Pediatric and young adult (YA) patients with acute myeloid leukemia (AML) who relapse after allogeneic hematopoietic cell transplantation (HCT) have an extremely poor prognosis. Standard salvage ...chemotherapy and donor lymphocyte infusions (DLIs) have little curative potential. Previous studies showed that natural killer (NK) cells can be stimulated ex vivo with interleukin-12 (IL-12), -15, and -18 to generate memory-like (ML) NK cells with enhanced antileukemia responses. We treated 9 pediatric/YA patients with post-HCT relapsed AML with donor ML NK cells in a phase 1 trial. Patients received fludarabine, cytarabine, and filgrastim followed 2 weeks later by infusion of donor lymphocytes and ML NK cells from the original HCT donor. ML NK cells were successfully generated from haploidentical and matched-related and -unrelated donors. After infusion, donor-derived ML NK cells expanded and maintained an ML multidimensional mass cytometry phenotype for >3 months. Furthermore, ML NK cells exhibited persistent functional responses as evidenced by leukemia-triggered interferon-γ production. After DLI and ML NK cell adoptive transfer, 4 of 8 evaluable patients achieved complete remission at day 28. Two patients maintained a durable remission for >3 months, with 1 patient in remission for >2 years. No significant toxicity was experienced. This study demonstrates that, in a compatible post-HCT immune environment, donor ML NK cells robustly expand and persist with potent antileukemic activity in the absence of exogenous cytokines. ML NK cells in combination with DLI present a novel immunotherapy platform for AML that has relapsed after allogeneic HCT. This trial was registered at https://clinicaltrials.gov as #NCT03068819.
•Immune-compatible donor memory-like NK cells expand and functionally persist for months after a single dose without exogenous cytokines.•Combined with standard therapy, donor ML NK cells safely induce remissions in poor prognosis, pediatric, relapsed AML after HCT.
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Purpose
We investigated the prognostic value of total metabolic tumour volume (TMTV) in diffuse large B-cell lymphoma (DLBCL).
Methods
TMTV was measured in 114 patients with newly diagnosed DLBCL who ...underwent
18
F-FDG PET/CT at baseline before immunochemotherapy. TMTV was computed by summing the volumes of all lymphomatous lesions after applying the local SUVmax threshold of 41 % using semiautomatic software. Prognostic value was assessed by Kaplan-Meier estimates of progression-free survival (PFS) and overall survival (OS).
Results
Median follow-up was 39 months. Average pretherapy TMTV was 509 ± 568 cm
3
. The 3-year estimates of PFS were 77 % in the low metabolic burden group (TMTV ≤550 cm
3
) and 60 % in the high metabolic burden group (TMTV >550 cm
3
,
p
= 0.04), and prediction of OS was even better (87 % vs. 60 %,
p
= 0.0003). Cox regression showed independence of TMTV for OS prediction (
p
= 0.002) compared with other pretherapy indices of tumour burden, such as tumour bulk and the International Prognostic Index.
Conclusion
Pretherapy TMTV is an independent predictor of outcome in patients with DLBCL.
The prognosis of patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) remains poor and current treatments are typically of limited benefit. Histone deacetylase (HDAC) inhibitors have ...proven effective for the treatment of relapsed/refractory PTCL. To date approved HDAC inhibitors for patients with T-cell lymphoma are vorinostat, romidepsin and, recently, belinostat. Here we review the pharmacology and the clinical activity of belinostat. Belinostat is a well-tolerated HDAC inhibitor that has shown activity in heavily pretreated patients with relapsed/refractory PTCL. Several clinical trials are currently investigating the use of belinostat in different cancers and in combination with other chemotherapeutic agents.
Natural killer (NK) cells are innate lymphoid cells that eliminate cancer cells, produce cytokines, and are being investigated as a nascent cellular immunotherapy. Impaired NK cell function, ...expansion, and persistence remain key challenges for optimal clinical translation. One promising strategy to overcome these challenges is cytokine-induced memory-like (ML) differentiation, whereby NK cells acquire enhanced antitumor function after stimulation with interleukin-12 (IL-12), IL-15, and IL-18. Here, reduced-intensity conditioning (RIC) for
-haploidentical hematopoietic cell transplantation (HCT) was augmented with same-donor ML NK cells on day +7 and 3 weeks of N-803 (IL-15 superagonist) to treat patients with relapsed/refractory acute myeloid leukemia (AML) in a clinical trial (NCT02782546). In 15 patients, donor ML NK cells were well tolerated, and 87% of patients achieved a composite complete response at day +28, which corresponded with clearing high-risk mutations, including
variants. NK cells were the major blood lymphocytes for 2 months after HCT with 1104-fold expansion (over 1 to 2 weeks). Phenotypic and transcriptional analyses identified donor ML NK cells as distinct from conventional NK cells and showed that ML NK cells persisted for over 2 months. ML NK cells expressed CD16, CD57, and high granzyme B and perforin, along with a unique transcription factor profile. ML NK cells differentiated in patients had enhanced ex vivo function compared to conventional NK cells from both patients and healthy donors. Overall, same-donor ML NK cell therapy with 3 weeks of N-803 support safely augmented RIC haplo-HCT for AML.
Abstract
Natural killer (NK) cells are an emerging cancer cellular therapy and potent mediators of antitumor immunity. Cytokine-induced memory-like (ML) NK cellular therapy is safe and induces ...remissions in patients with acute myeloid leukemia (AML). However, the dynamic changes in phenotype that occur after NK-cell transfer that affect patient outcomes remain unclear. Here, we report comprehensive multidimensional correlates from ML NK cell–treated patients with AML using mass cytometry. These data identify a unique in vivo differentiated ML NK–cell phenotype distinct from conventional NK cells. Moreover, the inhibitory receptor NKG2A is a dominant, transcriptionally induced checkpoint important for ML, but not conventional NK-cell responses to cancer. The frequency of CD8α+ donor NK cells is negatively associated with AML patient outcomes after ML NK therapy. Thus, elucidating the multidimensional dynamics of donor ML NK cells in vivo revealed critical factors important for clinical response, and new avenues to enhance NK-cell therapeutics.
Significance:
Mass cytometry reveals an in vivo memory-like NK-cell phenotype, where NKG2A is a dominant checkpoint, and CD8α is associated with treatment failure after ML NK–cell therapy. These findings identify multiple avenues for optimizing ML NK–cell immunotherapy for cancer and define mechanisms important for ML NK–cell function.
This article is highlighted in the In This Issue feature, p. 1775
Purpose
The role of interim PET/CT in guiding therapeutic strategies in diffuse large B-cell lymphoma (DLBCL) is debated, mainly because interpretation rules vary among centres. This study aimed to ...explore the reproducibility and confirm the prognostic value of early PET/CT using the Deauville criteria and ΔSUVmax.
Methods
This international confirmatory study retrospectively evaluated 114 patients with newly diagnosed DLBCL treated with a rituximab-containing regimen. All patients underwent
18
F-FDG PET/CT at baseline (PET0) and after two cycles (PET2), with no therapy change based on the latter. Scans were interpreted by three observers using the Deauville five-point scale and ΔSUVmax between PET0 and PET2 was calculated. Interpretations were evaluated for interobserver agreement and for progression-free survival (PFS) prediction.
Results
Median follow-up was 39 months. Early PET/CT was predictive of outcome when interpreted with the Deauville criteria and ΔSUVmax. Using the five-point scale, the overall kappa value was 0.66 with the reference background set in the liver (score ≥4) and interobserver agreement was even better using a 66 % ΔSUVmax cut-off (κ = 0.83). Moreover, the prognostic value of interim PET was slightly inferior when using a Deauville score ≥4 than when using a 66 % ΔSUVmax cut-off: for the Deauville score the 3-year PFS estimate was 59 % (45–73 %) in PET2-positive patients vs. 81 % (71–91 %) in PET2-negative patients (
P
= 0.003); for the 66 % ΔSUVmax cut-off the 3-year PFS estimate was 44 % (23–65 %) in PET2-positive patients vs. 79 % (70–88 %) in PET2-negative patients (
P
= 0.0002).
Conclusion
Although the Deauville criteria are valid for assessing the prognostic value of early PET/CT in DLBCL, computation of the ΔSUVmax leads to better performance and interobserver reproducibility, and should be preferred when a baseline scan is available.
A single subcutaneous (SC) injection of plerixafor results in rapid mobilization of hematopoietic progenitors, but fails to mobilize 33% of normal allogeneic sibling donors in 1 apheresis. We ...hypothesized that changing the route of administration of plerixafor from SC to IV may overcome the low stem cell yields and allow collection in 1 day. A phase 1 trial followed by a phase 2 efficacy trial was conducted in allogeneic sibling donors. The optimal dose of IV plerixafor was determined to be 0.32 mg/kg. The primary outcome of reducing the failure to collect ≥2 × 106 CD34+/kg recipient weight in 1 apheresis collection to ≤10% was not reached. The failure rate was 34%. Studies evaluating the stem cell phenotype and gene expression revealed a novel plasmacytoid dendritic cell precursor preferentially mobilized by plerixafor with high interferon-α producing ability. The observed cytomegalovirus (CMV) viremia rate for patients at risk was low (15%), as were the rates of acute grade 2-4 graft-versus-host disease (GVHD) (21%). Day 100 treatment related mortality was low (3%). In conclusion, plerixafor results in rapid stem cell mobilization regardless of route of administration and resulted in novel cellular composition of the graft and favorable recipient outcomes. These trials were registered at clinicaltrials.gov as #NCT00241358 and #NCT00914849.
•Plerixafor is a safe, effective, rapid mobilizing agent when administered intravenously.•Lower rates of GVHD and CMV viremia with plerixafor-mobilized grafts may be related to a unique cellular composition of the graft.
Anti-CD20 monoclonal antibodies (mAb) are an important immunotherapy for B-cell lymphoma, and provide evidence that the immune system may be harnessed as an effective lymphoma treatment approach. ...ALT-803 is a superagonist IL-15 mutant and IL-15Rα-Fc fusion complex that activates the IL-15 receptor constitutively expressed on natural killer (NK) cells. We hypothesized that ALT-803 would enhance anti-CD20 mAb-directed NK-cell responses and antibody-dependent cellular cytotoxicity (ADCC).
We tested this hypothesis by adding ALT-803 immunostimulation to anti-CD20 mAb triggering of NK cells in vitro and in vivo. Cell lines and primary human lymphoma cells were utilized as targets for primary human NK cells. Two complementary in vivo mouse models were used, which included human NK-cell xenografts in NOD/SCID-γc (-/-) mice.
We demonstrate that short-term ALT-803 stimulation significantly increased degranulation, IFNγ production, and ADCC by human NK cells against B-cell lymphoma cell lines or primary follicular lymphoma cells. ALT-803 augmented cytotoxicity and the expression of granzyme B and perforin, providing one potential mechanism for this enhanced functionality. Moreover, in two distinct in vivo B-cell lymphoma models, the addition of ALT-803 to anti-CD20 mAb therapy resulted in significantly reduced tumor cell burden and increased survival. Long-term ALT-803 stimulation of human NK cells induced proliferation and NK-cell subset changes with preserved ADCC.
ALT-803 represents a novel immunostimulatory drug that enhances NK-cell antilymphoma responses in vitro and in vivo, thereby supporting the clinical investigation of ALT-803 plus anti-CD20 mAbs in patients with indolent B-cell lymphoma.
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