All Stem Cells Japan

Safety analysis of ex vivo-expanded NK and NK-like T cells administered to cancer patients : a Phase I clinical study.

The chimeric state after allogeneic hematopoietic stem cell transplantation provides a platform for adoptive
immunotherapy using donor-derived immune cells. The major risk with donor lymphocyte infusions (DLIs)
is the development of graft-versus-host disease (GvHD). Development of new DLI products with antitumor
reactivity and reduced GvHD risk represents a challenging task in cancer immunotherapy. Although natural
killer (NK) and NK-like T cells are promising owing to their antitumor activity, their low concentrations in
peripheral blood mononuclear cells reduces their utility in DLIs. We have recently developed a system that
allows expansion of clinical-grade NK and NK-like T cells in large numbers. In this study, the safety of
donor-derived long-term ex vivo-expanded human NK and NK-like T cells given as DLIs was investigated
as immunotherapy for cancer in five patients following allogeneic stem cell infusion. Infusion of the cells
was safe whether administered alone or with IL-2 subcutaneously. No signs of acute GvHD were observed.
One patient with hepatocellular carcinoma showed markedly decreased serum α-fetoprotein levels
following cell infusions. These findings suggest that the use of ex vivo-expanded NK and NK-like T cells is
safe and appears an attractive approach for further clinical evaluation in cancer patients.

Discussion

In this Phase I clinical trial, we explored the safety and feasibility of administering ex vivo expanded NK and NK-like T-effector cells as DLI to five cancer patients after SCT. Cell infusions, with or without s.c. IL-2 injections, seemed to be safe as no aGvHD was observed.
One patient suffered from to the procedure associated septicemia. At present, our laboratory facilities allow the NK and NK-like T cell expansion using an automated and closed system to avoid any contaminations.
Currently, treatment options using pure NK cells or NK-enriched effector cell preparations are being investigated in Phase I/II clinical trials using purified/resting [20,21], short-term [22–24] or long-term [25] activated NK cells. Most of these studies report NK cell infusions to be well tolerated and partially effective; especially, in the haploidentical setting [26] and as DLI following SCT against various human cancers. One obstacle in clinical studies with these cells originates from their low number in PBMCs and in various ex vivo-expanded effector cell preparations such as cytotoxic T lymphocytes, LAK and CIK cells.
Obtaining a large number of NK and NK-like T cells may be instrumental in controlling certain tumors and GvHD. This would add to success gained in tailoring DLI regimens using a stepwise escalating-dose regimens demanding increasing cell numbers [27,28].
See More : www.ncbi.nlm.nih.gov/pubmed/20636021

Executive summary

Expansion of donor-derived NK and NK-like T cells using a feeder-free GMP-compatible expansion strategy is feasible and provides high number of cells for immunotherapy approaches.
Infusion of such ex vivo-expanded NK and NK-like T cells to cancer patients with or without IL-2 is safe with a possible antitumor activity. Further clinical studies to investigate the efficiency of this approach of cancer immunotherapy are warranted.
Source : Safety analysis of ex vivo-expanded NK & NK-like T cells in cancer patients, Immunotherapy (2009), future science group

KEYWORDS

: cellular, immunotherapy, donor, lymphocyte,infusion,ex vivo, expansion, hematopoietic stem cell, transplantation, NK cell, NK-like T cell