Clinical and immunological evaluation of zoledronate-activated Vγ9γδ T-cell-based immunotherapy for patients with multiple myeloma

Abe, Yu; Muto, Masato; Nieda, Mie; Nakagawa, Yasunori; Nicol, Andrew; Kaneko, Touru; Goto, Shigenori; Yokokawa, Kiyoshi; Suzuki, Kenshi

doi:10.1016/j.exphem.2009.04.008

Cited by 156 publications

(112 citation statements)

References 35 publications

Supporting

Mentioning

111

Contrasting

Unclassified

Order By: Relevance

“…In this regard, it has to be noted that most immunotherapeutic approaches using gd T cells and ZOL were conducted in patients with solid tumor, whereas only 3 studies were conducted in patients with hematologic disorders. 35,59,60 Two of the latter were performed by combining low-dose IL-2 together with ZOL to activate autologous gd T cells in patients with various hematologic disorders, who had not received an allograft. 35,60 Treatment was generally well tolerated, and clinical responses, including partial remission and disease stabilization, were observed in both trials.…”

Section: Discussionmentioning

confidence: 99%

γδ T-cell reconstitution after HLA-haploidentical hematopoietic transplantation depleted of TCR-αβ+/CD19+ lymphocytes

Airoldi

Bertaina

Prigione

et al. 2015

Blood

218

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

γδ T-cell reconstitution after HLA-haploidentical hematopoietic transplantation depleted of TCR-αβ+/CD19+ lymphocytes

Airoldi

Bertaina

Prigione

et al. 2015

Blood

218

View full text Add to dashboard Cite

show abstract

“…This culture method has been used in phase I clinical trials evaluating the safety and feasibility of Zoledronate-expanded γδ T cell transfer therapy in patients with multiple myeloma or lung cancer. 12,13 No conflicts of interest declared.…”

Section: Representative Resultsmentioning

confidence: 99%

Expansion of Human Peripheral Blood γδ T Cells using Zoledronate

Kondo

Izumi

Fujieda

et al. 2011

JoVE

View full text Add to dashboard Cite

Human γδ T cells can recognize and respond to a wide variety of stress-induced antigens, thereby developing innate broad anti-tumor and anti-infective activity. 1 The majority of γδ T cells in peripheral blood have the Vγ9Vδ2 T cell receptor. These cells recognize antigen in a major histocompatibility complex-independent manner and develop strong cytolytic and Th1-like effector functions. 1 Therefore, γδ T cells are attractive candidate effector cells for cancer immunotherapy. Vγ9Vδ2 T cells respond to phosphoantigens such as (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), which is synthesized in bacteria via isoprenoid biosynthesis; 2 and isopentenyl pyrophosphate (IPP), which is produced in eukaryotic cells through the mevalonate pathway. 3 In physiological condition, the generation of IPP in nontransformed cell is not sufficient for the activation of γδ T cells. Dysregulation of mevalonate pathway in tumor cells leads to accumulation of IPP and γδ T cells activation. 3 Because aminobisphosphonates (such as pamidronate or zoledronate) inhibit farnesyl pyrophosphate synthase (FPPS), the enzyme acting downstream of IPP in the mevalonate pathway, intracellular levels of IPP and sensitibity to γδ T cells recognition can be therapeutically increased by aminobisphosphonates. IPP accumulation is less efficient in nontransfomred cells than tumor cells with a pharmacologically relevant concentration of aminobisphosphonates, that allow us immunotherapy for cancer by activating γδ T cells with aminobisphosphonates. 4 Interestingly, IPP accumulates in monocytes when PBMC are treated with aminobisphosphonates, because of efficient drug uptake by these cells. 5 Monocytes that accumulate IPP become antigen-presenting cells and stimulate Vγ9Vδ2 T cells in the peripheral blood. 6 Based on these mechanisms, we developed a technique for large-scale expansion of γδ T cell cultures using zoledronate and interleukin-2 (IL-2). 7 Other methods for expansion of γδ T cells utilize the synthetic phosphoantigens bromohydrin pyrophosphate (BrHPP) 8 or 2-methyl-3-butenyl-1-pyrophosphate (2M3B1PP). 9 All of these methods allow ex vivo expansion, resulting in large numbers of γδ T cells for use in adoptive immunotherapy. However, only zoledronate is an FDA-approved commercially available reagent. Zoledronate-expanded γδ T cells display CD27 -CD45RA -effector memory phenotype and thier function can be evaluated by IFN-γ production assay. 7

show abstract

“…injection of 2310 9 -4310 9 cells/patient in six healthy volunteers, 10 patients with advanced non-small cell lung cancers, five patients with bone metastases from prostate or breast cancer, four patients with lung metastases from colon cancer 42 and six multiple myeloma patients. 43 This team further enrolled 25 additional patients carrying various solid tumors who had not undergone treatment with statins (blockers of endogenous phosphoantigen biosynthesis) for zoledronate-activated TCRVc9Vd2 1 cd T cell-based immunotherapy. Two of these patients received cd cells 3 times, five patients 4 times, one patient 5 times and 17 patients 6 times.…”

Section: Rationale For Harnessing CD Cells In Cancer Immunotherapymentioning

confidence: 99%

What lessons can be learned from γδ T cell-based cancer immunotherapy trials?

et al. 2012

View full text Add to dashboard Cite

During the last several years, research has produced a significant amount of knowledge concerning the characteristics of human cd T lymphocytes. Findings regarding the immune functions of these cells, particularly their natural killer cell-like lytic activity against tumor cells, have raised expectations for the therapeutic applications of these cells for cancer. Pharmaceutical companies have produced selective agonists for these lymphocytes, and several teams have launched clinical trials of cd T cell-based cancer therapies. The findings from these studies include hematological malignancies (follicular lymphoma, multiple myeloma, acute and chronic myeloid leukemia), as well as solid tumors (renal cell, breast and prostate carcinomas), consisting of samples from more than 250 patients from Europe, Japan and the United States. The results of these pioneering studies are now available, and this short review summarizes the lessons learned and the role of cd T cell-based strategies in the current landscape of cancer immunotherapies.

show abstract

Clinical and immunological evaluation of zoledronate-activated Vγ9γδ T-cell-based immunotherapy for patients with multiple myeloma

Cited by 156 publications

References 35 publications

γδ T-cell reconstitution after HLA-haploidentical hematopoietic transplantation depleted of TCR-αβ+/CD19+ lymphocytes

γδ T-cell reconstitution after HLA-haploidentical hematopoietic transplantation depleted of TCR-αβ+/CD19+ lymphocytes

Expansion of Human Peripheral Blood γδ T Cells using Zoledronate

What lessons can be learned from γδ T cell-based cancer immunotherapy trials?

Contact Info

Product

Resources

About

Clinical and immunological evaluation of zoledronate-activated Vγ9γδ T-cell-based immunotherapy for patients with multiple myeloma

Cited by 156 publications

References 35 publications

γδ T-cell reconstitution after HLA-haploidentical hematopoietic transplantation depleted of TCR-αβ+/CD19+ lymphocytes

γδ T-cell reconstitution after HLA-haploidentical hematopoietic transplantation depleted of TCR-αβ+/CD19+ lymphocytes

Expansion of Human Peripheral Blood &gamma;&delta; T Cells using Zoledronate

What lessons can be learned from γδ T cell-based cancer immunotherapy trials?

Contact Info

Product

Resources

About

Expansion of Human Peripheral Blood γδ T Cells using Zoledronate