Tag Archives: #bladdercancer

Oncotarget: Urine RNA Reveal Tumor Markers For Human Bladder Cancer (Medicine)

Oncotarget published “Transcriptome analyses of urine RNA reveal tumor markers for human bladder cancer: validated amplicons for RT-qPCR-based detection” which reported that in case of bladder cancer, urine RNA represents an early potentially useful diagnostic marker.

Here the authors describe a systematic deep transcriptome analysis of representative pools of urine RNA collected from healthy donors versus bladder cancer patients according to established SOPs.

This analysis revealed RNA marker candidates reflecting coding sequences, non-coding sequences, and circular RNAs.

Next, they designed and validated PCR amplicons for a set of novel marker candidates and tested them in human bladder cancer cell lines.

This Oncotarget work strongly suggests exploiting urine RNAs as diagnostic markers of bladder cancer and it suggests specific novel markers.

This Oncotarget work strongly suggests exploiting urine RNAs as diagnostic markers of bladder cancer and it suggests specific novel markers.

Dr. Georg Sczakiel from The Universität zu Lübeck and UKSH, said “Human bladder cancer (BCa) is one of the most common cancer types in humans.

With regard to BCa, RNA markers have been studied by transcriptome analyses of single cells, tissue samples and urine.

In case of BCa, urine is thought to be the most promising source for RNA-based tumor markers as direct physical contact between tumor cells and urine seems to be given.

On the other hand, urine RNA samples contain RNAs which are suitable for cDNA synthesis and RT-qPCR detection.

Cell-free RNA contained in urine samples can be protected against degradation, i.e., stabilization of RNA markers is possible such that shipping of samples and storage is possible.

This consists of SOP-based acquisition of urine, stabilization of urine RNA, delivery and storage of samples, RNA preparation, and deep transcriptome analyses.

The Sczakiel Research Team concluded in their Oncotarget Research Output that while all of these hits focus on conventional linear transcripts the authors also noted experimental evidence supporting the existence of circular RNAs that seem to be able to monitor differences between the healthy state and the cancer state.

This is reflected by a number of recent studies describing a link between circular RNA and cancer.

However, such evidence derived from in silico analyses does not necessarily prove that such circRNAs exist in reality.

A set of experimental evidence is necessary to sufficiently strongly verify their existence.

However, such assays go beyond the scope of this study although this is one promising way to proceed in order to identify new and potent RNA markers.

DOI – https://doi.org/10.18632/oncotarget.27954

Full text – https://www.oncotarget.com/article/27954/text/

Featured image: Filters for a systematic search of RNA-based markers  © 2021 Dubois et al. 

Reference: Dubois J., Rueger J., Haubold B., Far R. Kretschmer-Kazemi, Sczakiel G. Transcriptome analyses of urine RNA reveal tumor markers for human bladder cancer: validated amplicons for RT-qPCR-based detection. Oncotarget. 2021; 12: 1011-1023. Retrieved from https://www.oncotarget.com/article/27954/text/

Provided by Impact Journals LLC

Study Shows Novel Test Can Detect New and Recurrent Bladder Cancer (Medicine)

A revolutionary new urine screening test that utilizes a novel Keratin 17 (K17) cancer biomarker can detect the presence of new bladder cancer in patients with hematuria, or blood in the urine, according to a study led by researchers at Yale Cancer Center, Stony Brook University, and KDx Diagnostics, Inc. The findings also show the test can detect recurrent bladder cancer in patients under surveillance for relapse.

The study was published online June 4 in American Journal of Clinical Pathology.

According to the American Cancer Society, an estimated 81,000 cases of bladder cancer will be diagnosed in the United States this year. However, accurate detection of bladder cancer, or urothelial carcinoma (UC), is often difficult and expensive, requiring invasive camera-based testing methodology.

“Current methods used in cytology labs are based on subjective microscopic features that may not reliably distinguish between benign cells and low-grade urothelial carcinomas,” said Luisa Escobar-Hoyos, assistant professor of therapeutic radiology at Yale Cancer Center and co-lead author of the study. “There was an unmet clinical need to find biomarkers to improve diagnostic accuracy for UC. Following up on prior studies from our lab, this research confirms that K17 is a highly sensitive diagnostic test for initial screening and detection of recurrent cancer across all grades of UC.”

The study was defined by two matched cohorts: a discovery cohort in which the optimal number of positive cells for optimal sensitivity and specificity was identified, and a validation cohort in which a new set of patients was evaluated. In this validation cohort, the sensitivity and specificity in patients were 86% and 92%, respectively. When the patients were divided into hematuria and recurrent bladder cancer populations, the data showed sensitivity and specificity of 100% and 83%, respectively, in patients with hematuria, and sensitivity and specificity of 92% and 100%, respectively, in patients with recurrent bladder cancer.

“We are pleased to report that the test using a K17 biomarker continues to show high sensitivity in identifying both new cancers from hematuria patients and recurrent cancer from patients being monitored for UC,” said Nam W. Kim, PhD, chief executive officer and chief technology officer of KDx Diagnostics, Inc. “There is now a growing body of evidence that the non-invasive, K17 urine test will make a significant positive impact on detection and management of UC.”

Featured image: Brown staining of the Keratin 17 biomarker can be seen in malignant cells within a cluster of bladder cells (dark blue). The large, pale blue cells are normal cells from another tissue secreted in urine. © Yale University

Reference: Sruthi Babu, MD, PhD, Nam W Kim, PhD, Maoxin Wu, MD, PhD, Ina Chan, Luisa F Escobar-Hoyos, PhD, Kenneth R Shroyer, MD, PhD, Keratin 17 Is a Novel Cytologic Biomarker for Urothelial Carcinoma Diagnosis, American Journal of Clinical Pathology, 2021;, aqab050, https://doi.org/10.1093/ajcp/aqab050

Provided by Yale University

Immunotherapy after Bladder Cancer Surgery May Reduce Recurrence, Study Shows (Medicine)

New research from Memorial Sloan Kettering Cancer Center (MSK) medical oncologist Dean Bajorin, MD, and colleagues found that patients who received nivolumab (Opdivo®) after bladder cancer surgery reduced their overall risk for high-grade bladder cancer recurrence. This research was published today in the New England Journal of Medicine.

In this phase III randomized study, Dr. Bajorin and a team of investigators evaluated 709 patients who were at high risk for recurrence of urothelial cancer after removal of their bladder, ureter, or kidney for high-grade cancer. To evaluate for benefit, patients were randomized to receive either nivolumab or a placebo every two weeks for one year. Patients and physicians were blinded to the treatment. Both safety and quality of life were evaluated.

Dr. Bajorin and investigators found that in high-risk patients, nivolumab reduced recurrence after surgery compared to patients who received the placebo. The current standard of care following surgery that removes the bladder or kidney and ureter has been observation without adjuvant therapy — even in patients at high risk of recurrence and death. This is because no chemotherapy or immunotherapy has previously been shown to be of benefit. Participants who received nivolumab had disease-free survival of 21 months compared with 10.9 months in people receiving the placebo.

“We are very encouraged by the data and the results of the study,” said Dr. Bajorin, first and corresponding author of the study. “Despite available therapies for advanced metastatic bladder cancer, new options are needed to improve long-term disease control and patient survival. These findings have the potential to change the standard of care for bladder cancer.”

Urothelial cancers are tumors that start in the lining of the urine-collecting system that transports urine from the kidneys to the outside of our bodies. These cancers are often referred to as “bladder cancer” because most of them start in the bladder.

Dr. Bajorin and colleagues concluded that the survival data is not yet mature and will need additional research and follow-up. The primary endpoints of disease-free survival in the study population and disease free-survival in the subset of patients with PD-L1-positive tumors were met, and these findings are highly statistically significant and clinically relevant for a population of patients with a clear unmet medical need.

“The trial demonstrates that novel therapies can be identified as having patient benefit when the studies are conducted in a very rigorous fashion. We are hoping this treatment will get approval for all patients at high risk of recurrence after the US Food and Drug Administration has done a detailed review of all the data,” said Dr. Bajorin.

Making Pioneering Advances for Bladder Cancer Patients

Cancer immunotherapy was born at MSK a little over a century ago. Since then, physician-scientists across MSK have led the effort to develop immune-based treatments for different types of cancer. MSK has been at the epicenter of discoveries in the field, and the institution’s work is bringing exciting new treatment options to people around the world. MSK physicians have extensive experience using immunotherapy to treat people with melanoma, kidney cancer, lung cancer, and other cancers as well as handling immune-related side effects.

Without treatment, bladder cancer can be an aggressive disease. In 2021, it is estimated that there will be nearly 17,000 deaths due to bladder cancer in the United States — and numbers are expected to rise significantly in the next decade. 

“As physicians, we consistently strive to provide our patients with the most effective therapies and give those with advanced disease more options,” said Dr. Bajorin.

This trial was sponsored by Bristol Myers Squibb, Checkmate 274.

Reference: Dean F. Bajorin, J. Alfred Witjes, Jürgen E. Gschwend, Michael Schenker, et al., “Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma”, N Engl J Med 2021; 384:2102-2114
DOI: 10.1056/NEJMoa2034442

Provided by MSKCC

Oncotarget: Urine Protein Biomarkers Of Bladder Cancer (Medicine)

These Oncotarget findings suggest that urine IL-1α, IL-1ra and IL-8 are useful indicators of bladder cancer.

Oncotarget published “Urine protein biomarkers of bladder cancer arising from 16-plex antibody-based screens” which reported that the current study examines urine samples from 66 subjects, comprising of 31 Urology clinic controls and 35 bladder cancer patients, using a Luminex based screening platform.

ELISA validation was carried out for the top 4 prospective urine biomarkers using an independent cohort of 20 Urology clinic controls and 60 bladder cancer subjects.

Eight of these urine proteins were able to differentiate BC from control urine with ROC AUC values exceeding 0.70 at p < 0.0001, with specificity values exceeding 0.9. Upon ELISA validation, urine IL-1α, IL-1ra, and IL-8 were able to distinguish control urine from urine drawn from various bladder cancer stages, with IL-8 being the best discriminator.

These Oncotarget findings suggest that urine IL-1α, IL-1ra and IL-8 are useful indicators of bladder cancer.

These Oncotarget findings suggest that urine IL-1α, IL-1ra and IL-8 are useful indicators of bladder cancer.

Urine IL-8 not only distinguishes bladder cancer from controls, it also discriminates high grade from low grade disease, and the successive clinical stages of bladder cancer.

Dr. Chandra Mohan from The University of Houston said, “Bladder cancer (BC) is the sixth most common cancer diagnosis in the United States and is over four times more common in men than women.

Urine biomarkers could potentially provide preliminary confirmation of low-grade BC before invasive procedures are performed and facilitate surveillance of BC, as reviewed.

The present study implements a Luminex based screening platform with a cytokine/chemokine panel that simultaneously interrogates 16 urine biomarkers, followed by ELISA validation of 4 prospective urine biomarkers.

Of the 16 proteins screened by Luminex, 12 were within the detectable range and among these, 10 urine biomarkers showed significant elevation in BC compared to the controls.

ELISA validation for these 4 urine biomarkers was carried out using an independent cohort of 20 urology clinic controls and 60 BC subjects.

Of these 4 proteins, IL-8 displayed the highest significance in discriminating between controls and BC patients and discriminating highly advanced stages/grades of BC from less advanced stages/grades of BC.

The Mohan Research Team concluded in their Oncotarget Research Output that these studies indicate that urine IL-1α, IL-1ra, and IL-8 are potential biomarkers of BC, two of which re-affirm previous reports.

These studies shed additional light on the potential utility of these markers, since some of them also exhibit the ability to discriminate T1 and/or T2-T4 from Ta BC, as well as high grade from low grade BC.

Looking forward, systematic studies in larger patient cohorts are warranted to establish the specific clinical contexts in which these markers may be used, including the following: for initial diagnosis of BC, for surveillance of tumor recurrence, and/or for assessing treatment response following BCG therapy or other therapeutic modalities.

Finally, these newer urine biomarkers need to be compared against the performance of current yardsticks such as the Bladderchek and UroVysion FISH assay.

DOI – https://doi.org/10.18632/oncotarget.27941

Full text – https://www.oncotarget.com/article/27941/text/

Featured image: ROC-AUC curves for urine IL-8 in distinguishing different stages of bladder cancer. ROC-AUC curves were generated for urine IL-8 to determine its discriminatory capability among different BC groups. AUC values and p-values are listed on each curve. The closer the AUC value is to 1, the higher the discriminatory potential of the protein to distinguish between the two sample groups, with maximized sensitivity and specificity. All comparisons exhibited AUC values of 0.77 or higher, with p-values < 0.0001, except for the comparison between low grade versus urology clinic controls. © Correspondence to – Chandra Mohan – cmohan@central.uh.edu

Reference: Vanarsa K., Enan S., Patel P., Strachan B., Sam Titus A. Sam Crosslee Louis, Dennis A., Lotan Y., Mohan C. Urine protein biomarkers of bladder cancer arising from 16-plex antibody-based screens. Oncotarget. 2021; 12: 783-790. Retrieved from https://www.oncotarget.com/article/27941/text/

Provided by Impact Journals LLC

Oncotarget: MEK is a Promising Target in the Basal Subtype of Bladder Cancer (Medicine)

Oncotarget recently published in “MEK is a promising target in the basal subtype of bladder cancer” by Merrill, et al. which reported that while many resources exist for the drug screening of bladder cancer cell lines in 2D culture, it is widely recognized that screening in 3D culture is more representative of in vivo response.

To address the need for 3D drug screening of bladder cancer cell lines, the authors screened 17 bladder cancer cell lines using a library of 652 investigational small-molecules and 3 clinically relevant drug combinations in 3D cell culture.

Their goal was to identify compounds and classes of compounds with efficacy in bladder cancer.

Utilizing established genomic and transcriptomic data for these bladder cancer cell lines, they correlated the genomic molecular parameters with drug response, to identify potentially novel groups of tumors that are vulnerable to specific drugs or classes of drugs.

Importantly, the Oncotarget authors demonstrate that MEK inhibitors are a promising targeted therapy for the basal subtype of bladder cancer, and their data indicate that drug screening of 3D cultures provides an important resource for hypothesis generation.

“The Oncotarget authors demonstrate that MEK inhibitors are a promising targeted therapy for the basal subtype of bladder cancer, and their data indicate that drug screening of 3D cultures provides an important resource for hypothesis generation”

Dr. Matthew B. Soellner and Dr. Sofia D. Merajver from The University of Michigan said, “Bladder cancer is the most frequent cancer of the urinary system in the United States with nearly 82,000 new cases each year and 18,000 deaths, affecting men more often, in a 3:1 ratio.

Bladder cancer can be divided broadly into non-muscle-invasive bladder cancer and muscle-invasive bladder cancer.

The Genomics of Drug Sensitivity in Cancer represents one of the largest efforts in total drugs, screening 19 bladder cancer cell lines against 518 drugs.

Indeed, screening in 3D using ultra-low attachment plates is ideal for bladder cancer cell culture, and this method has been utilized in seminal studies for screening patient-derived organoids to predict patient response to drug treatments.

Therefore, there is a utility in screening bladder cancer cell lines in large drug screens in 3D cultures to identify novel therapeutic options for future testing in PDOs and, ultimately, patients.

Then, utilizing established genomic and transcriptomic data for these bladder cancer cell lines, including prioritized mutations, copy number variants, and RNA-based molecular subtyping, they correlated these molecular parameters with drug response identifying potentially novel groups of tumors that are vulnerable to specific drugs or classes of drugs.

The Soellner/Merajver Research Team concluded in their Oncotarget Research Paper, “this work is a valuable resource for the identification of experimental therapeutics in bladder cancer, having screened 652 investigational therapeutics and 3 drug combinations in 17 bladder cancer cell lines, using a 3D cell culture format. As next steps, we pose that this work be used to further test additional therapeutic options for patients with bladder cancer. Moreover, this work highlights a need for biomarkers of drug response, beyond mutational data. Lastly, using these methods, we identify MEK inhibitors as a promising therapeutic in the basal bladder cancer subtype. Important future work will investigate the specific molecular features of the basal subtype that make these cells more sensitive to MEK inhibition, and if this MEK sensitivity signature is applicable to other cancer subtypes.

Featured image: MEK inhibitor response correlates with basal subtype. Average and standard deviation for DSS3 response to (A) Trametinib, (B) TAK-733, (C) Normalized MEK inhibitors, and (D) Average drug response, grouped by cell line subtype. Each point represents an individual cell line. Center line is average and brackets are standard deviation. Significance determined using Mann-Whitney test, *p < 0.05, or Kruskal-Wallis with Dunn test for multiple comparisons, ***p < 0.001. © Oncotarget

Reference: Merrill N. M., Vandecan N. M., Day K. C., Palmbos P. L., Day M. L., Udager A. M., Merajver S. D., Soellner M. B. MEK is a promising target in the basal subtype of bladder cancer. Oncotarget. 2020; 11: 3921-3932. Retrieved from https://www.oncotarget.com/article/27767/text/

Provided by Impact Journals

Bladder Cancer – When to Use Chemotherapy (Medicine)

An analysis of immune status to predict treatment success.

In patients with bladder cancer, chemotherapy effectiveness is partially determined by the body’s immune system response to the malignancy. This is the conclusion of research conducted by a team of scientists from Charité – Universitätsmedizin Berlin and the Berlin Institute of Health. The findings, which have been published in Science Translational Medicine*, can be used to predict treatment success and may increase survival in patients with bladder cancer.

The research team plans to study patients with bladder cancer and other cancers to establish whether cell therapy might be used to encourage and enhance the immune system’s fight against the cancer. Photo: Hirscher/Charité

Bladder cancer is one of the ten most common types of cancer in Germany, and one of the five most common cancers in men. Nationwide, the disease affects approximately 30,000 people a year. The risk of the cancer spreading (metastasizing) is particularly high once it invades the muscle layer inside the bladder wall. In patients with non-metastatic muscle-invasive bladder cancer, treatment usually consists of the surgical removal of the bladder. According to current professional guidelines, patients must undergo chemotherapy prior to surgery; they receive drugs which will target the cancer’s fast-growing cells. The aim of this ‘neoadjuvant’ chemotherapy is to shrink the tumor prior to surgery in order to reduce the risk of recurrence and/or metastases. However, in more than fifty percent of patients, chemotherapy will not shrink the tumor. Not only do these people not benefit from neoadjuvant chemotherapy, they are losing valuable time – time during which the cancer can continue to grow and metastasize. 

An international team of researchers led by Dr. Michael Schmück-Henneresse, a scientist at the Berlin Institute of Health Center for Regenerative Therapies (BCRT) as well as Charité’s Institute of Medical Immunology and the Berlin Center for Advanced Therapies (BeCAT), has discovered a way to differentiate between patients who will benefit from chemotherapy and those who will not. The status of the patients’ immune systems before the start of treatment was found to hold the key. Subsequent chemotherapy only proved effective if the cancerous tissue contained large quantities of two specific immune system components known as CXCL11 and CXCR3alt. “The process of measuring these two components in the laboratory is relatively straightforward and only requires the biopsy sample which is collected in order to diagnose the cancer,” says Dr. Schmück-Henneresse. “This technologically simple method will make it possible to predict the likelihood of chemotherapy success in a specific patient at the point of diagnosis. If neoadjuvant chemotherapy is unlikely to be successful, one could dispense with this therapy altogether and directly move to the bladder cancer’s surgical removal. This type of personalized approach would not only spare patients the side effects of an ineffective treatment, it would probably increase their chances of survival. However, our results will need to be confirmed by further, independent studies before we can get to a stage where CXCL11 and CXCR3alt measurements become standard in patients with bladder cancer.”

As part of this research, the team studied tumor samples from 20 patients with muscle-invasive bladder cancer who had completed their chemotherapy treatment at Umeå University in Sweden. Dating back to before the start of treatment, the samples had been collected by Dr. Amir Sherif and his team during diagnostic cytoscopy procedures. The research group identified which immunological messengers were present in the biopsy tissue and which receptors (effectively the ‘recipients’ of these messengers) the immune cells inside the tumors were producing. For each of the components identified, they then tested whether there was a link between the quantities at which these were present and treatment success. Results confirmed this was the case for both the messenger substance CXCL11 and the receptor CXCR3alt. Chemotherapy only had an effect if the immune cell attractant CXCL11 was present at particularly high levels inside the tumor tissue and if specific immune system cells known as T cells produced the corresponding CXCR3alt receptor. The team subsequently examined their observations using existing data from ‘The Cancer Genome Atlas’. Their comparison confirmed that, out of a total of 68 patients with bladder cancer who had received chemotherapy, patients whose tumor tissue contained large quantities of CXCL11 were more likely to survive.

“The signaling molecule CXCL11 attracts specific T cells into the tumor tissue, where it prompts them to proliferate and fight the cancer,” explains the study’s first author, Tino Vollmer, a doctoral student at Charité’s Institute of Medical Immunology and scientist at the BCRT and BeCAT. “Chemotherapy appears to support the body’s own fight against the tumor, possibly because the resulting degradation of cancerous tissue makes it easier for T cells to invade it.” The immune system’s effect on treatment outcome directly contradicts established scientific consensus, which posits that the effect of chemotherapy drugs is solely due to the ability of cancer cells to divide and replicate. “Along with other studies, our research demonstrates the importance of the immune system’s active involvement in fighting the tumor,” says Vollmer.

As a next step, the researchers plan to study whether cell therapy could be used to activate the T cells of patients whose immune systems show a weak response to their bladder cancer. To do this, the team wants to harvest T cells from affected patients, fit them with synthetic CXCR3alt receptors in the laboratory, and then reintroduce them into these patients. The researchers will also study the same approach in relation to the treatment of other cancers. Furthermore, they plan to advance the use of personalized chemotherapy in patients with bladder cancer. To achieve this, the researchers intend to test the predictive power of both immune system components (CXCL11 and CXCR3alt) using a process known as ‘predictive validation’, which will involve the study of independent groups of patients with muscle-invasive bladder cancer at various European hospitals. “Should the method’s predictive reliability be confirmed, the analysis of a patient’s immune status could become a routine tool to support decision-making in the treatment of bladder cancer,” says Dr. Schmück-Henneresse.

Reference: Vollmer T et al., The intratumoral CXCR3 chemokine system is predictive of chemotherapy response in human bladder cancer. Sci Transl Med 2021 Jan 13. https://stm.sciencemag.org/content/13/576/eabb3735 doi: 10.1126/scitranslmed.abb3735

Provided by Charité Universitätsmedizin Berlin

Cancer Specialist Demonstrates Safety of Novel Agent (Medicine)

A novel therapy designed to help stimulate the body’s immune system response against cancer appears to be safe to use as alone or in combination with immune checkpoint inhibitors, according to an early phase clinical trial led by Martin Gutierrez, M.D., chief medical oncologist of the thoracic division at Hackensack University Medical Center’s John Theurer Cancer Center, a member of the Georgetown Lombardi Comprehensive Cancer Center Consortium.

The findings, published in the online edition of Clinical Cancer Research on November 4, suggest that BMS-986178, an investigational OX40 agonist, has an acceptable safety profile in patients with advanced solid tumors, whether used as monotherapy or in combination with the checkpoint inhibitors nivolumab (Opdivo) and/or ipilimumab (Yervoy). The rationale for using an OX40 agonist in this setting is based on its binding to the OX40 protein receptor found on memory T-cells, which can trigger a signal associated with production of additional T-cells. The newly published results appear to clear the way for the continued development of BMS-986178, starting with a Phase 2 breast cancer study.

“We were pleasantly surprised to find that T-cell stimulation with an OX40 agonist did not exacerbate the inflammatory response and other off-target effects of checkpoint inhibitors,” said Dr. Gutierrez, the study’s lead investigator and first author of the Clinical Cancer Research paper. “Indeed, the adverse events we observed in the monotherapy and combination cohorts were manageable, suggesting that BMS-986178 is safe to use in combination with checkpoint inhibitor therapy, and possibly also with a cancer vaccine.”

Bristol-Myers Squibb is developing BMS-986178 as a potential treatment for patients with solid tumors. BMS-986178 binds with a high affinity to the OX40 receptor, a member of the tumor necrosis factor receptor super family (TNFRSF), which includes several proteins with key roles in T-cell development and survival, immune activation, and anti-tumor immune responses.

“While nivolumab and ipilimumab have established a niche as viable treatments for several solid tumor types, many patients develop resistance to these checkpoint inhibitors, underscoring the need for novel immuno-oncology strategies,” explained Dr. Gutierrez. “In theory, adding an OX40 agonist to checkpoint inhibitor therapy would modulate the immunosuppression that occurs in the tumor microenvironment while enhancing the T-cell response. We tested whether we could safely combine these two immunomodulatory approaches.”

Dr. Gutierrez and colleagues conducted an open-label Phase 1/2a study of BMS-986178 (at doses ranging from 20-320 mg), both as monotherapy and in combination with nivolumab (240-480 mg) and/or ipilimumab (1-3 mg/kg of body weight), in patients with non-small cell lung cancer, renal cell carcinoma, bladder cancer, and other advanced solid tumors. Twenty patients were treated with BMS-986178 monotherapy, and 145 received various combination regimens.

After follow-up for as long as 103 weeks, the most common treatment-related adverse events (TRAEs) included fatigue, itching, rash, rise in body temperature, diarrhea, and infusion-related reactions. Overall, serious (Grade 3-4) TRAEs occurred in 1 of 20 patients (5%) receiving BMS-986178 monotherapy, 6 of 79 (8%) receiving BMS-986178 plus nivolumab, 0 of 2 receiving nivolumab monotherapy, 6 of 41 (15%) receiving BMS-986178 plus ipilimumab, and 3 of 23 (13%) receiving BMS-986178 in combination with both checkpoint inhibitors.

No deaths occurred in the study. There were no dose-limiting toxicities (side effects serious enough to prevent an increase in dose or level of treatment) observed with monotherapy. The maximum tolerated dose—the highest dose of a drug that does not cause unacceptable side effects—was not reached with escalating doses of either BMS-986178 monotherapy or any of the combination regimens.

The investigators did not observe objective tumor responses with BMS-986178 monotherapy. Objective response rates ranged from 0% to 13% among patients receiving combination therapy.

“We were somewhat surprised that the efficacy signals observed in preclinical trials did not translate to more robust efficacy in this first-in-human trial,” commented Dr. Gutierrez. “But our findings underscore the complexity of the immune system, and the importance of maintaining a delicate balance between the T-cell compartment and antigen-presenting cells in the tumor microenvironment.

“Our findings suggest we may be able to use OX40 activation as part of a priming intervention early in the course of certain cancers,” Dr. Gutierrez continued. “For example, we could use a cancer vaccine to prime T-cell stimulation, and then use an OX40 agonist to enhance T-cell activity.” As a next step, Dr. Gutierrez and colleagues plan to pursue such an approach in a Phase 2 study involving patients with triple-negative breast cancer, a type of breast cancer in which the tumor cells lack estrogen receptors, progesterone receptors, or large amounts of HER2/neu protein on their surface and have a more aggressive course than other breast cancers.

“Dr. Gutierrez, leading our Experimental Drugs program through phase I, has been at the forefront of immunotherapy, particularly in the use of checkpoint inhibitors that unleash the immune system and are now approved across many cancer subtypes,” said Andre Goy, M.D., M.S., chairman and director of JTCC and physician in chief for Oncology at Hackensack Meridian Health. “Our goal at JTCC is to explore additional combinations to re-engage the immune system to fight against cancer, and to increase the number of patients who can benefit from such potentially game-changing therapies, which are typically very durable, even after patients fail to respond to multiple lines of therapies,” added Dr. Goy, who is a Principal Investigator on a Bristol Myers Squibb research study that is unrelated to this study.

References: Martin Gutierrez et al, OX40 Agonist BMS-986178 Alone or in Combination With Nivolumab and/or Ipilimumab in Patients With Advanced Solid Tumors, Clinical Cancer Research (2020). https://clincancerres.aacrjournals.org/content/early/2020/11/04/1078-0432.CCR-20-1830 DOI: 10.1158/1078-0432.CCR-20-1830

Provided by Hackensack Meridian Health

Effectiveness Of Gemcitabine & Daily RT For Bladder Preservation In Muscle-invasive Bladder Cancer (Medicine)

Updated results of NRG Oncology trial display effectiveness of gemcitabine and daily radiation for bladder preservation in muscle-invasive bladder cancer patients.

Bladder preservation with trimodality therapy can be a safe and effective alternative to cystectomy for selected patients with muscle-invasive bladder cancer. The phase II NRG Oncology NRG-RTOG 0712 trial evaluated two regimens. One was the prior RTOG standard using 5-flourouracil and cisplatin with twice daily radiation (FCT), and the other a regimen of gemcitabine and daily radiation (GD) which had demonstrated efficacy in single institution clinical trials. This trial sought to determine if either or both of these regimens demonstrated sufficient efficacy to be included in future larger studies. The previously published results demonstrated high efficacy rates and low rates of distant metastasis in both arms. The updated results were presented at the virtual edition of the American Society for Radiation Oncology’s (ASTRO) Annual Meeting in October 2020.

NRG-RTOG 0712 accrued 66 eligible patients with muscle invasive bladder cancer for analysis and randomly assigned them to either receive the FCT or (GD) regimen. The trial was designed to determine if either or both treatments exceed a 3-year distant metastasis free (DMF3) rate of 75% defined as the benchmark for efficacy. Researchers on the trial also assessed 5-year distant metastasis free rates (DMF5), toxicity, complete response, and bladder intact distant free survival for each treatment arm. This trial was not statistically powered to compare the two treatment regimens.

With a median follow up of 7.3 years, the FCT treatment arm yielded a 79% DMF3 rate and the GD treatment arm had a DMF3 rate of 85%. Secondary objectives and efficiency endpoints data demonstrated that: DMF5 was 70% in the FCT arm and 77% in the GD arm; 3-year bladder-intact distant metastasis free (BI-DMF3) rates were 67% for the FCT treatment and 72.5% for GD and 5-year rates (BI-DMF5) were 65.1% for FCT and 72.5% for GD; and, post-induction complete response rates were 88% for FCT treatment and 76% for GD treatment. 58% of patients in the FCT treatment arm had treatment related-grade 3 or 4 hematologic, gastrointestinal, or genitourinary toxicities and 52% of patients in the GD arm exhibited these toxicities. Both regimens demonstrated a DMF3 greater than 75%, thus confirming gemcitabine and daily radiation is an acceptable alternative treatment option.

“Not only did this trial conclude that gemcitabine and daily radiation is an acceptable regimen with favorable distant metastasis free rates at 3 years, the results also indicate that both treatments maintain their high rates of distant metastasis free at 5 years and both treatments had low cystectomy rates with high overall survival rates. The efficacy of the GD regimen may facilitate wider adoption of bladder preservation as many patients have comorbidities that preclude the use of cisplatin. The daily radiation schedule is also easier for patients and treatment centers to administer than twice daily treatment which will also likely increase interest in this strategy. These findings are important to future trials that may assess a systemic therapy for this muscle-invasive bladder cancer,” stated John J. Coen, MD, of 21st Century Oncology and the Principal Investigator of the NRG-RTOG 0712 study.

References: Coen JJ, Rodgers JP, Saylor PJ, Lee CT, Wu CL, Parker W, Lautenschlaeger T, Zietman A, Efstathiou J, Jani AB, Kucuk O, Souhami L, Sandler HM, Shipley WU. (2020, October). Bladder Preservation with Twice-Daily Radiation plus 5-Flourouracil/Cisplatin or Daily Radiation plus Gemcitabine for MIBC – Updated Results of NRG/RTOG 0712: A Randomized Phase 2 Trial. Paper presented at the annual meeting of the American Society for Radiation Oncology. Virtual meeting platform.

Provided by NRG Oncology

Neo-adjuvant Immunotherapy Combination Effective For Non-metastatic Bladder Cancer (Oncology / Medicine)

This week, researchers at the Netherlands Cancer Institute published the results of the NABUCCO study in scientific journal Nature Medicine. In this publication, they show that neoadjuvant immunotherapy using a combination of two drugs (nivolumab and ipilimumab) is a feasible treatment for bladder cancer without harming the scheduled resection, and shows promising results.

With this publication, bladder cancer is officially the third cancer type – following melanoma and colorectal cancer – for which researchers at the Netherlands Cancer Institute have proven the immense added value of this combination of immunotherapy drugs before surgery for patients with non-metastatic cancer. Studies involving other cancer types are currently still running.

Decreasing risk of recurrence

This publication is an important milestone in our knowledge of the treatment for bladder cancer (urothelial carcinoma). Patients with this type of cancer often face a return of their illness after surgery. Treatment with immunotherapy before surgery aims to lower the risk of recurrence as much as possible. Immunotherapy does not target the tumor itself, but strengthens the body’s own immune system to fight the disease.

Medical oncologist Michiel van der Heijden, research leader: “Patients with bladder cancer at this stage have a high risk of relapse but not many good treatment options, especially when the cancer has spread to the lymph nodes. The results of this study can hopefully benefit these patients’ prospects.”

Surgery as scheduled, and effective?

24 patients with locally advanced (stage III) operable bladder cancer participated in the NABUCCO trial. Their cancer had not yet spread through the bloodstream. With this trials, the researchers tried to answer two questions. The main one: are all patients able to receive their surgery on time after immunotherapy treatment? Or, in other words: are we wasting valuable time by giving immunotherapy before surgery? The researchers also wanted to know whether this combination of neoadjuvant immunotherapy proves effective for this particular patient group.


The results were promising. Out of the 24 participants, 23 managed to receive their surgery within the planned 12 weeks – even patients with larger tumors. One patient had their surgery postponed for four weeks due to the treatment’s side effects. The main research question could be answered with a “yes”.

The study also showed that neoadjuvant immunotherapy is effective in treating locally invasive bladder cancer: the majority of tumors shrank significantly. 11 out of 24 patients (46%) even showed an absence of tumor cells in tissue taken after surgery for analysis by a pathologist: a pathological complete response.

Two out of 24 patients unfortunately relapsed within the year. This percentage is lower than what can be expected at this stage of the illness. One participant has since passed away from their metastatic cancer.

Which biomarkers make the difference?

The next important question: why do some patients have a better response to immunotherapy than others? Which biomarkers are involved that can help us predict a good response to the therapy? One of the benefits of neoadjuvant immunotherapy is that it allows for the opportunity to analyze these markers at a molecular level at the start of the treatment (in a tissue biopsy) and after surgery (in the resection margins removed during surgery).

The researchers looked into various known biomarkers that have proven to predict immunotherapy resistance for other cancer types, or (very) early stage bladder cancer. This led to the discovery that T cell density in the tumor, that can be a biomarker predicting the success if monotherapy with check point blockers in patients with (very) early stage bladder cancer, do not affect the combination therapy they researched.

Looking for the right ratio

The NABUCCO trial will continue: a follow-up study will try to find the best balance between efficacy and safety by trying to establish the right ratio of drugs that are used in this type of combination therapy: ipilimumab and nivolumab.

Several large-scale trials will need to follow before the results can be validated. Neoadjuvant immunotherapy will only be available as treatment as part of a trial for bladder cancer as well as other types of cancer.

The NABUCCO trial has been running since 2018, and is a investigor-initiated study, developed by medical oncologist and researcher Michiel van der Heijden and conducted by physician-scientist Nick van Dijk and researcher Alberto Gil-Jimenez, in collaboration with a multidisciplinary team of physicians and researchers.

References: Van Dijk, N., Gil-Jimenez, A., Silina, K. et al. Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial. Nat Med (2020). https://doi.org/10.1038/s41591-020-1085-z

Provided by Netherlands Cancer Institute