Der Einfluss einer Mangelernährung auf die Wirkung von Immun-Checkpoint-Inhibitoren

Zusammenfassung

Bei onkologischen Patienten kommt es durch unzureichende Nahrungsaufnahme, Maldigestion und -absorption durch die Grunderkrankung und antineoplastische Therapie, durch katabole metabolische Veränderungen und eine systemische Inflammationsreaktion oft zu einer Kachexie mit Gewichtsverlust und verringerter Muskelmasse und -kraft. Diese kann durch adäquate Kalorienzufuhr alleine nicht vollständig aufgehoben werden und führt zu einer zunehmenden funktionellen Einschränkung. Neben diesen funktionellen Veränderungen, der reduzierten Lebensqualität und der schlechteren Chemotherapieverträglichkeit mit geringerer Therapieadhärenz und erhöhtem Komplikationsrisiko ist die Kachexie mit einer verkürzten Überlebenszeit assoziiert. Die Einführung von Immun-Checkpoint-Inhibitoren (ICI) hat die Therapiekonzepte unterschiedlicher Krebsarten maßgeblich verändert und das Überleben signifikant verbessert. Allerdings profitieren nicht alle Patienten von diesem Therapieansatz und es fehlen verlässliche prädiktive Marker für das Therapieansprechen. Die Untersuchung von Resistenzmechanismen ist Gegenstand aktueller Forschung. Es konnte gezeigt werden, dass das Vorliegen einer Kachexie und Sarkopenie eine ICI-Resistenz begünstigt. Die Tatsache, dass gerade kachektische Patienten möglicherweise weniger von einer ICI-basierten Therapie profitieren, ist von hoher klinischer Relevanz, da die Einführung dieser Therapien in den vergangenen Jahren zu einer signifikanten Verbesserung des Überlebens gerade bei Entitäten mit hohem Kachexie-Risiko wie dem nichtkleinzelligen Bronchialkarzinom geführt hat. Es wird diskutiert, dass die katabole Stoffwechsellage, chronische Inflammation und das veränderte Darmmikrobiom bei kachektischen Tumorpatienten möglicherweise einen Einfluss auf die Wirksamkeit einer ICI-basierten Therapie und auf das Auftreten immunbedingter Nebenwirkungen haben. Ernährungsinterventionen scheinen daher eine vielversprechende Möglichkeit, die Wirksamkeit und Verträglichkeit einer solchen Therapie bei onkologischen Patienten zu verbessern.

Abstract

In oncological patients, insufficient food intake, maldigestion and malabsorption due to the underlying disease and antineoplastic therapy, catabolic metabolic changes and a systemic inflammatory reaction often lead to cachexia with weight loss and reduced muscle mass and strength. This condition is not completely reversible by adequate caloric intake alone and leads to increasing functional impairment. In addition to these functional changes, the reduced quality of life and poorer chemotherapy tolerance with lower treatment adherence and increased risk of complications, cachexia is associated with worse survival. The introduction of immune checkpoint inhibitors (ICI) significantly changed treatment concepts for different entities and improved survival. However, not all patients benefit from this therapeutic approach and there is a lack of reliable predictive markers for treatment response. The investigation of resistance mechanisms is the subject of current research. It has been shown that the presence of cachexia and sarcopenia favors ICI resistance. The fact that cachectic patients may benefit less from ICI-based therapy is of high clinical relevance, as the introduction of these therapies in recent years significantly improved survival, especially in entities with a high risk of cachexia such as non-small cell lung cancer. The catabolic metabolic state, chronic inflammation and the altered gut microbiome in tumor patients with cachexia may have an impact on the efficacy of ICI-based therapies and on immune-related side effects. Nutritional interventions therefore appear to be a promising way to improve the efficacy and tolerability of this therapeutic approach in oncological patients.

Schlüsselwörter

Mangelernährung - Tumorkachexie - Sarkopenie - Immun-Checkpoint-Inhibition

Keywords

malnutrition - cancer cachexia - sarcopenia - immun-checkpoint-inhibition

Publikationsverlauf

Eingereicht: 06. März 2025

Angenommen: 06. Mai 2025

Artikel online veröffentlicht:
05. Dezember 2025

• Literatur

• 1 Norman K, Pichard C, Lochs H. et al. Prognostic impact of disease-related malnutrition. Clin Nutr 2008; 27: 5-15
• 2 Cederholm T, Jensen GL, Correia MITD. et al. GLIM criteria for the diagnosis of malnutrition – A consensus report from the global clinical nutrition community. Clin Nutr 2019; 38: 1-9
• 3 McMillan DC. An inflammation-based prognostic score and its role in the nutrition-based management of patients with cancer: Nutrition Society and BAPEN Medical Symposium on ‘Nutrition support in cancer therapy’. Proc Nutr Soc 2008; 67: 257-262
• 4 Proctor MJ, Morrison DS, Talwar D. et al. An inflammation-based prognostic score (mGPS) predicts cancer survival independent of tumour site: a Glasgow Inflammation Outcome Study. Br J Cancer 2011; 104: 726-734
• 5 Tisdale MJ. Molecular Pathways Leading to Cancer Cachexia. Physiology 2005; 20: 340-348
• 6 Cruz-Jentoft AJ, Bahat G, Bauer J. et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing 2019; 48: 16-31
• 7 Fearon K, Strasser F, Anker SD. et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol 2011; 12: 489-495
• 8 Dolly A, Dumas J-F, Servais S. Cancer cachexia and skeletal muscle atrophy in clinical studies: what do we really know?. J Cachexia Sarcopenia Muscle 2020; 11: 1413-1428
• 9 Huiskamp LFJ, Chargi N, Devriese LA. et al. The Predictive Value of Low Skeletal Muscle Mass Assessed on Cross-Sectional Imaging for Anti-Cancer Drug Toxicity: A Systematic Review and Meta-Analysis. J Clin Med 2020; 9: 3780
• 10 Willemsen ACH, Hoeben A, Lalisang RI. et al. Disease-induced and treatment-induced alterations in body composition in locally advanced head and neck squamous cell carcinoma. J Cachexia Sarcopenia Muscle 2020; 11: 145-159
• 11 Nishioka N, Uchino J, Hirai S. et al. Association of Sarcopenia with and Efficacy of Anti-PD-1/PD-L1 Therapy in Non-Small-Cell Lung Cancer. J Clin Med 2019; 8: 450
• 12 Bilen MA, Martini DJ, Liu Y. et al. Combined Effect of Sarcopenia and Systemic Inflammation on Survival in Patients with Advanced Stage Cancer Treated with Immunotherapy. The Oncologist 2020; 25: e528-e535
• 13 Rounis K, Makrakis D, Tsigkas A-P. et al. Cancer cachexia syndrome and clinical outcome in patients with metastatic non-small cell lung cancer treated with PD-1/PD-L1 inhibitors: results from a prospective, observational study. Transl Lung Cancer Res 2021; 10
• 14 Cortellini A, Bozzetti F, Palumbo P. et al. Weighing the role of skeletal muscle mass and muscle density in cancer patients receiving PD-1/PD-L1 checkpoint inhibitors: a multicenter real-life study. Sci Rep 2020; 10: 1456
• 15 Degens JHRJ, Dingemans A-MC, Willemsen ACH. et al. The prognostic value of weight and body composition changes in patients with non-small-cell lung cancer treated with nivolumab. J Cachexia Sarcopenia Muscle 2021; 12: 657-664
• 16 Arribas L, Plana M, Taberna M. et al. Predictive Value of Skeletal Muscle Mass in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma Patients Treated With Immune Checkpoint Inhibitors. Front Oncol 2021; 11: 699668
• 17 Willemsen ACH, De Moor N, Van Dessel J. et al. The predictive and prognostic value of weight loss and body composition prior to and during immune checkpoint inhibition in recurrent or metastatic head and neck cancer patients. Cancer Med 2023; 12: 7699-7712
• 18 Chu MP, Li Y, Ghosh S. et al. Body composition is prognostic and predictive of ipilimumab activity in metastatic melanoma. J Cachexia Sarcopenia Muscle 2020; 11: 748-755
• 19 Young AC, Quach HT, Song H. et al. Impact of body composition on outcomes from anti-PD1 +/− anti-CTLA-4 treatment in melanoma. J Immunother Cancer 2020; 8: e000821
• 20 Daly LE, Power DG, O’Reilly Á. et al. The impact of body composition parameters on ipilimumab toxicity and survival in patients with metastatic melanoma. Br J Cancer 2017; 116: 310-317
• 21 Bertrand F, Montfort A, Marcheteau E. et al. TNFα blockade overcomes resistance to anti-PD-1 in experimental melanoma. Nat Commun 2017; 8: 2256
• 22 Mariathasan S, Turley SJ, Nickles D. et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 2018; 554: 544-548
• 23 Turner DC, Kondic AG, Anderson KM. et al. Pembrolizumab Exposure–Response Assessments Challenged by Association of Cancer Cachexia and Catabolic Clearance. Clin Cancer Res 2018; 24: 5841-5849
• 24 Flint TR, Fearon DT, Janowitz T. Connecting the Metabolic and Immune Responses to Cancer. Trends Mol Med 2017; 23: 451-464
• 25 Mace TA, Shakya R, Pitarresi JR. et al. IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer. Gut 2018; 67: 320-332
• 26 Damuzzo V, Solito S, Pinton L. et al. Clinical implication of tumor-associated and immunological parameters in melanoma patients treated with ipilimumab. OncoImmunology 2016; 5: e1249559
• 27 Tsukamoto H, Fujieda K, Miyashita A. et al. Combined Blockade of IL6 and PD-1/PD-L1 Signaling Abrogates Mutual Regulation of Their Immunosuppressive Effects in the Tumor Microenvironment. Cancer Res 2018; 78: 5011-5022
• 28 Machida K, Tahara SM. Immunotherapy and Microbiota for Targeting of Liver Tumor-Initiating Stem-like Cells. Cancers 2022; 14: 2381
• 29 Ubachs J, Ziemons J, Soons Z. et al. Gut microbiota and short-chain fatty acid alterations in cachectic cancer patients. J Cachexia Sarcopenia Muscle 2021; 12: 2007-2021