Expanded and activated allogeneic NK cells are cytotoxic against B-chronic lymphocytic leukemia (B-CLL) cells with sporadic cases of resistance

Abstract

Adoptive transfer of allogeneic natural killer (NK) cells is becoming a credible immunotherapy for hematological malignancies. In the present work, using an optimized expansion/activation protocol of human NK cells, we generate expanded NK cells (eNK) with increased expression of CD56 and NKp44, while maintaining that of CD16. These eNK cells exerted significant cytotoxicity against cells from 34 B-CLL patients, with only 1 sample exhibiting resistance. This sporadic resistance did not correlate with match between KIR ligands expressed by the eNK cells and the leukemic cells, while cells with match resulted sensitive to eNK cells. This suggests that KIR mismatch is not relevant when expanded NK cells are used as effectors. In addition, we found two examples of de novo resistance to eNK cell cytotoxicity during the clinical course of the disease. Resistance correlated with KIR-ligand match in one of the patients, but not in the other, and was associated with a significant increase in PD-L1 expression in the cells from both patients. Treatment of one of these patients with idelalisib correlated with the loss of PD-L1 expression and with re-sensitization to eNK cytotoxicity. We confirmed the idelalisib-induced decrease in PD-L1 expression in the B-CLL cell line Mec1 and in cultured cells from B-CLL patients. As a main conclusion, our results reinforce the feasibility of using expanded and activated allogeneic NK cells in the treatment of B-CLL.

A Novel Immune-Related Seventeen-Gene Signature for Predicting Early Stage Lung Squamous Cell Carcinoma Prognosis

“…Correlation analysis found that monocytes, neutrophils, NK cells resting, T cells CD4 memory resting, B cells memory, and mast cells activated were positively correlated with the risk score, and NK cells activated and T cells' follicular helper were negatively correlated with the risk score. Based on the results of the difference analysis and correlation analysis, we found that patients in the low-risk group had better long-term survival rates, which may be due to the high proportion of NK cells activated and T cells follicular helper (60)(61)(62). Most gene mutations were the initiating factor of tumorigenesis.…”

Expanded NK cells from umbilical cord blood and adult peripheral blood combined with daratumumab are effective against tumor cells from multiple myeloma patients

“… 7 Regarding eNK cells obtained from PB, the significant increase in the NKp44 + population previously described in Sanchez-Martinez et al 40 was clearly confirmed in our latest study. 45 Consequently, we have determined the expression of NKp44 ligands on the surface of patient MM cells and found faint levels of expression (Suppl. Fig 3).…”

“…This result is in agreement with the reported low PD-1 expression in most eNK cells obtained from PB in our previous study. 45

Figure 3. A.

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“…7 This increase in cytotoxicity could be associated with increased expression of activation markers, 7 and of the activating receptor NKp44. 45 Moreover, in a similar study using a 5-d activation protocol, it was shown that the main change justifying the increase in cytotoxicity was the net increase in the level of granzyme B expression in activated NK cells. 40 We observed how UCB eNKs showed a higher average cytotoxicity on MM cells than PB eNKs.…”

Approaches to Enhance Natural Killer Cell-Based Immunotherapy for Pediatric Solid Tumors

“…Instead, allogeneic hematopoietic stem cell transplant (HSCT) and adoptive cell therapy with donor-derived, allogeneic NK cells ( Figure 2 ) are attractive alternatives to augment the graft-versus-tumor effect of NK cells generated by KIR mismatch [ 27 , 28 ]. While there are several studies observing the benefit of KIR-mismatched NK cells in leukemias [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ], more clinical and preclinical studies are needed to demonstrate the benefit of KIR mismatch in pediatric solid tumors. Delgado et al [ 20 ] found that osteosarcoma cell lines were most sensitive to allogeneic NK cell lysis when KIR receptor-ligand incompatibility was maximized.…”