Manipulating Natural Killer Cells to Fight Myeloma

Using a patient’s own cord blood–derived natural killer (NK) cells in hematopoietic cell transplantation (HCT) appears to enhance the effectiveness of the transplant in patients with myeloma, according to updated results from a phase II trial. More than three-quarters of participants (n=26/33) experienced at least a very good partial response (VGPR) at day 100, the study’s primary endpoint.

Nina Shah, MD, from the University of California San Francisco and Helen Diller Family Comprehensive Cancer Center, shared the findings at the 2018 ASCO Annual Meeting, reporting that using cord blood–derived allogeneic NK cells in the setting of high-dose melphalan and autologous HCT is “a promising adjunct immunotherapy.”

“Patients who undergo HCT have long-term remission, suggesting an immune-mediated graft-versus-myeloma effect, so we’ve been interested in NK cells [for this patient population],” she explained. “Cord blood is a known source of hematopoietic cells that is immediately available, does not require donor manipulation, and has more flexibility in matching.”

The trial included 33 adults (median age = 59 years; range = 25-72 years) with symptomatic MM who were considered eligible for autologous HCT. Participants were also required to have at least a 4/6 HLA-matched cord blood unit available.

Nearly three-quarters (n=24; 73%) had at least one of the following adverse features:

  • high-risk cytogenetics/FISH (del1p, amp1q, t[4;14], t[14;20], t[14;16], del17p, and del13)
  • history of progression/relapse
  • International Staging System grade III disease

This was a “fairly higher-risk population than would normally be going on to transplant,” Dr. Shah noted.

At 19 days before scheduled transplant, the NK cells were separated from participants’ cord blood samples, then manipulated to expand the number of cells available for infusion. Patients also underwent conditioning with lenalidomide 10 mg daily from eight to two days before HCT and high-dose melphalan 200 mg/m2 seven days before HCT.

Patients were infused with freshly expanded cord blood–derived NK cells five days before autologous HCT, followed by autologous peripheral blood progenitor cells on the day of the transplant. This approach appeared to be safe, Dr. Shah observed. There were no infusion-related toxicities, graft-versus-host-disease, cytokine release syndrome, or neurotoxicity.

At three months post-transplant, nearly all patients responded to treatment, including 26 (79%) who achieved a best response of very good partial response or better and 21 (64%) who achieved a near complete or complete response.

The median time to best response was 100 days (range not reported).

With a median follow-up of 21 months (range not provided), 13 patients had progressive disease and three patients had died – all of whom had progressive disease.

The results raise the question of whether HLA-matched donors are needed at all. “It is likely that we don’t need to match between donor and recipient, and this [approach] will still be safe,” Dr. Shah said. “If that’s the case, we will truly have an off-the-shelf source of NK cells that we can apply more readily to more patients.”

Median progression-free survival and overall survival was not yet reached at the time of study presentation, and donor-derived NK cells were detected one to 13 days after infusion in most patients (n=24; 76%).

“In this generally high-risk patient population, responses to [HCT plus cord blood–derived NK cell therapy] are encouraging,” Dr. Shah concluded, adding that more sensitive analysis of donor-derived NK cells will help investigators better understand the in vivo phenotype and activation status of donor cells. For instance, she offered, “if it truly turns out that CD16 is more highly expressed, it would be nice to combine this with antibody therapy.”

The study’s findings are limited by its small patient population, as well as the lack of a comparator arm.

The authors report financial relationships with Celgene, which also provided financial support for the trial.

Reference

Shah N, Mehta R, Li L, et al. Phase II study of ex vivo expanded cord blood natural killer cells for multiple myeloma. Abstract #8006. Presented at the 2018 ASCO Annual Meeting, June 1, 2018; Chicago, IL.

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