The immunotherapy nivolumab after surgery helped reduce cancer recurrence in patients with urothelial cancer of the bladder


Immunotherapy after surgery helped reduce cancer recurrence in patients with urothelial cancer of the bladder or other sites in the urinary tract that had invaded the muscle and therefore posed a high risk for recurrence, according to clinical trial results presented at the American Urological Association (AUA) annual meeting in May.

The results support giving the immunotherapy nivolumab as an adjuvant treatment—a therapy given after surgery—as standard of care for patients who have muscle-invasive urothelial carcinoma.

About 700 patients participated in the phase 3, randomized, double-blind trial, named CheckMate 274; half were given nivolumab and the other half placebo after having surgery with chemotherapy beforehand.

“Longer-term follow-up data is important for reinforcing the initial results we published last year demonstrating for the first time that immunotherapy administered after surgery for bladder cancer and other urothelial cancer can decrease the risk of cancer recurrence,” said lead author and presenter Matthew Galsky, MD, Director of Genitourinary Medical Oncology, Mount Sinai Tisch Cancer Center. “Almost 200,000 people die each year of urothelial cancer worldwide, so advances like immunotherapy being used in this manner bring hope.”

Surgery that removes the bladder or kidney and ureter has been the standard of care for patients with urothelial cancer that has entered surrounding muscle or lymph nodes, but approximately half of these patients later relapse with lethal metastatic cancer.

Unfortunately for these patients, no consensus has emerged regarding treatments after surgery that might reduce the risk of cancer recurrence, which is why the results presented at AUA are important.

In CheckMate 274, with a minimum of 11 months follow-up, patients who received nivolumab had an approximately 30 percent lower likelihood of developing cancer recurrence than those who received placebo. Patients whose tumors had the gene PD-L1, making them more responsive to nivolumab’s cancer-fighting ability, and who received the immunotherapy had cancer-free rates that were even higher.

This longer-term disease-free survival data presented at AUA built upon initial data presented by Dr. Galsky and colleagues in The New England Journal of Medicine. Follow-up with patients on this trial, which was funded by Bristol Myers Squibb, is ongoing.

The genitourinary system encompasses reproductive organs and the urinary system. The latter comprises the kidneys, which are being connected to the bladder in the lower pelvis via the ureters. The bladder is a hollow organ, which releases upon muscle contraction urine via the urethra. Bladder cancer (BC) is the second most common genitourinary malignant disease and the 10th most common cancer, causing nearly 570.000 new cases and 210.000 deaths worldwide each year (1, 2).

It typically affects older adults, and peak incidence occurs in the seventh and eighth decades of life. Males are four times more likely to develop bladder cancers. Hence BC is the sixth most common cancer in males and the ninth leading cause of cancer-related deaths (2).

Bladder cancer is categorized by cell type and by stage of tissue invasion. Besides urothelial carcinoma/transitional cell carcinoma (UC/TCC), which is by far the most common type of bladder cancer (90-95%), other malignancies as squamous cell carcinoma (2-5%), adenocarcinoma (0.5–2%), and small-cell carcinoma (<1%) all describe tumors of the bladder (3). Even though UC/TCC predominantly occurs in the bladder, the ureters and the urethra can be affected as well.

In general, UCs are classified as either non-muscle-invasive bladder cancer (NMIBC), which accounts for approximately 75% of cases, or muscle-invasive bladder cancer (MIBC), which is found in approximately 25% of patients (4, 5). Both are further staged using the Tumor, Node, Metastasis (TNM) classification. This describes how far a tumor has grown (T), whether the cancer has spread to nearby lymph nodes (N) and whether it has started to metastasize (M).

Ta describes a non-invasive papillary carcinoma confined to the mucosa growing from the inner lining (urothelium) into the lumen of the bladder (Figure 1). Tumors growing flat on the urothelium, not invading the connective tissue, and not extending into the lumen are classified as carcinoma in situ (CIS), known as Cis/Tis. Papillary tumors invading the lamina propria and the connective tissue are classified as T1.

Ta, Tis, and T1 are classified as NMIBC, while stages ≥ T2 are classified as MIBC. In T2a or T2b, the cancer has invaded the inner or the outer detrusor muscle, and at T3, the tumor has invaded beyond the muscle layer and the surrounding fat tissue. At T4, the tumor has begun to grow through the bladder wall into the pelvic or abdominal wall, invading adjacent organs and/or started to spread to nearby lymph nodes or even to more distant organs (metastasis, M1) (6).

Figure 1 Anatomical illustration of different bladder cancer stages. The bladder as a whole, as well as a zoomed-in illustration of the bladder wall is shown. Different tumors in different tumor stages are illustrated as well as their invasion into the muscle tissue. While Ta, Tis, and T1 are defined as non-muscle-invasive, muscle-invasive bladder cancer (MIBC) disease begins with T2. After penetrating the muscle and reaching the fatty tissue, the T3 stage is reached, where T4 is characterized as growth of the tumor into other organs or metastasizing. Created with

This staging system was created by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC). Histological grading follows the 2004 World Health Organization (WHO) grading system for flat and papillary lesions (4). The system was an upgrade to the previous system from 1973, which uses grades 1, 2, and 3 and may still be used. In 2016 the WHO further improved the classification system to the most recent version (7). Today tumors can be classified as low grade or high grade. While the previously defined grade 2 can be classified as low or high grade, CIS belongs to high grade.

Today, the diagnosis of bladder cancer is performed more and more utilizing molecular analysis (8, 9). Genetic profiling allows for the subdivision of tumors into the basal and luminal subtype, which has a distinct impact on the success of chemotherapeutic treatment (10–12). Following diagnosis and tumor staging, NMIBC tumors are stratified by risk of recurrence and/or progression: While low-grade tumors consist of slowly growing, more differentiated cells, high-grade tumors are poorly differentiated and tend to spread faster.

Furthermore, low-grade tumors have a lower risk of recurrence, while high-grade tumors have a higher risk of progression and metastasizing (6). Physicians have multiple options for diagnosing of UCs. However, cystoscopy is considered the key diagnostic tool for bladder cancer. To evaluate the cell type and stage of tissue invasion, a Transurethral Resection of the Bladder (TURB) is performed to confirm the diagnosis and stage the patient correctly.

All papillary tumors are resected completely during the TURB, which in some cases can be considered a cure. CIS cannot be resected completely during the TURB and thus need additional instillation therapy to reduce tumor burden, recurrence, and/or progression (4). For high and intermediate risk NMIBC patients, there is evidence of significantly reducing recurrence rate by additional instillation therapy to the bladder of either a chemotherapeutic agent, like mitomycin c, or Bacillus Calmette Guérin (BCG). Single instillation (SI) of mitomycin c (postoperative), a potent chemotherapeutic agent which crosslinks DNA, has been shown to reduce the 5-year recurrence rate by 14% (59%-45%) (13).

For most NMIBC patients, intravesical immunotherapy utilizing BCG is the standard of care (14, 15). BCG is a non-pathogenic bacillus derived from Mycobacterium bovis and represents the only available vaccine for tuberculosis (16). Most of the time, BCG treatment starts after TURB, aiming at preventing tumor recurrence (17).

Although failure after BCG instillation therapy is observed in 30% to 40% of cases (18, 19), patients who experience early failure are defined as having BCG unresponsive NMIBC disease (20, 21). These patients are very unlikely to benefit from further BCG therapy and are recommended radical cystectomy, which describes the complete removal of the bladder.

The primary treatment for patients with MIBC depends on the M (metastasis) status. For localized MIBC (M0), the primary and standard treatment is the complete removal of the bladder and creation of a urinary diversion (radical cystectomy) +/- neoadjuvant therapy. In very select cases, a bladder-sparing approach can be adopted. Controversies exist regarding age and type of diversion (5).

Non-eligible patients can be offered radiotherapy. 10-15% of patients with muscle-invasive disease are already metastatic at diagnosis (22). As first-line treatment in advanced stages, platinum-based chemotherapeutics, like cisplatin, are utilized, which interfere with DNA replication in fast-growing cells (23). Furthermore, intravenous application of the nucleoside-analog gemcitabine, structurally related to cytidine, and instillation of mitomycin c are chemotherapeutic treatment options (24).

Even though bladder cancer is relatively chemosensitive, reoccurrence after first-line treatment with the chemotherapeutics gemcitabine plus cisplatin results in poor prognosis (25). Resistance mechanisms include the elevated drug efflux as well as reduced influx. Furthermore, increased repair of the DNA leads to drug resistance. Multiple enzymes and repair mechanisms, including ERCC1, PARP, Nrf2, CTR1, are involved in the development of drug resistance (26).

A detailed review on resistance of bladder cancer against conventional therapies can be found elsewhere (26, 27). If treatment fails, it might become necessary to perform cystectomy, where the bladder is partly or completely removed (28). As this is a radical measure with a significant impact on the quality of life for respective patients, new treatment options are necessary, allowing for a more precise treatment and circumventing side effects that are observed in classical chemotherapies.

Immunotherapy approaches revolutionized cancer therapy in the last decades. It is based on the concept of activating the patients’ immune system to eradicate the malignant cells. Even though a successful biotherapy applied for approximately 40 years, the anti-tumor mechanisms associated with BCG are not fully understood (29). Nevertheless, BCG-mediated effects are presumably based on the involvement of CD4+ and CD8+ lymphocytes, natural killer (NK) cells, and granulocytes, as well as a variety of cytokines (29).

As BCG-failure is observed in 30% to 40% of NMIBC patients (18, 19), there is a need for new immunotherapy-based drugs. Different engineering strategies and antibody formats were investigated in (pre-)clinical settings over the last decades to employ new mechanism of actions. On the one hand, novel approaches based on antibody engineering like monoclonal antibodies (mAbs), antibody-drug-conjugates (ADCs), and bispecific molecules have been explored.

On the other hand, gene therapeutics, mRNA- and cell-based therapies are emerging as promising tools to treat urologic cancers. Here we review those engineering strategies, illuminate the mechanism of action, and discuss clinical trials (Table 1).

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Journal information: New England Journal of Medicine


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