‘Truly Impressive’ Responses in Lymphoma With Novel Cell Therapy

Cancer researchers confessed to being “favorably surprised” by the quality of tumor responses among patients with relapsed or refractory CD30-positive lymphomas who were treated with a novel cellular therapy consisting of natural killer (NK) cells complexed with a bispecific antibody.

The first-in-class therapy is composed of NK cells derived from cord blood that are “preactivated” with cytokines and expanded in the laboratory, and are combined with a novel CD30/CD16A bispecific antibody construct labeled Innate Cell Engager (ICE) AFM13 (developed by Affimed). The antibody binds to CD30 on lymphoma cells and 16A on NK cells.

The responses were seen in a Phase 2/3 study in patients with lymphoma that had relapsed after many different treatments, and some patients were in a very poor condition at enrolment, the researchers said.    

“We were surprised at the beginning; we saw very good responses from the get-go, even at the first dose level, and we were very definitely surprised,” said principal investigator Yago L. Nieto, MD, PhD, from the Department of Stem Cell Transplantation and Cellular Therapy at the University of Texas MD Anderson Cancer Center (MDACC) in Houston.

“We’re not surprised anymore,” he added. “We treat patients now and expect them to respond.”

“Among the first few patients that we treated, some were very debilitated and they tolerated this treatment extremely well,” Nieto said in an interview with Medscape Medical News.

He presented clinical results of the new product here at the American Association for Cancer Research (AACR) 2022 annual meeting.  

“This is truly a first-in-human approach, and never before in mankind have we seen this approach really leading to very staggering results,” said Timothy A. Yap, MBBS, PhD, who is also at MDACC but was not involved in the study. He moderated a conference media briefing during which the new results were highlighted.

Yap said that anyone looking at the study’s waterfall plot of tumor responses “can see for themselves how impressive these results are, and in addition to that, the tolerability profile is truly excellent, with no instances of the cytokine release syndrome, no neurotoxicity, and no [graft-vs-host disease]. Truly, truly impressive.”

Abstract discussant Jeffrey S. Miller, MD, an NK cell therapy researcher at the University of Minnesota in Minneapolis, said the study provides proof-of-concept that making memory-like NK cell infusions antigen-specific with a combination engager can lead to excellent short-term responses.

He emphasized that longer follow-up is needed, however, because five of the patients with complete responses relapsed within 1 year of follow-up.

Also, he noted that the therapeutic package included multiple active components, including preactivated and expanded cord blood NK cells precomplexed with AMF13, lymphodepleting chemotherapy, and additional AMF13 infusions, so it will be necessary to tease out which specific components contributed to the anti-tumor response.

Stronger Together

The study was designed to address the needs of patients with disease progression following treatment with the current standard of care for CD30-positive advanced lymphomas, the antibody-drug conjugate brentuximab vedotin (Adcetris, Seagen).

In previous studies, monotherapy with the AFM13 antibody construct had shown activity against Hodgkin lymphoma, T-cell lymphoma, and peripheral T-cell lymphoma.

But as study coauthor Katy Rezvani, MD, PhD, also from MDACC, showed in animal models, complexing AFM13 with cord blood-derived NK cells prior to infusion was more effective than either AFM13 or unlinked NK cells alone.

To see whether the complex was safe and had synergistic efficacy in humans, investigators enrolled 15 men and seven women who were a median age of 40 years. All patients had CD30-positive lymphomas that had relapsed despite treatment with brentuximab vedotin. All but one patient had previously received immunotherapy with a programmed cell death protein 1 (PD-1) inhibitor, 14 (of the 22) had undergone autologous or allogeneic stem cell transplant, and two had previously received chimeric antigen receptor (CAR) T-cell therapy.

Patients had received a median of six prior therapies for relapsed or progressive disease, but some had received up to 14 prior therapies.

In this trial, patients underwent immune cell conditioning with fludarabine and cyclophosphamide, followed by two cycles of the novel AFM13/NK cell complex, and then additional infusions of AFM13 alone at 7, 14, and 21 days after the second infusion of the complexed cells.

The novel cell-antibody complex was administered at doses of 1 million, 10 million, or 100 million cells/kg; the highest dose was chosen as the recommended phase 2 dose. In all, 53% of patients had a complete response, 37% had a partial response, and 11% had disease progression. The overall response rate was 100% for the 13 patients who received the higher dose (100 million cells/kg), with eight complete and five partial responses.

At a median follow-up of 9 months, the rate of progression-free survival was 52%, and the rate of overall survival was 81%. The respective rates among patients who received the recommended phase 2 dose were 67% and 93%.

Hematologic toxicities were primarily related to pre-infusion conditioning and included neutropenia in 63% of patients and thrombocytopenia in five patients. There were no cases of neutropenic fever or bleeding.

As noted by Yap, there were no cases of cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS), or graft-vs-host disease. In addition, the were no immune-related reactions of any grade among 40 infusions of the AFM13-NK complex, and among 108 infusions of AFM13 alone, there were only five infusion-related reactions, including one of grade 3 and four of grade 2 severity.

Nieto told Medscape Medical News that the study protocol is being amended to allow up to four cycles of the novel complex.

In addition, investigators plan to shorten the interval between cycles and investigate combining the therapy with targeted agents known to enhance NK cell function.

The study was funded by Affimed Therapeutics. Nieto has reported being on the advisory board for Affimed and receiving research funding from the company, as well as from AstraZeneca, Secura Bio, and Novartis. Yap has reported receiving consulting fees from multiple companies. Miller has reported relationships with Fate Therapeutics, GT Biopharma, Sanofi, and ONK Therapeutics.

AACR 2022 Annual Meeting. Abstract CT003. Presented April 10, 2022.

Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.

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