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IL15-activated CIK cells post-HCT show broad efficacy

Donor-derived allogeneic interleukin-15–activated cytokine-induced killer (IL15-CIK) cell therapy was feasible, safe, and effective in high-risk patients with a broad spectrum of haematological malignancies. IL15-CIK demonstrated durable relapse-preventive activity following allogeneic haematopoietic stem cell transplantation (HCT).

“There is an urgent need for novel treatments, especially in the paediatric setting, for acute leukaemia relapsing within 6 months after allogeneic HCT,” said Dr Eva Rettinger (University Cancer Center Frankfurt, Germany). She presented the first in-human, disease burden–guided study (EudraCT 2013-005446-11) evaluating donor-derived IL15–activated CIK cells, which combine T-cell and natural killer cell properties. This prospective, multicentre phase 1/2 trial included 56 adult and paediatric patients with haematological malignancies who required urgent intervention due to imminent relapse following human leukocyte antigen (HLA)-matched or HLA-mismatched transplantation (n=28 each).

IL15-CIK was administered as monotherapy, without lymphodepletion or graft-versus-host disease (GvHD) prophylaxis. Most patients had either B-cell acute lymphoblastic leukaemia (B-ALL; 34%) or acute myeloid leukaemia (AML; 42%). At the time of the first infusion, disease status was complete molecular remission (n=7), complete remission with impending relapse (n=34), or overt relapse (n=15). Patients at continued risk of relapse were eligible to receive additional IL15-CIK infusions, with a total of 169 infusions administered.

Centralised, on-demand manufacturing of IL15-CIK and their shipment to the 5 participating centres in Germany was feasible. Therapy-related adverse events were infrequent and predominantly mild. Acute GvHD of grades 1–2 and grade 3 occurred in 27% and 4% of patients, respectively.

“After a median follow-up of 7.3 years, response rates were excellent,” Dr Rettinger reported. Five-year overall survival was 71% (95% CI 26–92) in the consolidation cohort, 61% (95% CI 41–75) in the pre-emptive cohort, and 20% (95% CI 5–42) in the salvage cohort. At 700 days, the cumulative incidence of complete molecular remission was 74% in the pre-emptive cohort and 13% in the salvage cohort.

Dr Rettinger concluded that the efficacy of IL15-CIK was primarily determined by disease burden at the time of intervention, while prior serotherapy appeared to modulate the risk of post-HCT relapse.

  1. Rettinger E, et al. First-in-human trial of IL15-activated CIK cell therapy post-HCT: durable remission and serotherapy-associated immune reconstitution in high-risk hematologic malignancies. OS08-08, EBMT congress 2026, 22–25 March, Madrid, Spain.

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High 3-year efficacy and favourable safety of liso-cel in 3L+ FL

After 3 years of follow-up, results from the TRANSCEND FL study confirm the high efficacy and sustained favourable safety profile of lisocabtagene maraleucel (liso-cel) in patients with third-line or later relapsed/refractory follicular lymphoma (3L+ R/R FL). A single infusion resulted in high rates of deep and durable responses, as well as favourable survival outcomes, regardless of early progression after first-line chemoimmunotherapy (POD24) or prior exposure to bendamustine [1].

Liso-cel is a CD19-directed CAR T-cell therapy that has demonstrated favourable efficacy with a manageable safety profile across B-cell malignancies. In the primary analysis of the open-label phase 2 TRANSCEND FL study (NCT04245839), liso-cel achieved an overall response rate (ORR) of 97% with a favourable safety profile in patients with R/R FL [2]. Prof. Alejandro Martín García-Sancho (University of Salamanca, Spain) presented 3-year follow-up results for patients with 3L+ FL from the TRANSCEND FL trial [1].

In total, 107 patients were evaluable for safety and 103 for efficacy. The median age was 62 years (range 23–80); 95 patients (89%) had Ann Arbor stage III/IV disease, and 61 (57%) had high-risk disease per FL International Prognostic Index.

Three-year response rates were consistent with the primary analysis, as noted by Prof. García-Sancho. The ORR was 97% (95% CI 92–99%); the complete response rate (CRR) was 94% (95% CI 88–98%). The median duration of response was not reached; 70% of patients (95% CI, 60–78%) remained in response at 3 years.

Subgroup analyses demonstrated an ORR exceeding 95% in patients with high-risk features, including POD24, bulky disease, and double-refractory disease. Patients who received bendamustine ≥12 months prior to leukapheresis showed durable responses and high 3-year progression-free survival rates, comparable to the overall population.

Long-term safety analyses confirmed a favourable long-term safety profile for liso-cel, with no new signals identified. Grade ≥3 neutropenia and hypogammaglobulinaemia decreased over time, and the rate of severe infection remained low. These findings support the feasibility of outpatient management and suggest a potential for reduced healthcare resource utilisation with liso-cel in clinical practice.

  1. Dreyling M, et al. Three-year efficacy and longitudinal safety of lisocabtagene maraleucel (liso-cel) in patients with third-line or later (3l+) follicular lymphoma (fl) from TRANSCEND FL. OS02-02, EBMT congress 2026, 22–25 March, Madrid, Spain.
  2. Morschhauser F, et al. Nat Med. 2024;30(8):2199-2207.

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Risks and causes of non-relapse mortality after CAR T-cell therapy

A retrospective registry study by the European Society for Blood and Marrow Transplant (EBMT) evaluated the risk and causes of non-relapse mortality (NRM) associated with CAR T-cell therapy, as well as differences by disease indication and therapeutic product [1]. NRM remains a clinically relevant concern, with infectious complications representing a leading cause. Other causes of NRM included CAR T-cell therapy-related toxicities (32.8%) and secondary malignancies (9.5%).

“Approval studies of CAR T-cell products demonstrated low mortality due to small patient numbers and relatively short follow-up. Early real-world data showed higher NRM, which may reflect treatment of more advanced patients later in the disease course,” noted Dr Charlotte Graham (King’s College London, UK). A recent meta-analysis reported an NRM of 5–10% following CAR T-cell therapy for haematological malignancies [2]. The study presented by Dr Graham was conducted by the EBMT Transplant Complications Working Party, using real-world registry data to assess NRM risk across disease types and CAR T-cell products.

A total of 6,928 adult patients who received a licensed CAR T-cell therapy between 2019 and 2023 for a haematological malignancy were included. Of these, 5,573 patients were treated for B-cell lymphoma (BCL), 583 for multiple myeloma (MM), 514 for mantle cell lymphoma (MCL), and 258 for B-cell acute lymphoblastic leukaemia (B-ALL). There were 2,887 deaths overall; 2,214 (76.7%) were attributed to disease progression or relapse. NRM accounted for 673 deaths (23.3%).

The 1-year post-infusion incidence of NRM by disease indication was:

  • MCL: 13.3% (95% CI 10.5–16.5);
  • B-ALL: 9.8% (95% CI 6.5–14.0);
  • BCL: 6.9% (95% CI 6.2–7.6);
  • MM: 5.3% (95% CI 3.6–7.5).

The highest 1-year NRM was observed in patients with MCL treated with brexucabtagene-autoleucel (brexu-cel) (13.3%), followed by patients with B-ALL treated with brexu-cel (11.4%). The lowest 1-year NRM was seen in patients with BCL treated with lisocabtagene maraleucel (liso-cel) (4.0%).

The leading causes of NRM were infection (n=191, 35.4%), CAR T-cell therapy-related toxicities (n=177, 32.8%), and secondary malignancies (n=51, 9.5%). “Our results allow us to create strategies focused on infection prophylaxis, surveillance and management, which could enhance CAR T-cell outcomes,” concluded Dr Graham.

  1. Graham C, et al. Non-relapse mortality following CAR-T cell therapy: a study by the EBMT Transplant Complications Working Party. GS2-6, EBMT congress 2026, 22–25 March, Madrid, Spain.
  2. Cordas Dos Santos DM, et al. Nat Med. 2024;30(9):2667-2678.

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