Therapeutic potential of natural killer cells in multiple myeloma

Multiple Myeloma (MM) is an incurable plasma cell neoplasm with a median length of survival after diagnosis of approximately three years; therefore new treatment modalities to eradicate the disease are needed. Although the disease remains incurable, current main alternatives are drug treatment modalities and autologous stem cell transplantation (ASCT).

In order to study the contribution of autologous infused cells to relapse as well as the long term persistence of a transgene in haematopoietic cells following ASCT for MM, we genetically marked autologous CD34+ enriched bone marrow or peripheral blood cell grafts from eight myeloma patients using retroviral vectors (paper I). The transgene could be detected for up to five years post-transplant in normal bone marrow cells, even in remission following relapse. No side effects related to retroviral gene transfer were observed. There were no marked myeloma cells observed in the patients either in remission or in relapsing disease. This supports the idea that lack of complete eradication of residual myeloma cells by conditioning, rather than the reintroduced myeloma cells during ASCT, is the cause of relapse.

Based on this finding, we set up a model to analyse new myeloma treatment modalities (paper II). In this study, 5T33MM cells were transduced with a retroviral vector coding GFP and injected to syngeneic C57BL/KaLwRij mice. Marked MM cells were successfully detected in different organs during disease development. The establishment of this model not only simplified the analysis of homing pattern of MM cells, but also eased the evaluation of therapeutic effects of different treatment approaches.

Using the C57BL/KaLwRij model, we determined anti-MM activity by NK cells following IL-2 administration, and if ex vivo activated and administered NK cell prolonged survival (paper III). Our data strongly support that IL-2 activated NK cells are not only the main effectors responsible for autologous myeloma cell killing in the C57BL/KaLwRij myeloma model, but also they increase life expectancy through adoptive transfer.

We are currently investigating the feasibility of expanding NK cells from MM patients with the aim of using them as a supportive or pre-emptive therapy. For this purpose, NK cells of 7 patients with MM were expanded in a clinical grade setting and their cytotoxic activity against autologous myeloma cells was evaluated. Our preliminary data show that ex vivo expanded primary human NK cells show autologous anti-myeloma activity.

Due to the effects of IL-2 on different cell populations in vivo, and the side effects such as cytokine leak syndrome in humans, we have created a retroviral vector that allows NK cells to be auto-activated by internal IL-2 production (paper IV). We then transduced an IL-2 dependent NK cell line as a proof of principle, and IL-2 dependent cells kept proliferating.

The above findings suggest that NK cells are important effector cells against MM and IL-2 is an important factor for their anti-myeloma activity. This indicates that IL-2 induced NK cells (gene modified or unmodified) can be analysed for feasibility in human settings.

List of scientific papers

I. Alici E, Bjorkstrand B, Treschow A, Aints A, Smith CI, Gahrton G, Dilber MS (2006). Long-term follow-up of gene-marked CD34(+) cells after autologous stem cell transplantation for multiple myeloma. Cancer Gene Ther. [Accepted]
https://pubmed.ncbi.nlm.nih.gov/17082794

II. Alici E, Konstantinidis KV, Aints A, Dilber MS, Abedi-Valugerdi M (2004). Visualization of 5T33 myeloma cells in the C57BL/KaLwRij mouse: establishment of a new syngeneic murine model of multiple myeloma. Exp Hematol. 32(11): 1064-72.
https://pubmed.ncbi.nlm.nih.gov/15539084

III. Alici E, Konstantinidis KV, Sutlu T, Aints A, Gahrton G, Ljunggren HG, Dilber MS (2006). Cytokine induced natural killer cells kill autologous myeloma cells in C57BL/KaLwRij. [Manuscript]

IV. Konstantinidis KV, Alici E, Aints A, Christensson B, Ljunggren HG, Dilber MS (2005). Targeting IL-2 to the endoplasmic reticulum confines autocrine growth stimulation to NK-92 cells. Exp Hematol. 33(2): 159-64.
https://pubmed.ncbi.nlm.nih.gov/15676209