Researchers Discover Biomarkers Predicting Response to Immunotherapy for Kidney Cancer

Researchers Discover Biomarkers Predicting Response to Immunotherapy for Kidney Cancer

Johns Hopkins researchers from the Kimmel Cancer Center and Bloomberg~Kimmel Institute for Cancer Immunotherapy have identified a biomarker signature consisting of the quantity of immune cells within and surrounding kidney tumors, the degree of cancer tissue necrosis, and mutations in a tumor suppressor gene called PBRM1. This signature can predict the response of kidney cancer patients to immunotherapy prior to treatment.

According to research directed by investigators at the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy, a biomarker signature consisting of the number of immune cells in and around kidney tumors, the absence of dead cancer tissue, and a mutation in the PBRM1 gene can predict how well patients with kidney cancer will respond to immunotherapy. The investigators reviewed 136 kidney tumor biopsies from previous studies and found that patients with all three positive factors had the best overall survival at five years. This study was published in the journal Cell Reports Medicine on Feb. 21.

According to lead study author Julie Stein Deutsch, M.D., a clinical fellow in dermatopathology at the Johns Hopkins University School of Medicine, the treatment options for patients with metastatic clear cell renal carcinoma, a type of kidney cancer, are rapidly advancing and now include regimens based on immunotherapy.

According to lead study author Julie Stein Deutsch, M.D., a clinical fellow in dermatopathology at the Johns Hopkins University School of Medicine, there is a need for biomarkers that can assist in matching patients to the regimens that are most likely to be effective. While such markers have been studied in other cancers, including lung cancer, they have not demonstrated the same predictive ability in patients with kidney cancer.

According to Julie Stein Deutsch, M.D., a clinical fellow in dermatopathology at the Johns Hopkins University School of Medicine and lead study author, the classic hematoxylin and eosin-stained (H&E) pathology slide, which is considered the gold standard for diagnosing and staging cancer worldwide, has been largely ignored as a potential source of biomarker information.

According to Deutsch, while numerous studies are exploring biomarkers for immunotherapy response using high-tech tools that require skilled professionals and costly equipment, the potential of the classic hematoxylin and eosin-stained (H&E) pathology slide to provide biomarker information has been largely ignored. She believes that the ability to use data from an H&E slide taken before treatment to forecast the overall survival of patients receiving immunotherapy is highly effective and can be applied even in resource-constrained environments.

Senior author Janis Taube, M.D., M.Sc., who is also the co-director of the Tumor Microenvironment Laboratory at the Bloomberg~Kimmel Institute for Cancer Immunotherapy and director of the Division of Dermatopathology, explains that immunotherapies targeting the protein PD-1 (programmed cell death 1) have become the forefront of cancer therapy by inducing an immune response against cancer cells.

Taube notes that although anti-PD-1 immunotherapies are a groundbreaking cancer treatment, they are not effective for all patients. The recent discoveries could aid in identifying the most suitable therapy for patients in advance.

The potential of commonly available H&E slides to serve as biomarkers was examined by investigators who analyzed 136 metastatic tumor samples from patients with renal cell cancers before treatment. Of these, 63 biopsies were obtained before patients received the immunotherapy nivolumab as either their first or later treatment, 58 biopsies were obtained from patients receiving later-line nivolumab or the chemotherapy drug everolimus, and 15 biopsies were obtained from patients who had not received therapy before and who were treated with nivolumab plus the immunotherapy ipilimumab.

The amount of tumor-infiltrating immune cells (referred to as TILplus) and the presence of necrosis (dead tissue) were evaluated and scored by the researchers in the specimens.

Patients with immune infiltrates (tumor-infiltrating lymphocytes, macrophages, plasma cells) in their biopsy specimens that interacted with tumors (TILplus score of 1) had better overall survival than those without such infiltrates (specimens with TILplus score of 0) in the first group of 63 biopsies, as well as in samples from all three groups of patients who received immunotherapy. Those with a TILplus score of 1 had a median overall survival of 47.9 months, whereas those with a score of 0 had a median overall survival of 16 months. The median progression-free survival was 7.5 months in those with a TILplus score of 1 and 2.7 months in those with a score of 0.

However, the association between TILplus score and overall survival was not observed in patients who received everolimus, indicating that the results were specific to immunotherapy. Moreover, the presence of necrosis was found to impact the benefits of immune system infiltration in the tumor. In two groups of biopsies, patients with tumors having a significant amount of necrosis (more than 10% surface area) had lower overall survival compared to those with the same TILplus score but without necrosis. This finding was observed in patients from two cohorts. Once again, combining TILplus and necrosis scores did not predict outcomes for patients receiving everolimus.

Deutsch emphasizes the significance of their findings, stating that areas of necrosis have been traditionally excluded from biomarker studies due to their inability to be used for genomic or transcriptomic analysis. However, their study highlights the importance of including these areas in investigations as they provide valuable information about a negative impact on patient outcomes.

Lastly, the researchers examined the relationship between mutations in the PBRM1 gene and how it affects the other biomarkers. Although these mutations were correlated with overall survival, they were not associated with TILplus. However, a statistical analysis of all three biomarkers revealed that the combination of H&E scoring and PBRM1 mutation status could divide patients into three distinct groups.

The researchers analyzed the impact of mutations in the PBRM1 gene and its correlation with the other two factors. Although such mutations were found to be associated with overall survival, they did not have any relation with TILplus score. However, the statistical analysis of all three factors showed that patients could be divided into three groups based on the combination of H&E scoring and PBRM1 mutation status. Patients who exhibited all three positive factors – a TILplus score of 1, a necrosis score of 0, and a PBRM1 mutation – had the highest overall survival at five years. Those with two of the three features showed intermediate survival, while patients with only one feature had the worst survival rates.

According to the investigators, their literature search failed to find other studies that incorporated H&E features as part of tumor characterization using multimodality approaches. This suggests that the potential of H&E insights in biomarker discovery for immunotherapies has not been fully utilized.

Taube has stated that the next course of action will involve verifying the results in bigger patient groups and possibly conducting a clinical trial to validate the findings.

Source: Johns Hopkins University School of Medicine