NEW ORLEANS – A novel treatment approach involving natural killer (NK) cells derived from donor umbilical cord blood combined with Affimed's bispecific antibody AFM13 before infusion led to encouraging response rates in a Phase I clinical trial of CD30-positive advanced lymphoma patients, according to data presented Sunday during the American Association for Cancer Research (AACR) annual meeting.
Yago Nieto, a professor at the MD Anderson Cancer Center's Department of Stem Cell Transplantation and Cellular Therapy, presented the results of the first-in-human trial, which was sponsored and conducted by MD Anderson investigators with collaboration from the Heidelberg, Germany-based drugmaker Affimed.
Among 19 response-evaluable patients with relapsed or refractory Hodgkin and non-Hodgkin lymphoma — all of whose cancers were CD30-positive, defined as tumors expressing CD30 in at least 1 percent of cells by immunohistochemistry — 17 patients experienced metabolic responses, yielding an 89.5 percent overall response rate. All 13 patients who received the recommended Phase II dose of the treatment responded and eight had complete responses.
The 22 patients included in the study were heavily treated, having received a median of seven prior lines of therapy. Patients with Hodgkin lymphoma, anaplastic large cell lymphoma, and mycosis fungoides had to have prior treatment with Seagen's Adcetris (brentuximab vedotin) to be eligible to receive the NK cells combined with the bispecific antibody. Fourteen patients received prior stem cell transplants, and two received prior CAR T-cell therapy.
After a median follow-up of nine months, the event-free survival rate was 52 percent, and the overall survival rate was 81 percent. Among the subset of patients treated with the recommended Phase II dose — 1x108 cells per kilogram — these rates were 67 and 93 percent, respectively.
Because AFM13 has an affinity for both the CD30 target on lymphoma cells and CD16A on the NK cells, the bispecific antibody plays the role of directing the donor NK cells specifically to the patients' cancer cells.
Although prior clinical trials have evaluated AFM13 monotherapy as a lymphoma treatment approach, the concept of linking it with NK cells from donor cord blood is altogether new. The rationale for using NK cells from donor cord blood, according to Nieto, is that lymphoma patients have dysfunctional NK cells, whereas donor NK cells from healthy donor cord blood retain their killing capacity and can be expanded before infusion to increase this killing capacity further yet.
During a presentation given to members of the press on Sunday, Nieto explained the process for manufacturing and then treating patients with this first-of-its-kind therapy. First, researchers separated the NK cells from the frozen donor umbilical cord blood. Then, over the course of two weeks in a good manufacturing practices (GMP) cell therapy lab, they pre-activated the cells in the presence of cytokines and expanded them in the presence of feeder cells. At the end of the two-week incubation period, the cells were combined, or pre-complexed, with AFM13.
While this process was taking place, the patients underwent a lymphodepleting chemotherapy regimen. Then, the patients received their infusions of the AFM13-complexed NK cells. After the infusion, because the AFM13 remains on the surface of the NK cells for about a week, the patients received three weekly infusions of AFM13 on days 7, 14, and 21 following infusion. On day 28, the investigators evaluated the patients for a response. That whole process constitutes one cycle, Nieto said, adding that because the NK cells persist for about three weeks with an activated phenotype, lymphoma patients on the trial underwent two sequential cycles. In the second cycle, the NK cells came from a different cord blood donor than the first cycle.
The treatment was encouragingly safe and tolerable, with no instances of cytokine release syndrome, neurotoxicity, or graft-versus-host disease.
"The tolerability profile is truly, truly excellent," said Timothy Yap, a medical oncologist and associate professor in MD Anderson's Department of Stem Cell Transplantation and Cellular Therapy, who wasn't involved in the study.
Manufacturing advantages, broad applicability
Though the trial was early-phase, Nieto and colleagues took a moment on Sunday to consider what it might be like to scale their therapy for commercial use should it reach the market. They expect that many more patients will access this type of treatment compared to autologous CAR T-cell therapy.
Given the manufacturing complexity, the treatment could face some of the logistic and cost barriers that have challenged widespread adoption of marketed CAR T-cell therapies. The cell incubation and expansion process takes several weeks, for instance, even though the next step of co-complexing the cells with AFM13 only takes a few hours.
That said, the fact that the therapy is not entirely bespoke like autologous CAR T-cell therapy and does not rely on difficult-to-procure viral vectors could be an advantage.
"NK cell engineering obviously does have the same cost and complexity as expanding … CAR T cells," said Katy Rezvani, also a professor in MD Anderson's Department of Stem Cell Transplantation and Cellular Therapy. But, "the difference here is that we are hoping with NK cells from one donor, we can manufacture multiple doses, which allows us to treat multiple patients [and] increase accessibility and reduce the cost of therapy."
Instead of engineering the NK cells using a viral vector — an approach that has been riddled with logistical barriers and industry-wide bottlenecks in the autologous CAR T-cell therapy space — the AFM13-NK approach involves a much simpler combination step, Rezvani said.
"We don't need a viral vector for the manufacturing," she explained. "All we are doing is at the end of expansion, we are loading our NK cells for about an hour with the AFM13 engager … that's all it takes." After loading the NK cells with the engager, the engager is washed off and the treatment is infused in the patient.
The ease of manufacturing could allow this strategy to be applied with other engagers, too, Nieto explained. Theoretically, by switching out AFM13 for a different innate cell engager, the approach could be applicable in other cancer types. For example, an EGFR engager could be used for patients with certain EGFR-positive solid tumors, or BCMA engagers could be used for certain BCMA-expressing multiple myelomas. Affimed, of note, has several innate cell engagers directed at different targets in its development pipeline.
Because the therapy's activity is due to the engager's role directing the NK cells to the cancer cells, the biomarker selection aspect is critical. For patients in this trial to benefit, their cancers had to be CD30-positive. Similarly, in order for patients with other cancers to be eligible for a similar therapy with other engagers swapped out, their tumors would likewise need to be screened for their respective biomarkers.
"We believe this approach warrants further investigation for treatment of CD30-positive lymphomas," Nieto said, sharing that as a next step, he and his team hope to work on shortening the interval between treatment cycles and increasing the number of cycles that patients receive from two to four, each with NK cells from different donor cohorts. And as researchers move forward with evaluating and improving the treatment, addressing its complexity may be a focus.
"The therapy package [included] multiple components that need to be further thought about and re-evaluated," said Jeffrey Miller, deputy director of the University of Minnesota Masonic Cancer Center and co-leader of the center's immunology program, in a discussion of the data following Nieto's Sunday afternoon presentation. "Really, the question is, how do we deconvolute this to understand the best attributes that had anti-tumor activity long term."