NEW ORLEANS — Patients with heavily treated Hodgkin’s or non-Hodgkin’s lymphoma (NHL) had dramatic responses to activated natural killer (NK) cells linked to a bispecific antibody, a preliminary study has shown.
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 treatment. Five of the 13 responses occurred after a single dose of the cell therapy, which targets tumor cells expressing the CD30 antigen, reported Yago Nieto, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston.
The therapy was well tolerated and resulted in 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).
“This is the first clinical trial using ex vivo expanded memory-like, cord blood-derived, cytokine-induced natural killer cells pre-complexed with the AFM13 innate cell engage (ICE) construct to treat patients with CD30 -Positive Hodgkin lymphoma or relapsed/refractory 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 the treatment of CD30-positive lymphomas.”
These results were “incredible” and the responses depicted in the waterfall diagrams were “breathtaking,” said Timothy Yap, MD, PhD, also of MD Anderson, who hosted a press briefing that included Nieto’s presentation.
“As a first human approach, we have never seen such stunning results,” he said. “With the waterfall charts, anyone can see how impressive these results are. On top of that, the tolerance profile is really excellent.”
The treatment has shown excellent short-term results, but more follow-up is needed to determine the durability of treatment, said Jeffrey S. Miller, MD, AACR guest discussant, University of Minnesota Minneapolis. . More work is needed to determine which components of therapy contribute to activity.
“There is preactivated and expanded cord blood that has been precomplexed with AFM13, lymphodepleting chemotherapy, AFM13 infusions,” Miller noted. “The question is, how do you deconvolute this to understand the best attributes that have long-term antitumor activity?”
“There was a somewhat limited NK PK [pharmacokinetics] in the absence of cytokines, which is a recurring theme, I think, in the field of allogeneic adoptive transfer,” he added. “Can this be improved with cytokines? Can we manipulate NK cells to avoid the need for lymphodepleting chemotherapy, making it more patient friendly? What’s more important: AMF13 or infusions? What is the best source of NK cells? These are some of the questions that remain.”
The ICE platform used in the study isn’t the only one being studied, Miller pointed out. Several NK cell engagers are being evaluated 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 cell types. In preliminary clinical studies, the antibody has demonstrated activity in Hodgkin’s lymphoma and T-cell lymphomas.
However, preclinical studies have shown that precomplexation of cord blood-derived NK cells with AFM13 prior to infusion elicits chimeric antigen receptor (CAR)-like responses that are more robust than with AFM13 or NK cells. activated on their own, Nieto said. NK cell persistence was enhanced by preactivation with interleukin (IL)-12, IL-15, and IL-18 to induce a memory phenotype. NK cells underwent a 1000-fold expansion in the presence of antigen-presenting cells.
Trial design, key results
The researchers hypothesized that an AFM13-NK cell complex would increase the cytotoxic potential of NK cells. The first clinical evaluation involved patients with Hodgkin’s lymphoma, T-cell lymphoma or B-cell lymphoma with CD30 expression documented by immunohistochemistry. Patients eligible to receive the antibody-drug conjugate brentuximab vedotin (Adcetris) had been shown to be refractory or intolerant to the drug.
After lymphodepleting chemotherapy with fludarabine and cyclophosphamide, patients completed two treatment cycles, each consisting of an infusion of one of three doses of the complex treatment followed by three weekly infusions of AFM13 alone.
Of the 22 patients enrolled so far, all but two had relapsed/refractory Hodgkin’s lymphoma. Patients had received a median of seven prior lines of therapy and up to 14. All had previously received brentuximab vedotin and all but one had received a PD-1/L1 inhibitor. Two patients had received CAR T-cell therapy and 14 had previously undergone stem cell transplantation. All patients had progressive disease in response to the most recent therapy.
The efficacy evaluation of 19 patients showed an objective response rate of 89%. Five patients achieved complete responses after the initial course 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 treatment dose had an EFS rate of 67% and an OS rate of 93%.
In addition to the absence of CAR T-like toxicities (CRS, neurotoxicity), no immune-mediated reactions occurred after a total of 40 infusions of the AFM13-NK complex. Lymphodepleting therapy resulted in 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 occurred in association with 108 infusions of AFM13 alone.
During a discussion following his presentation, Nieto said the clinical study of complex therapy will continue in patients with CD30-positive malignancies, noting that the treatment strategy can be adapted to other targets. than CD30.
The study was supported by Affirmed Therapeutics.
Nieto disclosed relationships with Affirmed Therapeutics, AstraZeneca, Bio Secura and Novartis.