In the scientific journal Nature Medicine, researchers in the Netherlands report 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 for 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, says, “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.”
Twenty-four 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 trial, the researchers tried to answer two questions. 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? And will this combination of neoadjuvant immunotherapy prove 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 study also showed that neoadjuvant immunotherapy is effective in treating locally invasive bladder cancer: The majority of tumors shrank significantly. Eleven 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 to 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, which 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 are required 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.
Since the 20thcentury, cancer therapy has been characterized by ups and downs that are not only due to the ineffectiveness of therapies and side effects, but also conditioned by hope and the fact that in many cases, there has been complete remission .
Chemotherapy was the first identified therapeutic approach that systemically delivered chemical agents into tumor tissue and destroyed the large mass, but did not eliminate the disease .
In addition to short-term improvement in survival, this treatment has some limitations, such as the high risk of toxicity for rapidly renewing cells, like skin and gastrointestinal cells, and blood stem cells .
Moreover, several chemotherapies lead to the development of resistance of the cancer cells, thus limiting their use as monotherapy in further treatment lines .
Radiation therapy was considered an important part of cancer therapy, with nearly 50% of all cancer patients undergoing radiation therapy during the progression of the disease .
In recent years, immunotherapy has metamorphosed into an important therapeutic option and is now the first choice in many cases. However, depression, fatigue, dermatitis, cardiovascular disease, mucositis and esophagitis, and pneumonitis are some of the important side effects of radiation therapy in different cancers [6,7,8].
More than one century ago, the ability of the immune system to act against tumors was discovered by Dr. William Coley in 1893, when he used bacteria as a stimulator for the immune system to treat cancer . Tumor cell growth and progression are related to immune suppression and they can activate several immune checkpoint pathways that have suppressive roles.
In particular, cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1(PD-1) are two important immune checkpoints that were formerly identified as molecules performing a role in apoptosis, T cell activation, and the maintenance of acquired immune system tolerance .
Recently, a wide range of monoclonal antibodies blocking immune checkpoints has appeared as potent agents in the oncological models . Monoclonal antibodies targeting PD-1 (including pembrolizumab and nivolumab) as well as PD-L1 (including avelumab, atezolizumab, and durvalumab,) and those targeting CTLA-4 (including ipilimumab and tremelimumab) , have been approved by the FDA for several cancers, such as melanoma, renal cell cancer, lung cancer, and colorectal cancer .
Nivolumab, a fully human immunoglobulin G4 anti-PD-1 monoclonal antibody that was created from Chinese hamster ovary cells, is approved for multiple advanced tumors, including melanoma, non-small cell lung cancer (NSCLC), renal cell cancer, Hodgkin’s lymphoma, squamous head and neck cancer, and urothelial carcinoma .
Pembrolizumab is an effective, fully humanized immunoglobulin G4 anti-PD-1 antibody used in cancer immunotherapy . Recently, pembrolizumab plus lenvatinib received approval in treating patients with specific types of endometrial carcinoma  and bladder cancer .
Atezolizumab is a fully humanized immunoglobulin G1 anti-PD-L1 antibody used in cancer immunotherapy . In 2016 and 2017, it was approved by the FDA for urothelial carcinoma  and as first-line treatment for advanced bladder cancer, respectively . Avelumab is a fully humanized anti-PD-L1 antibody used in urothelial carcinoma, Merkel cell carcinoma, and renal cell carcinoma .
Durvalumab is a human immunoglobulin G1, an anti-PD-L1 monoclonal antibody that is approved for the treatment of advanced bladder cancer and NSCLC [22,23]. Preclinical and clinical studies have begun to investigate immunotherapeutic strategies in combination with chemotherapy and radiation .
However, there are many challenges in the application of these molecules. For example, a large proportion of patients (~80%) do not respond to ICI treatment or some of them develop resistance to therapy . Herein, we review data concerning the clinical activity and the adverse events of ipilimumab and nivolumab combination therapy, assessing ongoing clinical trials to identify clinical outlines that may support combination therapy as an effective treatment.
This review—by addressing the primary details of CTLA-4 and PD-1 pathways and the results from clinical studies that evaluated the combination of ipilimumab and nivolumab—aims to support future research in combination therapy as the new standard of care for cancer treatment. To the best of our knowledge, this paper is one of the first studies to evaluate the efficacy and safety of ipilimumab and nivolumab combination therapy in several cancers.
Ipilimumab is a fully humanized monoclonal anti-CTLA-4 antibody that was approved by the FDA in 2011 for the late-stage of melanoma . In earlier surveys, ipilimumab was commonly used as the treatment of malignant melanoma by 60% of patients in the USA and 40% of patients in European countries .
In 2017, it was approved for use in pediatric cases with a history of metastatic melanoma. Studies showed a positive effect of ipilimumab when combined with other agents, including vaccines or other immune checkpoint inhibitors against cancer. The FDA approved the positive results of ipilimumab in combination with nivolumab for metastatic melanoma, metastatic colorectal cancer, and advanced renal cell carcinoma [36,37,38].
Hodi FS et al. discovered ipilimumab as a safe and active treatment. All patients in this study had metastatic melanoma that could not be surgically removed . In this study, 676 metastatic melanoma patients were randomly treated with ipilimumab (3 mg/kg) plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136).
Ipilimumab was administered with or without gp100 every three weeks for up to four treatments. Based on their results, ipilimumab presented a strong response and stable disease (SD) rate in patients who received treatment. The recommended dose of ipilimumab monotherapy for unresectable/metastatic melanoma is 3 mg/kg with intravenous (IV) administration, over 90 min, every three weeks with a maximum of four doses. In addition, the recommended dose of combination therapy for renal cell carcinoma and colorectal cancer is IV administration of 1 mg/kg ipilimumab over 30 min, following nivolumab administered on the same day, every three weeks with up to four doses or until intolerable toxicity or disease progression .
Ipilimumab has many side effects, such as fatigue, diarrhea, skin rash, endocrine deficiencies, and colitis. Additionally, 12.9% of patients showed autoimmune reactions .
Nivolumab is a fully humanized monoclonal anti-PD1 antibody that interacts with its ligands PD-L1 and PD-L2 and has an indispensable role in fine-tuning T cell function and maintaining immune system homeostasis. Nivolumab is a genetically engineered monoclonal antibody produced from ovary cells of the Chinese hamster .
In 2014, nivolumab received its first Food and Drug Administration (FDA) approval for patients with unresectable or advanced melanoma who did not respond to other therapies .
Subsequently, in 2015, the FDA approved the use of nivolumab to treat lung cancer . Until February 2020, nivolumab monotherapy or combination with ipilimumab received FDA approval for use in several different cancers, including NSCLS and small cell lung cancer (SCLS), renal cell carcinoma (RCC), Hodgkin’s lymphoma (HL), head and neck cancer (HNC), urothelial carcinoma (UC), colorectal cancer (CRC), and hepatocellular carcinoma [49,50,51].
The usual adult dose for nivolumab is 240 mg IV every two weeks over 30 min until disease progression and 480 mg IV every four weeks over 30 min. Nivolumab affects several body organs including skin, liver, gastrointestinal, respiratory system, endocrine, and cardiovascular systems, and has many common side effects (called immune-related adverse events (irAEs)) .
Dermatologic side effects including rash (21%), pruritus (19%), vitiligo (11%), and erythema (10%)  also occur. Hepatic side effects (elevated AST (28%), elevated alkaline phosphatase (22%) , elevated ALT (16%)) appear along with gastrointestinal side effects (diarrhea or colitis (21%)) , respiratory side effects (cough (17%), upper respiratory tract infection (17%)) , cardiovascular side effects (peripheral edema (10%)), and endocrine side effects (hypothyroidism and hyperthyroidism)  (Figure 2).
The activation of T cells is mediated by the interaction of the TCR and the CD28 receptor with an MHC-II and B7 co-stimulatory molecule located on the APCs. The CTLA-4: B7 binding delivers an inhibitory signal that is effectively inhibited by anti-CTLA-4 antibodies.
On the other side, the PD-1: PD-L1 binding between T cells and tumor cells is prevented by anti-PD-1/PD-L1 antibodies. The figure was produced using Servier Medical Art (http://smart.servier.com/). Abbreviations: PD-1, programmed death receptor-1; PD-L1, programmed cell death receptor ligand-1; TCR, T cell receptor; MHC II, major histocompatibility complex class II.
Combination Therapy in Urothelial Carcinoma
Urothelial carcinoma (UC), including urinary bladder cancer (UBC) and upper tract urothelial carcinoma (UTUC), is one of the most common cancers in the USA . Nearly all cases of UC are UBC, while UTUC is considered in just 5–10% of all UCs . Platinum-based chemotherapy is the standard therapy for patients. Recently, the advent of ICIs in the treatment of UBC leads to the improvement of treatment options for patients in advanced stages .
Among ICIs, five monoclonal antibodies including atezolizumab, pembrolizumab, avelumab, durvalumab, and nivolumab have previously received FDA approval in UCs . In a multi-center, phase 2 trial, Sharma P et al. assessed the safety and activity of nivolumab (3 mg/kg) in metastatic UC. A total of 265 patients in 11 countries were treated with nivolumab (3 mg/kg). The primary endpoint was ORR.
The median OS was 7 months and confirmed ORR was achieved in 52 (19.6%) of patients. Also, in 81 patients who had PD-L1 expression of 5% or greater, ORR was obtained in 23 (28.4%) of them . CheckMate 032 evaluated the efficacy of nivolumab in recurrent/advanced UC. Patients received nivolumab (3 mg/kg IV) every two weeks until disease progression.
The OR was obtained in 19 of 78 patients. Serious side effects were reported in 36 (46%) of 78 patients, and nivolumab monotherapy showed a durable clinical response and a safety profile . CheckMate 275 evaluated the efficacy of nivolumab in patients with advanced or metastatic UC. A total of 270 patients were treated with nivolumab.
The ORR was 20.4%; mPFS was 1.9 (95%CI: 1.9–2.3); and the median OS was 8.6. The most common irAEs were fatigue (18.1%) and diarrhea (12.2%) .
On the whole, ICIs have shown beneficial clinical activity in patients with advanced UC as first- and second-line therapy. Ongoing investigations will help determine the optimal dosage, possible adverse effects, and combination approaches.
reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352976/
More information: Nick van Dijk et al. Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial, Nature Medicine (2020). DOI: 10.1038/s41591-020-1085-z