Adoptive Cellular Therapy using Cells Enriched for NKG2D+CD3+CD8+T Cells after Autologous Transplantation for Myeloma

Abstract

The number of circulating lymphocytes on day 15 after transplantation correlates with improved survival in patients with myeloma, but the lymphocyte subset responsible is unknown. NKG2D is a natural killer (NK) cell activating receptor that mediates non-MHC restricted and TCR-independent cell lysis. Our preliminary results indicate that CD3+CD8+ T cells expressing NKG2D may be a critical lymphocyte population. A phase II trial examined the feasibility of infusing ex vivo-expanded cells enriched for NKG2D+CD3+CD8+ T cells at weeks 1, 2, 4, and 8 after an autologous transplantation. In addition, low-dose IL-2 (6 × 105 IU/m2/day) was administered for 4 weeks, beginning on the day of transplantation. Twenty-three patients were accrued and 19 patients are evaluable. There were no treatment-related deaths. All patients completed their course of IL-2 and demonstrated normal engraftment. When compared with patients with myeloma who underwent transplantation not receiving posttransplantation immune therapy, the treated patients demonstrated an increase in the number of circulating NKG2D+CD3+CD8+ T cells/μL (P < .004), CD3+CD8+ T cells/μL (P < .04), CD3+CD8+CD56+ T cells/μL (P < .004), and NKG2D+CD3−CD56+ T cells/μL (P < .003). Myeloma cell-directed cytotoxicity by the circulating mononuclear cells increased after transplantation (P < .002). When compared to posttransplantation IL-2 therapy alone in this patient population, the addition of cells enriched for NKG2D+CD3+CD8+ T cells increased tumor-specific immunity, as demonstrated by enhanced lysis of autologous myeloma cells (P = .02). We postulate that this regimen that increased the number and function of the NKG2D+CD3+CD8+ T cells after transplantation may improve clinical outcomes by eliminating residual malignant cells in vivo.

Clinically Applicable Magnetic-Labeling of Natural Killer Cells for MRI of Transcatheter Delivery to Liver Tumors: Preclinical Validation for Clinical Translation

“…Given the possibility that NK-92 cells may be eliminated prematurely by a host's immune system, further studies are clearly needed to rigorously evaluate therapeutic efficacy in the setting of adoptive immunotherapy. An additional limitation was that MRI tracking of labeled NK migration within target liver tissues was performed at only two time points postinfusion (30 min and 12 h) and our study protocol examined only one NK dose (2 × 10 7 cells) [42]. The currently used dose was selected from references and our initial experiences [8,30,43–44]; additional studies will be valuable to determine how many labeled NK cells provide measureable changes and the optimal postinfusion time intervals for follow-up imaging measurements.…”

Natural Killer Cell Responses in Hepatocellular Carcinoma: Implications for Novel Immunotherapeutic Approaches

“…NKG2D-based CARs can recognize NKG2D ligands expressed on several human tumor types, but these ligands are also expressed in some immune-mediated diseases such as rheumatoid arthritis, in celiac and inflammatory bowel diseases and in multiple sclerosis, which raises concerns about "on-target off-tumor" toxicity [86]. However, large numbers of activated lymphocytes, that express NKG2D and recognize NKG2D ligand expressing cells, have been infused into patients with little systemic toxicity [87][88][89][90].…”

NKG2D CARs as Cell Therapy for Cancer

“…However, large numbers of activated lymphocytes (>10 9 cells), which express NKG2D and can recognize NKG2D ligand expressing cells (e.g. NKT cells, gd T cells, NK cells), have been infused into patients with little toxicity 33-36 .…”