乌鸦传媒

NEW ORLEANS -- Patients with heavily treated Hodgkin or non-Hodgkin lymphoma (NHL) had dramatic responses to activated natural killer (NK) cells linked to a bispecific antibody, a preliminary study showed.

All but two of the first 19 patients who received the therapy had objective responses, including 10 complete responses. All 13 patients treated with the recommended phase II dose responded to the treatment. Five of 13 responses occurred after a single dose of the cellular therapy, which targets tumor cells expressing CD30 antigen, reported Yago Nieto, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston.

The therapy was well tolerated and led to no cytokine release syndrome (CRS), neurotoxicity, or graft-versus-host disease (GVHD), he said during his presentation at the American Association for Cancer Research (AACR) meeting.

"This is the first clinical trial using off-the-shelf, cord blood-derived, cytokine-induced, memory-like ex vivo expanded natural killer cells precomplexed with the innate cell engager (ICE) AFM13 construct to treat patients with CD30-positive relapsed/refractory Hodgkin lymphoma or NHL," Nieto noted. "Donor NK cells persist in the recipient for up to 3 weeks with an activated phenotype. This approach warrants further investigation for treatment of CD30-positive lymphomas."

These results were "amazing" and the responses represented in waterfall plots were "staggering," said Timothy Yap, MD, PhD, also of MD Anderson, who moderated a press briefing that included Nieto's presentation.

"As a first-in-human approach, we have never before seen such really staggering results," he pointed out. "With the waterfall plots, everyone can see themselves how impressive these results are. In addition to that, the tolerability profile is truly excellent."

More to Come

The treatment led to excellent short-term results, but more follow-up is needed to determine the durability of the treatment, said AACR invited discussant Jeffrey S. Miller, MD, of the University of Minnesota in Minneapolis. More work is required to determine which components of the therapy contribute to the activity.

"There's a preactivated and expanded cord blood that was precomplexed with AFM13, lymphodepleting chemotherapy, AFM13 infusions," noted Miller. "The question is, how do we deconvolute this to understand the best attributes that have antitumor activity long term?"

"There was somewhat limited NK PK [pharmacokinetics] in the absence of cytokines, which is a recurring theme, I think, in the allogeneic adoptive-transfer field," he added. "Can this be improved with cytokines? Can we manipulate NK cells to obviate the need for lymphodepleting chemotherapy, which would make it more patient friendly? What's more important: the AMF13 or the infusions? What's the best source of NK cells? These are some of the questions that remain."

The ICE platform used in the study is not the only one under investigation, Miller pointed out. Multiple NK-cell engagers are under evaluation and others are in development. Whether one will prove better or offer advantages over the others remains to be seen.

The AFM13 antibody simultaneously targets CD30 expressed by lymphoma cells and CD16A expressed by NK cells, acting as a bridge between the two types of cells. In preliminary clinical studies, the antibody demonstrated activity in Hodgkin lymphoma and T-cell lymphomas.

However, preclinical studies showed that precomplexing cord blood-derived NK cells with AFM13 prior to infusion led to chimeric antigen receptor (CAR)-like responses that were more robust than with AFM13 or activated NK cells alone, said Nieto. Persistence of NK cells was enhanced by preactivation with interleukin (IL)-12, IL-15, and IL-18 to induce a memory phenotype. NK cells underwent expansion by 1,000-fold in the presence of antigen-presenting cells.

Trial Design, Key Results

Investigators hypothesized that an AFM13-NK cell complex would increase NK cells' cytotoxic potential. The first clinical evaluation involved patients with Hodgkin lymphoma, T-cell origin lymphoma, or B-cell lymphoma with CD30 expression documented by immunohistochemistry. Patients eligible to receive the antibody-drug conjugate brentuximab vedotin (Adcetris) had proven refractory or intolerant to the drug.

Following lymphodepleting chemotherapy with fludarabine and cyclophosphamide, patients completed two cycles of therapy, each consisting of an infusion of one of three doses of the complexed therapy followed by three weekly infusions of AFM13 alone.

Of the 22 patients enrolled thus far, all but two had relapsed/refractory Hodgkin lymphoma. The patients had received a median of seven prior lines of therapy and as many as 14. All had received prior brentuximab vedotin and all but one had received a PD-1/L1 inhibitor. Two patients had received CAR T-cell therapy, and 14 had undergone prior stem cell transplantation. All of the patients had progressive disease in response to the most recent therapy.

The efficacy assessment involving 19 patients showed an 89% objective response rate. Five patients attained complete responses after the initial cycle of treatment. After a median follow-up of 9 months and a range of 1 to 19 months, the cohort had an event-free survival (EFS) rate of 52% and an overall survival (OS) rate of 81%. The 13 patients who received the phase II dose of therapy had an EFS rate of 67% and an OS rate of 93%.

In addition to the absence of CAR T cell-like toxicities (CRS, neurotoxicity), no immune-related reactions have occurred following a total of 40 infusions of the AFM13-NK complex. The lymphodepleting therapy led to grade 3/4 neutropenia in 84% of patients and grade 3/4 thrombocytopenia in 21% of patients. No neutropenic fever or bleeding occurred. Five infusion-related reactions have occurred in association with 108 infusions of AFM13 alone.

During a discussion that followed his presentation, Nieto said clinical investigation of the complexed therapy will continue in patients with CD30-positive malignancies, noting that the treatment strategy can be adapted to targets other than CD30.

Comment