Bladder cancer: When chemotherapy makes sense

Immune status allows estimation of therapy success

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In patients with bladder cancer, the body’s own fight against the tumor by the immune system contributes to the effectiveness of chemotherapy. This has now been reported by a research team from Charité – Universitätsmedizin Berlin and the Berlin Institute of Health (BIH) in the journal Science Translational Medicine*. This finding can be used to predict the success of therapy and could increase the survival chances of patients in the future.

Bladder cancer is one of the ten most common tumor diseases in Germany, and one of the five most common in men. Every year, around 30,000 people are diagnosed with the disease in Germany. Particularly if the bladder cancer has already grown into the muscle layer of the bladder wall, there is an increased risk that it will „spread“, i.e. form metastases. Patients with muscle-invasive bladder cancer that has not yet spread therefore usually have the bladder surgically removed. According to the guideline, patients should also receive chemotherapy in advance, i.e. an agent that attacks fast-growing cells. The aim of this pre-treatment is to reduce the size of the tumor before surgery, thus reducing the risk of recurrence and the formation of metastases. However, in slightly more than half of those affected, the size of the tumor does not decrease as a result of chemotherapy. These patients therefore do not benefit from pre-treatment, but on the contrary lose valuable time during which the bladder cancer can continue to grow and form metastases.

An international research team led by Dr. Michael Schmück-Henneresse, a scientist at the Berlin Institute of Health Center for Regenerative Therapies (BCRT), the Institute of Medical Immunology and the Berlin Center for Advanced Therapies (BeCAT) at Charité, has now found a way to distinguish which patients benefit from chemotherapy and which do not. The key was found in the immune system of the patients even before the start of treatment: only if the tumor tissue showed two specific immunological components, CXCL11 and CXCR3alt, in large quantities, did the subsequent chemotherapy have an effect. „These two components are comparatively uncomplicated to measure in the laboratory; the biopsy taken to diagnose the tumor is sufficient as a sample,“ says Dr. Schmück-Henneresse. „With this technically simple method, it is therefore possible in principle to estimate the success of chemotherapy in the affected person or persons already at the time of diagnosis. If it is unlikely that the pre-treatment will be successful, it would be possible to dispense with chemotherapy and surgically remove the bladder cancer directly. Such a personalized approach would not only spare patients the side effects of ineffective treatment, but would also likely increase their chances of survival. However, before detection of CXCL11 and CXCR3alt can be routinely used in patients with bladder cancer, further studies are needed to independently confirm our findings.“    

For the study, the researchers examined tumor samples from 20 patients with muscle-invasive bladder cancer undergoing treatment at Umeå University in Sweden after completion of chemotherapy. The team led by Amir Sherif, M.D., had already taken the biopsies for diagnosis prior to therapy during a cystoscopy. The research group analysed which immunological messengers were found in the tissue and which receptors, i.e. „receivers“ for these messengers, the immune cells produced in the tumor. For all components found, the researchers then tested whether their quantity was related to the success of the therapy. This was the case for both the messenger CXCL11 and the receptor CXCR3alt: chemotherapy was only effective if there was a particularly high amount of CXCL11, an attractant for immune cells, in the tumor tissue and if certain cells of the immune system, the T cells, produced the appropriate receptor CXCR3alt. The team then checked their observations against existing data from the Cancer Genome Atlas. Again, it showed that of 68 bladder cancer patients who received chemotherapy, those with large amounts of CXCL11 in tumor tissue were more likely to survive.

„We interpret our results to mean that the signaling molecule CXCL11 attracts specific T cells to the tumor and stimulates them to proliferate and thus take stronger action against the cancer,“ explains first author of the study Tino Vollmer, a doctoral student at the Institute of Medical Immunology at Charité and a scientist at BCRT and BeCAT. „Chemotherapy then seems to support this endogenous fight against the tumor, for example because the T cells can migrate in more easily due to the decay of the cancerous tissue.“ Here, the influence of the immune system on the outcome of therapy contradicts the long-standing doctrine that the effect of chemotherapeutic drugs is based solely on the high ability of cancer cells to divide. „Together with other studies, our current work emphasizes how important it is here that the immune system actively fights the tumor,“ Vollmer says.

The research group therefore next wants to investigate whether the T cells of patients whose own immune system is less vigorous against bladder cancer can be activated using a cell therapy approach: To do this, the team wants to equip the T cells of affected individuals with an artificial CXCR3alt receptor outside the body and then reintroduce them into the body. The scientists will also explore this therapeutic approach for other types of cancer. In addition, they want to advance the personalized administration of chemotherapy for bladder cancer. To this end, the predictive power of the two immune components CXCL11 and CXCR3alt will be tested with the aid of a so-called prospective validation, which will examine independent groups of patients with muscle-invasive bladder cancer at different European hospitals. „If the reliability of the prediction is confirmed, the analysis of immune status could be regularly used in the future as a basis for decision-making on bladder cancer treatment,“ said Dr. Schmück-Henneresse.

*Vollmer T et al, The intratumoral CXCR3 chemokine system is predictive of chemotherapy response in human bladder cancer. Sci Transl Med 2021 Jan 13. doi: 10.1126/scitranslmed.abb3735

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