Early recovery of aggressive cytotoxic cells and improved immune resurgence with post-transplant immunotherapy for multiple myeloma

Meehan, Kenneth R.; Wu, Jillian; Bengtson, Elizabeth M.; Hill, John M.; Ely, Pamela; Szczepiórkowski, Zbigniew M.; Kendall, Michelle A.; Ernstoff, Marc S.

doi:10.1038/sj.bmt.1705665

Cited by 8 publications

(6 citation statements)

References 40 publications

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“…IFNγ also upregulates the expression of TRAIL and leads to increased apoptosis of myeloma cells [42]. GM-CSF is often included in clinical trials for the treatment of myeloma and may play a role in increasing tumor antigen presentation and regeneration of host immune cells after chemotherapy and stem cell transplantation [2,3,43,44]. In mouse models of lymphoma and ovarian cancer, chNKG2D T cell-derived IFNγ and GM-CSF were critical for anti-tumor efficacy in vivo [27,28].…”

Section: Discussionmentioning

confidence: 99%

Chimeric NKG2D receptor–expressing T cells as an immunotherapy for multiple myeloma

Barber

Zhang

Megli

et al. 2008

Experimental Hematology

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Objective Most myeloma tumor cells from patients express NKG2D ligands. We have reported the development of a chimeric NKG2D receptor (chNKG2D), which consists of the NKG2D receptor fused to the CD3ζ chain. T cells expressing this receptor kill and produce cytokines in response to NKG2D-ligand+ tumor cells. Therefore we investigated whether human chNKG2D T cells respond against human myeloma cells. Methods ChNKG2D T cells were generated from healthy donors and myeloma patients. The effector phase of chNKG2D T cells was analyzed by cell-surface marker expression and human myeloma cell lines were tested for expression of NKG2D ligands. Lysis of myeloma cell lines and cytokine secretion by chNKG2D T cells was determined. ChNKG2D T cells grown in serum-free media, or cyropreserved, were assessed for effector cell functions. Results Myeloma cell lines expressed NKG2D ligands. ChNKG2D T cells from healthy donors and myeloma patients lysed myeloma cells, and secreted proinflammatory cytokines when cultured with myeloma cells or patient bone marrow but not with PBMCs or normal bone marrow. Lysis of myeloma cells was dependent on chNKG2D T cell expression of NKG2D and perforin. Additionally, chNKG2D T cells upregulated CD45RO, did not express CD57, and maintained expression of CD27, CD62L, and CCR7, indicating that the T cells were at an early effector stage. Finally, we showed that chNKG2D T cells generated with serum-free media, or when cryopreserved, maintained effector functions. Conclusion ChNKG2D T cells respond to human myeloma cells and can be generated using clinically applicable cell culture techniques.

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Section: Discussionmentioning

confidence: 99%

Chimeric NKG2D receptor–expressing T cells as an immunotherapy for multiple myeloma

Barber

Zhang

Megli

et al. 2008

Experimental Hematology

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“…The dose and duration of IL-2 (Prometheus Laboratories Inc, San Diego, CA) were based on our prior clinical trials [7,17–19]. IL-2 (6 × 10 5 IU/m 2 /day) was started on day 0 and administered as a twice-a-day subcutaneous injection, and given on a 5-days on 2-days off cycle for 4 consecutive weeks.…”

Section: Methodsmentioning

confidence: 99%

“…Patients also received posttransplantation IL-2 for 4 weeks [5,7,8,17,18]. The clinical objectives were to define engraftment and toxicity in patients conditioned with this regimen.…”

Section: Introductionmentioning

confidence: 99%

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

Meehan

Talebian

Tosteson

et al. 2013

Biology of Blood and Marrow Transplantation

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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.

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“…It is intriguing that the long term follow up of these subjects indicates nearly 2/3 of these high risk subjects remain as long term remitters. Prior studies in the autologous setting have noted improved lymphocyte recovery and documented increased cytokine release, though there has been limited clinical benefit of delivering IL2 following high dose therapy 19,20,21 . In a modified autologous setting with transient allogeneic lymphocyte boosts combined 22 , data has been somewhat more encouraging in a small report noting safety and potential clinical benefit, indicating the allogeneic setting may offer enhanced opportunities for the activated immune system to target the cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Feasibility of Low-Dose Interleukin-2 Therapy Following T-Cell-Depleted Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation From HLA-Matched or -Mismatched Family Member Donors

Rizzieri

Crout

Storms

et al. 2010

Cancer Investigation

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High relapse rates and infections remain primary causes of failure in non-myeloablative transplantation. Interleukin-2 (IL-2) may stimulate the immune system and improve outcomes. The primary objective of this pilot study was to evaluate the feasibility of administering IL-2 following a T cell-depleted nonmyeloablative hematopoietic stem cell transplant. Methods Patients received T cell depleted nonmyeloablative transplant from a matched or mismatched related donor. Those with allogeneic engraftment, < grade 2 acute GVHD at time of study entry, and no severe end organ damage were eligible and received IL2 starting 6 weeks after the first day of stem cell infusion. Patients received 1 mu/m2 daily for 5 days each week for 4 weeks followed by a 2 week rest period for a 6 week cycle to continue for up to 1 year. Results Eight patients aged 28–69 were treated. Significant toxicities were limited to GVHD of the skin ≤ grade 2 in 3 patients and severe fatigue in 4 patients, limiting the duration of therapy. Two of the 8 patients died of relapsed disease and one from CMV. With a median overall duration of follow up of survivors of 48 months, five patients (63%) remain alive and in continuous complete remission.

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Early recovery of aggressive cytotoxic cells and improved immune resurgence with post-transplant immunotherapy for multiple myeloma

Cited by 8 publications

References 40 publications

Chimeric NKG2D receptor–expressing T cells as an immunotherapy for multiple myeloma

Chimeric NKG2D receptor–expressing T cells as an immunotherapy for multiple myeloma

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

Feasibility of Low-Dose Interleukin-2 Therapy Following T-Cell-Depleted Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation From HLA-Matched or -Mismatched Family Member Donors

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