1. Froelich, Warren

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By combining activated natural killer (NK) cells harnessed from donated cord blood with an antibody that targets specific cell-surface tumor antigens, a team led by researchers at The University of Texas MD Anderson Cancer Center was able to significantly improve treatment response among patients with advanced CD30+ lymphoma, according to preliminary Phase I/II results.

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Among patients receiving the recommended Phase II dose, the overall response rate was 100 percent, including eight complete responses and five partial responses. The treatment not only shrank tumors, but it was less complex to use and far gentler on patients than other cell therapies that harness a patient's own immune system to attack cancer cells.


"We saw very encouraging activity in this population of very heavily pre-treated patients," said Yago Nieto, MD, PhD, Professor of Stem Cell Transplantation and Cellular Therapy at MD Anderson, who presented the study during the 2022 American Association for Cancer Research (AACR) Annual Meeting, held April 8-13 in New Orleans. "We believe this approach warrants further investigation for treatment for CD30+ lymphomas."


Timothy Yap, MD, PhD, Medical Director of the Institute for Applied Cancer Science at MD Anderson, who moderated a press briefing on this topic, said the results were "truly impressive."


"In addition to that, the actual co-morbidity profile is truly excellent with no instance of cytokine release syndrome, no neurotoxicity, no graft-versus-host disease ... truly impressive," he stated.


These latest findings stem from several years of preclinical studies seeking new methods to treat patients with CD30+ lymphoma or non-Hodgkin lymphoma that are recurrent or refractory. In many cases, relapsed CD30+ lymphoma can be successfully treated with brentuximab vedotin and, with Hodgkin lymphoma, checkpoint inhibitors as well. But not all tumors respond to the current standard of care for patients with advanced lymphoma, and those tumors that remain become extremely difficult to kill.


Study Details

With a dearth of clinical choices remaining, Nieto and colleagues began studies with new protein drugs called bispecific monoclonal antibodies. As designed, these artificial antibodies can simultaneously bind to two different types of antigens or two different epitopes on the same antigen. Naturally occurring antibodies typically only target one antigen.


One bispecific antibody called AFM13 provides a molecular bridge that links CD16A found on NK cells to a tumor marker called CD30 on lymphoma cells. NK cells are part of the innate immune system and work naturally to eliminate cancer cells in the body. To borrow a movie title, they're "natural-born killers" that seek out and destroy unwelcome invaders, including viruses and tumor cells. More than 1,000 NK cells can be found in every drop of blood.


In early patient studies, however, the potency of infused NK cells derived from a patient's own serum failed to produce significant results. Katy Rezvani, MD, PhD, Professor in the Department of Stem Cell Transplantation and Cellular Therapy at MD Anderson, suggested the fault might lay with the NK cells themselves. Because they were harvested from frail patients, she reasoned, they might be too weak to aggressively attack the tumor cells.


So, for the next round of experiments, the team turned to NK cells derived from cord blood donated from healthy individuals. The researchers found they could improve the persistence and effectiveness of the anti-tumor activity of NK cells in culture by pre-activating them with IL-12/15/18 cytokines. With the addition of feeder cells, they were able to expand NK cell proliferation by a factor of 1,000. Following 2 weeks of incubation, the mixture was then pre-complexed with AFM13. Preclinical studies in laboratory mice demonstrated that this mixture of NK cells from cord blood donations linked to AFM13 was far more effective than treatments with just AFM13 or the unlinked NK cells alone.


Moving to the clinic, Nieto and team recruited 22 patients-20 with relapsed CD30+ lymphoma and two with T-cell non-Hodgkin lymphoma-most of whom experienced other advanced treatments, including chemotherapy, checkpoint inhibitors, stem cell transplants, and two patients with CAR-T therapy that failed.


"They all had progressive disease at the time of involvement and no adjuvant therapy was given after enrollment," Nieto said.


Patients, ages 20-75, were treated with AFM13-NK cell complexes following immune cell depletion using fludarabine and cyclophosphamide. Because AFM13 remains attached to the NK cells for a week, the patients received three weekly infusions on days 7, 14, and 21. Some 19 patients were treated with this regimen.


Following evaluation after the first cycle, the patients received a second cycle using cord blood from different donors. Three patients received 2 cycles of 1 million cells/kg, three patients received 10 million cells/kg, with another 13 receiving 100 million cells/kg-the highest dose, which was recommended for the Phase II trial.


"We saw very encouraging activity in this population of very heavily pre-treated patients," Nieto said.


Apart from the expected hematological toxicity from pre-infusion immune cell depletion, the researchers observed no adverse events from the natural killer cells and only one adverse event of Grade 3 or higher from a subsequent AFM13 infusion.


Of the 19 patients treated, 17 responded for an overall response rate of 89 percent. Across all dose levels, 53 percent of patients experienced a complete response, 37 percent a partial response, and 11 percent had progressive disease. All 13 patients treated with the recommended Phase II dose experienced an overall response, including eight complete responses and five partial responses.


At a median follow-up of 11 months across all dose levels, the overall survival rate was 53 percent; for those who received the recommended Phase II dose, the overall survival was 79 percent.


Asked about the potential wider use of this methodology in the clinic, Rezvani said the costs and complexity of expanding NK cells was the same as current methodology used for CAR-T cells, currently the best-known form of cell therapy.


"The difference here is that we are hoping with NK cells we can manufacture multiple doses from one donor, which then allows us to treat multiple patients, and this, in itself, would increase its accessibility and reduce the cost of cell therapy," she said.


Also, patients generally can be treated only once with CAR-T, with the host becoming sensitive to a second dose.


"That's the big difference from autologous CAR-T cells, which is pretty much a one-time treatment," Nieto said. "When a second cycle of autologous CAR-T is given, the levels are much poorer because the patient has already been sensitized against those CAR-T cells."


As for next steps, Nieto said he wants to expand the cohort in the next clinical trial to include more patients with other lymphomas, in addition to increasing the number of treatment cycles from 2 to 4. Limitations of the study include a relatively short duration of follow-up and limited information about the durability of response from the 2 cycles.


Warren Froelich is a contributing writer.