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BERKELEY, CA (UroToday.com) - Presently, despite immunotherapy with bacillus Calmette-Guérin (BCG) - which represents the gold standard adjuvant treatment of non-muscle invasive bladder cancer (NMIBC) - the optimal dose, schedule of instillations, and the ideal strain still remain undefined.

Recently developed immunotherapeutic agents, like anti-cytotoxic T lymphocyte antigen 4 antibody (CTLA4), anti-programmed cell death 1 (PD1) or anti-programmed cell death-ligand 1 (PDL1), have demonstrated substantial potential for the treatment of a variety of malignancies.

Immune checkpoint inhibitors (ICI) have dramatically changed the face of cancer treatment and are gaining in importance. The ICIs have now been approved for the treatment of advanced cancers, including melanoma, non-small-cell and small cell lung cancers, renal cell carcinoma, Hodgkin's lymphoma, head and neck cancers and urothelial carcinoma and further indications are to be expected.

Management of genitourinary (GU) cancers is improving rapidly with the development of immunotherapy agents, especially anti-PD-1/anti-PD-L1 therapies. Large studies have shown better outcomes for the treatment of these patients, leading to new drug approvals and recent changes in standards of care in renal, prostate and bladder cancer.

Nivolumab, an anti-PD1 immune control point inhibitor, is the first treatment that has improved the overall survival of patients after first-line metastatic renal cell carcinoma in 2015. Over the past two years, a large number of trials on these treatments and the interest of associations are being evaluated.

The algorithms for treatment of metastatic cancers are evolving due to positive results obtained with immunotherapy. Therapeutics approaches to stimulate the immune system have already been used in the treatment of kidney and bladder cancer, such as the administration of cytokines and BCG therapy, confirming the immunogenicity of these tumors.

Improved understanding of the immunomodulatory interactions between tumor cells and immune cells has led to new and promising systemic therapeutic approaches in the first- and second-line therapy of urological tumors.

Therapeutic intervention using oncolytic viruses is called virotherapy. This type of virus is defined by the ability to replicate in tumor cells only and to destroy these cells upon replication. In addition, this virus type is able to induce a tumor-directed immune response.

Prostate cancer is the second most common malignant neoplasm in men worldwide and the fifth cause of cancer-related death. Although multiple new agents have been approved for metastatic castration resistant prostate cancer over the last decade, it is still an incurable disease.

The CRISPR-based technology has revolutionized genome editing in recent years. This technique allows for gene knockout and evaluation of function in cell lines in a manner that is far easier and more accessible than anything previously available.

Current first-line standard of therapy for metastatic urothelial carcinoma is platinum-based combination chemotherapy. Pembrolizumab in phase III has demonstrated a promising overall response rate of 21.

This study investigated the effect of metronomic cyclophosphamide (CPA) in combination with personalized peptide vaccination (PPV) on regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC), and whether it could improve the antitumor effect of PPV.

The treatment of bladder cancer has evolved over time to encompass not only the traditional modalities of chemotherapy and surgery, but has been particularly impacted by the use of immunotherapy. The first immunotherapy was the live, attenuated bacterial Bacillus Calmette-Guérin vaccine, which has been the standard of care non-muscle-invasive bladder cancer since 1990.

Immunotherapies for cancer are transforming patient care, but clinical responses vary considerably from patient to patient. Simple, inexpensive strategies to target treatment to likely responders could substantially improve efficacy while simultaneously reducing health care costs, but identification of reliable biomarkers has proven challenging.

We performed a sensitivity analysis, cumulating all randomized clinical trials (RCTs) in which patients with metastatic castration-resistant prostate cancer (mCRPC) received systemic therapy, to evaluate if the comparison of RCTs may drive to biased survival estimations.

Several drugs have demonstrated clinical activity in metastatic renal cell carcinoma (mRCC). The identification of key metabolic pathways has led to the development of novel targeted therapies which have drastically changed the treatment paradigm of mRCC.

Immunotherapy is heralded as one of the most important advances in oncology. Until recently, only limited immunotherapeutic options were available in selected immunogenic cancers like melanoma and renal cell carcinomas.

Urothelial bladder cancer displays a high number of somatic mutations that render these tumors more responsive to immunotherapy. Several immunotherapeutic agents were examined in patients with advanced stage urothelial bladder cancer and recently atezolizumab - an (PDL-1) immune checkpoint inhibitor antibody - was approved for the treatment of patients with metastatic disease progressing after platinum combination therapy.

M7824 (MSB0011359C) is a novel first-in-class bifunctional fusion protein consisting of a fully human IgG1 anti-PD-L1 monoclonal antibody (with structural similarities to avelumab) linked to the extracellular domain of two TGFβ receptor 2 (TGFβR2) molecules serving as a TGFβ Trap.

BERKELEY, CA (UroToday.com) - Sipuleucel-T, an autologous cellular immunotherapy, was approved by the US FDA in 2010 with the indication for use in men with metastatic castrate-refractory prostate cancer with the clinically defined disease parameters of minimal or absent symptoms of metastasis.

Immunotherapy with programmed cell death 1/ligand 1 (PD-1/PD-L1) checkpoint inhibitors has expanded a previously limited pool of effective treatment options for patients with metastatic urothelial carcinoma, particularly those with recurring or refractory disease and those who are ineligible for cisplatin.

Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is used for the treatment of bladder cancer. The recruitment of neutrophlis to the bladder after BCG instillation exerts anti-tumor activity against bladder tumor.

To propose and validate a new approach to stratify clinically staged organ-confined muscle-invasive bladder cancer patients (cT2N0M0) that are pathologic non-responders to neoadjuvant chemotherapy (NAC) to better characterize NAC non-response.

Until recently, there has been little advancement in the management of invasive and metastatic urothelial cancer in over 30 years, and outcomes with cisplatin-based chemotherapy remain unchanged. Inhibitors targeting PD-1 signaling on cytotoxic T-cells have revolutionized bladder cancer therapy leading to durable responses.

Metastatic bladder cancer is an aggressive malignancy with a poor prognosis when presenting with advanced stage. Cisplatin-based therapy has been the mainstay of first-line treatment but therapy in second-line setting has been an unmet medical need for decades.

SAN DIEGO, CA USA (UroToday.com) - Presented by Neal Shore, MD, FACS at the American Urological Association (AUA) Annual Meeting - May 4 - 8, 2013 - San Diego Convention Center - San Diego, California USA

SAN DIEGO, CA USA (UroToday.com) - Presented by E. David Crawford, MD,¹ Adam S. Kibel, MD,² and Neal D.Shore, MD, FAC ³ at the American Urological Association (AUA) Annual Meeting - May 4 - 8, 2013 - San Diego Convention Center - San Diego, California USA

SAN DIEGO, CA USA (UroToday.com) - Presented by Thomas Gardner,¹ Daniel Petrylak,² John Corman,³ Simon Hail,⁴ Ralph Weinstein,⁵ Robert Sims,⁶ Todd DeVries,⁶ and Celestia Higano⁷ at the American Urological Association (AUA) Annual Meeting - May 4 - 8, 2013 - San Diego Convention Center - San Diego, California USA

SAN DIEGO, CA USA (UroToday.com) - Presented by Matthew R. Cooperberg, MD,¹ Oliver Sartor, MD,² Christopher Pieczonka, MD,³ Raoul S. Concepcion, MD, FACS,⁴ Vahan Kassabian, MD,⁵ Ronald Tutrone, MD, FACS, CPI,⁶ James Bailen, MD,⁷ Neal Shore, MD, FACS,⁸ Lawrence Karsh, MD, FACS,⁹ Bernard Hertzman, MD,¹⁰ David Penson, MD, MPH,¹¹ Candice Mccoy, MD,¹² Andrew Sandler, MD,¹² Robert Tyler, PhD,¹² James Whitmore, PhD,¹² and Celestia S. Higano, MD¹³ at the American Urological Association (AUA) Annual Meeting - May 4 - 8, 2013 - San Diego Convention Center - San Diego, California USA

Metastatic urothelial carcinoma (UC) remains an aggressive disease associated with limited treatment options and a reduced survival. In spite of this, the first-line treatment based on platinum-based combinations has remained virtually unchanged for the last 20-30 years.

In the past 40 years, intravesical immunotherapy with Mycobacterium bovis bacillus Calmette-Guérin has been carried out as the most effective treatment for preventing local recurrences and tumor progression of non-muscle-invasive bladder cancer.

BERKELEY, CA (UroToday.com) - It seems to have become a recurring theme of discussion among urologists that intravesical bacillus Calmette-Guérin (BCG) immunotherapy, while effective in a certain population of patients, can also be seen as simply delaying the inevitable in another subgroup of patients.

Bladder cancer has a high incidence and involves high associated morbidity and mortality. Since its initial clinical suspicion, early diagnostic confirmation and multimodal treatment involve different medical specialties.

Cancer immunotherapy has experienced remarkable advances in recent years. Striking clinical responses have been achieved for several types of solid cancers (e.g. melanoma, non-small cell lung cancer, bladder cancer and mismatch repair-deficient cancers) after treatment of patients with T-cell checkpoint blockade therapies.

Although counteracting innate defenses allows oncolytic viruses (OVs) to better replicate and spread within tumors, CD8(+) T-cells restrict their capacity to trigger systemic anti-tumor immune responses.

BACKGROUND - Cell based vaccines encoding Hyper-IL-6 (H6) and Hyper-IL-11 (H11) present high activity in murine melanoma and renal cancer model. We evaluated the efficacy of cellular vaccines modified with H6 or H11 combined with cyclophosphamide in orthotopic murine prostate cancer model.

The field of immunotherapy in urinary malignancy is expanding in several directions and checkpoint inhibitors are leading the way. The aim of this report is to highlight the efficacy and safety profile of the two classes of molecules, anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed death receptor-1/programmed death ligand type 1, that are under investigation and represent potential candidates to be used in the near future for the management of bladder and renal cell cancer.

Checkpoint inhibitors are monoclonal antibodies attach to several different receptors on T-cells or tumour cells expressing receptors for cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death-1 (PD-1) and their ligand (PD-L1).

Nivolumab is approved for patients with metastatic renal cell carcinoma (mRCC) refractory to prior antiangiogenic therapy. The clinical activity of nivolumab in patients with non-clear cell RCC subtypes remains unknown as these patients were excluded from the original nivolumab trials.

Prostate cancer is the most common cancer in men, and the second leading cause of cancer-related death in Western countries. Prostate cancer-related death occurs in patients with metastatic castration-resistant prostate cancer.

Renal cell carcinoma (RCC) represents the seventh (men) respectively tenth (women) most frequent cancer in western countries. After one or more lines of VEGF-targeted therapy, immunotherapy with nivolumab is strongly recommended in patients with metastatic RCC.

Metastatic renal cell carcinoma (MRCC) exhibits primary resistance to both chemotherapy and radiotherapy. As an immunogenic cancer, MRCC is relatively sensitive to immunotherapy such as that with cytokines, immune checkpoint inhibitors and adoptive T-cell therapy.

Sipuleucel-T, a therapeutic dendritic-cell vaccine, was Food and Drug Administration-approved for prostate cancer in 2010. No new immunotherapies for prostate cancer have been approved since. However, novel agents and combination approaches offer great promise for improving outcomes for prostate cancer patients.

Recent efforts on genome wide profiling of muscle invasive bladder cancer (MIBC) have led to its classification into distinct genomic and transcriptomic molecular subtypes that exhibit variability in prognosis.

High-dose interleukin-2 (HD IL-2) was approved for treatment of metastatic renal cell carcinoma (mRCC) in 1992 and for metastatic melanoma (mM) in 1998, in an era predating targeted therapies and immune checkpoint inhibitors.

The introduction of targeted therapy has revolutionized the treatment of patients with metastatic renal cell carcinoma (mRCC). The current standard of care focuses on the inhibition of angiogenesis through the targeting of the vascular endothelial growth factor receptor (VEGFR) and the mammalian target of rapamycin (mTOR).

In recent years, new drugs have been introduced for second-line treatment of advanced renal cell carcinoma (RCC). Nivolumab increases overall survival and is associated with less toxicity compared to everolimus in this setting according to the CheckMate 025 study.

Immune-modulating drugs have recently been introduced to the second-line setting of advanced bladder cancer. Pembrolizumab increases overall survival and is associated with less toxicity compared with chemotherapy in this setting based on the Keynote 045 study.

CRPC - The New Frontier

Leanne Schimke, MSN, CRNP, CUNP
Lancaster Urology

Immunotherapy has historically been of interest in the management of metastatic renal cell cancer (mRCC) because of its relative chemoresistance and the reproducible but low incidence of spontaneous remission in metastatic disease.