Natural killer cells plus high-dose chemotherapy, HSCT show promise for B-cell lymphoma
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Combining natural killer cells with high-dose chemotherapy and autologous stem cell transplant did not increase toxicity among patients with B-cell non-Hodgkin lymphoma, according to results presented at TCT Meetings Digital Experience.
About two-thirds of patients remained in remission a median 18 months after receiving the investigational treatment regimen, according to researchers.
The regimen included infusion with ex vivo-expanded, cord blood-derived allogeneic natural killer (NK) cells plus high-dose chemotherapy and autologous hematopoietic stem cell transplantation.
“We wanted to exploit the major role of NK cells in antitumor immunity,” Yago L. Nieto, MD, PhD, professor of stem cell transplantation at The University of Texas MD Anderson Cancer Center, told Healio.
Nieto said autologous NK cells from patients with lymphoma are often dysfunctional, so his team deployed allogeneic cord blood-derived NK cells expanded at MD Anderson’s Good Manufacturing Practice lab using a method based on artificial antigen-presenting cells. The result is a “massive” increase of NK cells that can be infused into the patient, he added.
“Building on our prior work in patients [with myeloma], in this pilot trial we consistently expanded the [cord blood]-derived NK cells more than 1,000-fold over a 2-week period,” Nieto said.
The NK cells are not directed toward a particular tumor antigen and did not undergo genetic manipulation during expansion, Nieto said.
Nieto and colleagues enrolled 20 patients (median age, 60 years; range 33-70; 70% men) with B-cell NHL between December 2017 and July 2020. Sixteen patients had diffuse large B-cell lymphoma, two patients had mantle cell lymphoma and one patient had follicular lymphoma.
Thirteen patients had relapsed disease and four patients had primary refractory disease The two patients with mantle cell lymphoma received the regimen as first-line therapy. Patients had a median two (range, 1-4) previous lines of therapy.
Patients received a high-density chemotherapy regimen that began 12 days before autologous HSCT. The chemotherapy regimen included 300 mg/m2 carmustine on day 12, 200 mg/m2 etoposide and 200 mg/m2 cytarabine twice daily on days 11 to 8, and 140 mg/m2 melphalan on day 7 before transplant. Patients also received rituximab (Rituxan; Genentech, Biogen) to prevent antibody-dependent cellular cytotoxicity and lenalidomide (Revlimid, Bristol Myers Squibb) to support NK cell proliferation and effector function.
Five days before transplant, patients received an infusion of expanded allogeneic NK cells of up to 108 cells/kg. One patient died before receiving the infusion due to rapid tumor progression.
Safety, based on 30-day treatment-related mortality, served as the study’s primary endpoint. Secondary endpoints included RFS, OS, and duration of infused NK cells.
Median follow-up was 18 months (range, 4-340).
Researchers reported no adverse events resulting from infusion with the expanded NK cells. This included a lack of infusion-related reactions, neurotoxicity, cytokine release syndrome or graft-versus-host disease.
One patient died of pneumonia 2 months after receiving allogeneic HSCT and two patients died of disease progression.
Efficacy results showed an OS rate of 84% and RFS rate of 68%. Eleven patients (69%) with diffuse large B-cell lymphoma remained in remission as of the data cutoff point.
Researchers expanded the NK cells a median 1,552-fold (range, 317-4,767); infusions contained a highly purified product that was detectable for a mean 2 weeks (range, 2-3) in peripheral blood.
Analysis also showed infused NK cells expressed a higher percentage of two activation receptors — NKG2D and NKp30 — than the recipient’s own NK cells from weeks 1 to 3 after infusion. This indicated an effector phenotype, according to the researchers. Additionally, persistence of the expanded NK cells was not affected by degree of HLA mismatch with the patient, they wrote.
It would be premature to compare results of this small pilot trial with response rates of currently available therapies, Nieto said. However, he said the results are encouraging given that 69% of patients with diffuse large B-cell lymphoma remained in remission a median 18 months after therapy.
In terms of safety, Nieto said the results show allogeneic cord blood-derived NK cells can be added to high-dose chemotherapy and autologous HSCT with no increase in adverse effects.
“This study is a stepstone in our strategy to improve outcomes of autologous [stem cell transplant] for lymphomas through the combination of [high-dose chemotherapy] with effective immunotherapies,” he told Healio. “Future efforts will focus on the use of targeted NK cells (eg, by CAR technology) or frozen off-the-shelf NK cells, which will expedite treatment for these patients.”
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Nieto Y, et al. Abstract LBA15. Presented at: The 2021 TCT Meetings Digital Experience (virtual meeting); Feb. 8-12, 2021.
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