Natural killer cells, multiple myeloma, and daratumumab : a love-hate relationship

Multiple myeloma is a treatable, but not yet curable, malignant plasma cell disease. Over the last decades, the overall survival time of multiple myeloma patients has constantly increased thanks to improvements in conventional treatment methods like chemotherapy as well as autologous stem cell transplantation both in combination with novel drugs such as proteasome inhibitors or immunomodulatory drugs. However, no cure has been found yet. The only treatment that has the potential to cure multiple myeloma is allogeneic stem cell transplantation. However, it is seldomly used due to lack of donor availability, high risk for treatment related mortality and occurrence of graft versus host disease. The development of monoclonal antibody treatments for several cancer indications has shown great success. Lately, the emergence of Daratumumab, an anti-CD38 monoclonal antibody targeting plasma cells, has given a new hope for patients. Daratumumab has a minor direct effect on the MM cells but the majority of its effectiveness lies in utilizing the patient’s own immune cells to find and clear the body from MM cells. Several immune cells are known to be involved in this process such as natural killer cells, T cells and macrophages. Natural killer cells are experts in detecting virus infected or malignant transformed cells without the need for prior activation, and they are at the forefront of immune response against malignant cells and thus a promising option for cancer immunotherapy.

In study I we could show that two heavily pretreated, triple refractory multiple myeloma patients, who received Daratumumab treatment and progressed, could be re-challenged with the same drug. We observed that the recurring multiple myeloma cells showed normal CD38 expression after a short treatment interruption. This made those patients eligible for a second line of Daratumumab treatment which has proven to be save. In both patients a partial response could be observed. Additionally, we reported that natural killer cells were depleted immediately after Daratumumab administration. The lack of natural killer cells in Daratumumab treated patients leaves them at risk for viral reactivation or bacterial infection. In study II we observed that an unusually high percentage of Daratumumab treated patients suffered from infectious complications, of which viruses of the herpes family were the most prominent. We monitored the immune status of those patients and their clinical parameters and one of our observations was that natural killer cells were reduced in general, but in particular the more mature natural killer cell population was depleted. These findings led us to the conclusion that combining monoclonal antibody treatment with adoptive cell transfer may have a synergistic effect and allow for better disease control.

Producing natural killer cells in large quantities for clinical trials is challenging. One pivotal factor for robust cell expansion is serum, which is an undefined component with big batch to batch variation that will have a big impact on expansion rates und functionality of the cells. In order to circumvent this problem, we adapted the clinically used natural killer cell line NK-92 to serum-free conditions with inherited phenotype and growth rate. Additionally, we reported that serum-free NK-92 cells showed elevated functionality towards K562 cells after reintroduction of serum. We also performed RNA sequencing to compare serum-free cultured NK-92 cells with cells cultured under standard conditions to investigate the biological mechanisms involved in serum reduction.

Altogether we propose that growing serum-free NK-92 cells is feasible and the reported protocol is robust, cheap and can be adapted for clinical grade production. Whether the combination of these cells with other advanced treatments will show additive or synergistic treatment outcomes for multiple myeloma patients, needs to be evaluated in future studies.

List of scientific papers

I. Alici E, Chrobok M, Lund J, Ahmadi T, Khan I, Duru AD, Nahi H. Re-challenging with anti-CD38 monotherapy in triple-refractory multiple myeloma patients is a feasible and safe approach. Br J Haematol. 2016 Aug;174(3):473-7.
https://doi.org/10.1111/bjh.13776

II. Nahi H, Chrobok M, Gran C, Lund J, Gruber A, Gahrton G, Ljungman P, Wagner AK, Alici E. Infectious complications and NK cell depletion following daratumumab treatment of Multiple Myeloma. PLoS One. 2019 Feb 13;14(2):e0211927.
https://doi.org/10.1371/journal.pone.0211927

III. Chrobok M, Dahlberg CIM, Sayitoglu EC, Beljanski V, Nahi H, Gilljam M, Stellan B, Sutlu T, Duru AD, Alici E. Functional assessment for clinical use of serum-free adapted NK-92 cells. Cancers (Basel). 2019 Jan 10;11(1), pii: E69.
https://doi.org/10.3390/cancers11010069