Haploidentical Natural Killer Cells Infused before Allogeneic Stem Cell Transplantation for Myeloid Malignancies: A Phase I Trial

Abstract

Allogeneic stem cell transplantation is an effective treatment for high-risk myeloid malignancies, but relapse remains the major post-transplant cause of treatment failure. Alloreactive NK cells mediate a potent antileukemic effect and may also enhance engraftment and reduce GvHD. Haploidentical transplants provide a setting in which NK cell alloreactivity can be manipulated, but are associated with high rates of GvHD. We performed a phase I study infusing escalating doses of NK cells from an HLA haploidentical related donor – selected for alloreactivity when possible – as a component of the preparative regimen for allotransplantation from a separate HLA identical donor. The goal of infusing third party alloreactive NK cells was to augment the antileukemic effect of the transplant without worsening GvHD, and thus improve the overall outcome of hematopoietic transplantation. Twenty-one patients with high-risk AML, MDS, or CML refractory or beyond first remission received a preparative regimen with busulfan and fludarabine followed by infusion of apheresis-derived, antibody-selected, and IL-2-activated NK cells. Doses were initially based on total nucleated cell content and later based on CD56+ cells to reduce variability. CD56+ content ranged from 0.02 to 8.32 × 106/kg. IL-2, 0.5 × 106 units/m2 SQ was administered daily for five days in the final cohort (n=10). CD3+ cells in the NK cell product were required to be <105/kg. Median relapse-free, overall, and GvHD-free/relapse-free survival for all patients enrolled was 102, 233, and 89 days, respectively. Five patients are alive, five patients died of transplant-related causes, and eleven patients died of relapse. Despite the small sample size, survival was highly associated with CD56+ cells delivered (p = 0.022) and development of ≥ Grade 3 GvHD (p = 0.006). There were nonsignificant trends toward higher survival rates in those receiving NK cells from KIR ligand mismatched donors and KIR-B haplotype donors. There was no association with disease type, remission at time of transplant, or KIR content. GvHD was not associated with TNC, CD56+, or CD3+ cells infused in the NK cell product or the stem cell product. This trial demonstrates a lack of major toxicity attributable to 3rd-party NK cell infusions delivered in combination with an HLA compatible allogeneic transplantation. The infusion of haploidentical alloreactive NK cells was well tolerated and did not interfere with engraftment or increase the rate of GvHD after allogeneic hematopoietic transplantation. Durable complete remissions occurred in five patients at high risk for disease recurrence. This approach is being further developed in a Phase I/II trial with ex vivo expanded NK cells to increase the NK cell dose with the objective of reducing relapse and improving the outcome of allogeneic hematopoietic transplantation for AML/MDS.

PD-L1 blockade enhances anti-tumor efficacy of NK cells

“…14 Recently, increasing evidence from preclinical and clinical studies supports the potential efficacy of NK cell therapeutics in multiple cancer types. 15-19 Clinical studies also showed a positive correlation between outcomes of the therapy and the dose of NK cells administered, prompting the development of effective methods to grow NK cell in vitro . 19,20 …”

“…15-19 Clinical studies also showed a positive correlation between outcomes of the therapy and the dose of NK cells administered, prompting the development of effective methods to grow NK cell in vitro . 19,20 …”

Hepatocellular carcinoma: Prospects for natural killer cell immunotherapy

“…Autologous mononuclear cells incubated with IL‐2 and CD3 to produce cytokine‐induced killer (CIK) cells have shown promising results as an adjuvant therapy for HCC, with improved recurrence‐free survival . Allogeniec and haploidentical NK cell infusions have aimed to capitalise on KIR‐HLA mismatch, resulting in a loss of inhibition of infused NK cells coupled with tumour‐induced activation because of an increase in surface expression of stress‐induced ligands on tumour cells . Although no major detrimental side effects have been cited for these infusions, direct anti‐tumour efficacy has not yet been proven in solid tumours, and issues remain with determining the longevity of infused NK cell responses.…”

Emerging therapies for acute myeloid leukemia: translating biology into the clinic

“…NK cell-based therapy has been utilized in the setting of an allotransplant to enhance the GVL effect without compromising graft integrity (117,118). Advances in cellular processing and increased access to good manufacturing practices-compliant (GMP-compliant) laboratories has enabled ex vivo activation and expansion (using IL-2 or IL-15) of donor-derived NK cells for use in patients with active disease (119).…”