Natural killer (NK) cells combined with a novel bispecific antibody AFM13 achieved effective responses in patients with refractory lymphoma


Researchers from The University of Texas MD Anderson Cancer Center showed that natural killer (NK) cells derived from donated umbilical cord blood, combined with a novel bispecific antibody known as AFM13 that targets CD16A and CD30, achieved effective responses in patients with pretreated and refractory CD30+ lymphoma. The study was presented today at the American Association for Cancer Research (AACR) Annual Meeting 2022.

There was an 89% overall response rate (ORR) in 19 patients, including 10 complete responses (CR). The progression free survival and overall survival rates across all three dose levels were 53% and 79%, respectively, after a median follow-up of 11 months and lead-in follow-up of 19 months. Expansion of NK cells occurred immediately after infusion and persisted for two weeks.

Dose level three (108 NK/Kg) was established as the recommend Phase II dose (RP2D). All 13 patients treated at this dose level had a response to therapy (100% ORR), including eight CR (62%).

“Patients with relapsed CD30+ lymphoma can sometimes be successfully treated with current regimens, but, if those treatments fail, the tumors develop treatment resistance and patients are left with few effective therapeutic options,” said study presenter Yago Nieto, M.D., Ph.D., professor of Stem Cell Transplantation and Cellular Therapy and principal investigator on the trial.

“Our preliminary results indicate promising activity and tolerability in this heavily pretreated patient population and warrant further investigation of this approach.”

NK cells are a type of white blood cells that monitor the body for virus-infected and cancerous cells. The technology to isolate and expand NK cells from umbilical cord blood was developed at MD Anderson.

Affimed’s AFM13 is a proprietary bispecific antibody designed to bind to CD16A on NK cells and CD30 on lymphoma cells, allowing NK cells to eliminate cancer cells. Before infusion, the NK cells are activated with cytokines, expanded in the presence of artificial antigen-presenting cells, and finally complexed with AFM13.

This combination approach was developed in the laboratory of Katy Rezvani, M.D., Ph.D., professor of Stem Cell Transplantation and Cellular Therapy. Affimed and MD Anderson are advancing the clinical development of AFM13 through a strategic collaboration agreement.

This single-center Phase I/II trial has enrolled 22 patients with relapsed or refractory CD30+ lymphoma. Most trial participants had been diagnosed with Hodgkin lymphoma and had received a median of seven prior lines of therapy. All patients had active progressive disease at enrollment and no bridging therapy was given. Patients were enrolled at three dose levels, and 19 patients completed both planned cycles. The racial breakdown of participants was 15 White (68.2%), 3 Hispanic (13.6%), 3 Middle Eastern (13.6%) and 1 Black (4.5%), with a median age of 37.

The treatment was well tolerated, with minimal side effects beyond the expected myelosuppression from the preceding lymphodepleting chemotherapy. There were no cases of cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome or graft versus host disease. There were six infusion-related reactions in 110 infusions of AFM13 alone and no reactions to the AFM13-loaded NK cells.

Six patients received a stem cell transplant after a response to this treatment, which limits the evaluation of duration of responses.

“This data suggests that this new therapeutic option, either used as a bridge to stem cell transplantation or perhaps even as a curative treatment, offers an effective treatment option for patients with CD30+ lymphoma,” Nieto said. “We are excited about these findings and the possibility of bringing this treatment to this patient population with a large unmet need.”

The trial was originally designed with short follow-up. To assess durability beyond two cycles, an amendment has been approved by the Food and Drug Administration to increase the length of treatment from two to four cycles, enabling longer follow up of patients.

Though the majority of patients diagnosed with HL will respond to frontline therapy and be cured, a sizeable fraction (up to 30%) may relapse and a number of patients may have refractory disease. Treatment options in the relapsed and/or refractory setting have changed dramatically since the turn of the century with a number of novel agents revo- lutionizing our approach to treatment. CAR T cells have now joined the armamentarium for treatment of r/r HL and demonstrate exceptional promise with high response rates in this population, along with the potential for durable responses. How this therapy fits with the current treatment paradigm in r/r HL is the key question going forward. The fact that there has been limited toxicity observed with anti-CD30 CAR T cells to date is especially encouraging and may cause us to rethink how we view the timing and role of transplant for r/r HL in the future. That being said, much work remains to determine how best to optimize this therapy and whether or not the durable responses we have seen thus far truly translate to a ‘cure’ for these patients. Further clarification of the optimal target for CAR T cell design in HL is also needed, especially when considering that the majority of cells encountered are not malignant HRS cells, but rather immunosuppressive cells of the adaptive and innate immune systems. Combinatorial treatment approaches that address both of these populations may be needed to fully eradicate the tumor. The success of this will ultimately dictate the degree to which CAR T cells can be relied upon for treatment in r/r HL. The results from early-phase clinical trials to date would suggest that the future here is bright and that even the most refractory patients could see long-term disease control.

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Figure 1. Novel CAR T approaches in HL: Emerging strategies for optimizing CAR T therapy include the following: (1) Modulation of the Immunosuppressive TME—the hallmark of classical Hodgkin lymphoma is relatively few malignant Hodgkin Reed–Sternberg (HRS) cells interspersed in an immune infiltrate dominated by immunosuppressive cells, including regulatory T cells, tumor- associated macrophages (TAMs), and myeloid-derived suppressor cells, among others. As these immune cells represent the bulk of the tumor, therapies targeting the TME could improve treatment response in cases of relapsed and/or refractory HL. To date, this has included CAR T products targeting TAMs (anti-CD123), as well as regulatory B-cells (anti-CD19), in the TME. The PD-1/PD- L1/L2 axis represents a critical mechanism that leads to CAR T dysfunction and combined use of checkpoint inhibitors may allow for a more prolonged anti-tumor effect. (2) Increased CAR T cell Persistence—Ongoing tumor control requires that CAR T cells be successfully recruited to the TME in order to carry out their function. HRS cells are known to secrete high levels of CCL17, which is generally used to recruit immunosuppressive cells. CAR T cells engineered to express the receptor to CCL17 (CCR4) may allow for increased penetration of CAR T cells into the TME, leading to enhanced antitumor activity. Memory T cells have been shown to persist longer than traditional effector cells and strategies to enhance their formation, including the cytokine milieu (i.e., IL-7 and IL-15) that is used for their ex vivo expansion, may impact the number of infused memory cells.
(3) Novel antigens—Natural killer (NK) cells are emerging as an alternative to traditional T cells for
the introduction of the chimeric antigen receptor. Supporting the efficacy of NK cells for this purpose, studies have demonstrated that a CD16/CD30 bispecific antibody that re-engages NK cells to target HRS cells can lead to tumor regression in relapsed/refractory HL patients. While HRS cells do not appear to experience antigen loss as a mechanism of CAR T cell resistance as of yet, novel targets may allow for the development of other CAR T cells or even multiantigen targeted CAR T cells to improve responses in patients. Similar to this idea, cytotoxic T cells expanded ex vivo to recognize tumor-associated antigens, such as WT1, PRAME, or Survivin, have shown promise in treating HL. Figure created with

More information: CT003—Innate cell engager (ICE) AFM13 combined with preactivated and expanded cord blood (CB)-derived NK cells for patients with refractory/relapsed CD30+ lymphoma,! … 7/presentation/20145


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