can induce responses in patients with high-risk CD19-positive cancers with relatively few adverse events aside from transient myelotoxicity.”
In contrast, they noted, for patients with NHL who receive anti-CD19 CAR T cells, there is just a 43% rate of progression-free survival at 1 year, and this drops to 30% among patients with CLL.
Liu E, Marin D, Banerjee P, et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med. 2020;382(6);545-553. doi: 10.1056/NEJMoa1910607.