Antibody overcomes resistance to cancer immunotherapy

Tumours can outwit the immune system by producing the surface protein PD-L1. When this protein binds to the PD-1 receptor on T cells, it inhibits their attack on the tumour. Modern immunotherapies release this brake, thereby reactivating the body’s own defence against cancer.

Nevertheless, many patients do not respond adequately to this treatment. One reason for this is the presence of other immunosuppressive mechanisms, such as the signalling molecule GDF-15, which is produced by many tumours. Professor Jörg Wischhusen’s tumour immunology research group at the Würzburg Gynaecological Clinic, in collaboration with its spin-off CatalYm, has demonstrated in preclinical models that blocking GDF-15 can significantly enhance the efficacy of established immunotherapies.

Visugromab, an antibody developed in Würzburg, has now achieved long-lasting tumour remissions in an international study among patients in whom established immune checkpoint therapies had previously failed. The long-term data from the so-called GDFATHER-01 study have been published in the renowned Journal of Haematology & Oncology .

“For the first time on a large clinical scale, we are seeing that the targeted blockade of GDF-15 is effective in a group of patients for whom there have been virtually no convincing treatment options to date,” comments Wischhusen. “The fact that many of these remissions remain stable for years is a very strong signal from the perspective of a tumour immunologist.”

In the study, visugromab was used in combination with the PD-1 inhibitor nivolumab in heavily pre-treated patients with non-small cell lung cancer, urothelial carcinoma and liver cancer. All study participants had previously shown no response, or only a temporary response, to anti-PD-1 or anti-PD-L1 immunotherapy.

Exceptional efficacy despite resistance to immunotherapy

The combination of visugromab (10 mg/kg) and nivolumab (240 mg), administered every two weeks until disease progression or intolerance, demonstrated promising efficacy. Objective response rates in all three tumour types studied were around 14 to 19 percent. Particularly noteworthy was the median duration of response of 28.8 months, which was more than twice as long as the 12 months observed with the original standard immunotherapy. Furthermore, 61.5 percent of patients who responded to the treatment achieved complete radiological or metabolic remission. Seven of the eight complete remissions were still ongoing at the time of the evaluation.

“For a cohort that had undergone such intensive prior treatment and was defined as refractory to immunotherapy, the depth and duration of the remissions observed are exceptional,” reports Dr Maria Elisabeth Goebeler, Head of the Early Clinical Trial Unit at the Comprehensive Cancer Centre and Medical Clinic II at the UKW, where the patients were treated. “The fact that many of these remissions have persisted for more than two years and are often more pronounced than the initial response to the first immunotherapy strongly suggests that resistance mechanisms have genuinely been overcome.”

International study paves the way for further clinical development

The study was conducted at several centres in Spain, Germany, Switzerland and Italy. In addition to the Würzburg research group, Professor Ralf Bargou (Chair of Translational Oncology at the UKW and Director of the Comprehensive Cancer Centre Mainfranken) on the Advisory Board, the international coordinating principal investigator Professor Ignacio Melero (Pamplona/Oxford) and Professor Eugen Leo, then Chief Medical Officer of the company CatalYm. Leo regards, in particular, the long duration of remissions and the favourable safety profile as an important basis for further clinical development.

The development of visugromab is already continuing in further studies, such as in first-line treatment of non-small cell lung cancer and as neoadjuvant therapy for muscle-invasive bladder cancer. Preliminary data suggest that combination with nivolumab may significantly increase response rates and the frequency of pathological complete remissions, even in patients who have not previously received immunotherapy. In addition, a cachexia trial is being prepared at the UKW. Here, visugromab is to be used to combat uncontrolled weight loss and muscle wasting, which frequently occur as comorbidities of cancer.

Translational immuno-oncology from Würzburg

The development of visugromab and the key role played in its clinical trial exemplify the strength of translational immuno-oncology in Würzburg. Here, findings from basic research are consistently translated into new therapeutic approaches and, at an early stage, into clinical trials.

Professor Hermann Einsele, Director of Medical Clinic II and Spokesperson for the National Centre for Tumour Diseases (NCT WERA), sums up: “The results now published exemplify how a basic scientific idea in Würzburg can give rise to an international clinical development programme. For our patients, this opens up additional long-term treatment options in situations where conventional immunotherapies have so far reached their limits.”

Publication

Melero I, de Miguel M, Garralda Cabanas E, et al. Long-term follow-up of a phase 1/2 trial of the anti-GDF-15 antibody visugromab plus the anti-PD-1 antibody nivolumab in anti-PD-1/-L1 relapsed/refractory solid tumours. J Hematol Oncol. 2026; Article in Press. doi:10.1186/s13045-026-01818-2