The Landscape of Immunotherapy for Urothelial Carcinoma

It is theorized that our bodies create "malignant" cells throughout our lifetime, but our highly evolved and functional immune system prevents these cells from establishing a foothold and becoming a "cancer." Over the last few decades, there have been a number of advances in the understanding of the fundamental regulatory mechanisms governing host immune cell activation and function. With this improved understanding of the immune system came the ability to manipulate immunity to treat diseases – and the field of immunotherapy was born. Immunotherapy refers to the ability to treat diseases (in this case cancers) by inducing, enhancing, or suppressing an immune response. In cancer treatment, immunotherapy encompasses targeted manipulations of the host immune response in order to promote effective immune-mediated tumor destruction. The primary goal of antitumoral immunotherapy is to generate a systemic antigen-specific T-cell response that is capable of destroying the primary tumor, its potential metastases, and if possible the parent tissues that the tumor arises.

Immune Editing Hypothesis

The Immune Editing Hypothesis was put forth by Dunn, Old and Schrieber in 2004 and is described as "The 3 E's" of immunological tumorigenesis.[1] T-cells are an important role in the adaptive immune system and play an important role in mediating anti-tumor immunity. T-cells include CD4 (helper) T-cells and CD8 (killer) T cells. Elimination is conducted through the innate and adaptive immune systems and allows early tumors to be recognized in a productive, proactive way leading to elimination (or destruction) of tumor cells. However, as tumors progress through equilibrium, they acquire genetic and epigenetic alterations that render anti-tumor immune response less effective. Progression can be slowed by an ongoing immune response, however tumors in this phase can no longer by successfully eliminated. Ultimately, tumors escape the immune response through a variety of mechanisms including: down regulation of tumor antigens, induction or expansion of regulatory T cells (Treg) and aberrant expression of T cell co-regulatory molecules that actively inhibit the immune response.

 

Figure 1. Dunn, Old and Schreiber, Immunity 2004

Immunotherapy in Urologic Oncology: 

Intravesical immunotherapy – BCG

While immunotherapy is an emerging and exciting therapeutic option for the treatment of localized and metastatic cancer in multiple tumor types (including melanoma, ovarian, and kidney cancer), it has long played a role in the treatment of urothelial cancers. In fact, BCG (Bacillus Calmette-Guerin) immunotherapy is the mainstay of treatment for non-invasive urothelial malignancies, demonstrating improvements in recurrence, progression and survival in a number of well-established studies. (See our previous blog on Success Rates for Intravesical BCG Treatments for Bladder Cancer) BCG works through both the innate and adaptive immune systems to prevent urothelial cancers from recurring or progressing (See our previous blog on BCG For Bladder Cancer: Why it Works, How it Works).

PD-1 (Marker of Antigen Encounter) and PD-L1 (Marker of Pre-existing Immune Activation) and Urothelial Cancer

A number of cytokines and stimulators exist within the immune system to promote or decrease the immune response to a given stimulus. Negative co-stimulators such like CTLA-4, PD-1 act to inhibit T-cell function and diminish T-cell survival leading to a decrease in immune response and an increase in cancer cell survival. Programmed Death Ligand-1 (PD-L1) and its receptor programmed death-1 (PD-1) are normally used by healthy cells to prevent the immune system from destroying them. Cancer cells can exploit these mechanisms and use PD-L1 and PD-1 to escape the immune system and proliferate. The use of PD-L1 and PD-1 inhibitors have demonstrated incredible response in early studies of patients with advanced kidney cancer (See our blog on Systemic Treatment of Renal Cell Carcinoma: Programmed Death Ligand 1 Inhibitors for more details about the PD-L1/PD-1 Response and Kidney Cancer).
In urothelial cancers, PD-L1 is associated with higher stage and grade, leading to the conclusions that PD-L1 may facilitate local-stage advancement of cancer, attenuate BCG immunotherapy response through altered T-cell response and predict all-cause mortality after radical cystectomy.[2,3]

Figure 2. Inman et. al., Cancer 2007 [2]

In addition, work from Johns Hopkins and other centers have demonstrated that low PD-L1 expression and the presence of CD8+ (killer) T-cells in a tumor specimen may portend a better prognosis – as it indicates that the immune system is functional and fighting off the cancer cells.

Unmet Needs and Future Directions for research and therapy

There are many unanswered questions when considering immunotherapy for urothelial cancer. For instance,

• What are the target antigen(s) when BCG results in cure?
• Besides PD-1 /PD-L1, what are the other mechanisms of escape in urothelial cancer?
• Does chemotherapy promote or prohibit an anti-urothelial cancer immune response?
• Do the epigenetic changes in urothelial cancer render it more or less immunologically sensitive?
• Would combination therapies including chemotherapy, immunotherapy and even radiation therapy results in more durable responses?
  • And what is appropriate timing/sequence of therapy?

To answer these questions and others, researchers at the Brady Urological Institute at Johns Hopkins are developing a genetically engineered mouse model to study combination immunotherapy, chemotherapy and radiation therapy for the treatment of urothelial cancer.

Summary

• Cancer immunotherapy is a rapidly advancing field of both clinical and pre-clinical study, and progress in this area has been especially strong in genitourinary cancers.
• The future of immunotherapy will most likely involve combination approaches, including surgery, immune checkpoint blockade, radiation therapy, conventional chemotherapy.

 
This blog was extracted from "Landscape of Immunotherapy for Urothelial Carcinoma," given by Trinity J. Bivalacqua, MD, PhD; Associate Professor of Urology, Surgery, and Oncology and Director of Urologic Oncology at the Johns Hopkins Medical Institutions and Sidney Kimmel Comprehensive Cancer Center (SKCCC) at the 9^th Annual BCAN (Bladder Cancer Advocacy Network) Think Tank in San Diego, California, August 7-9, 2014.

 

 

 
REFERENCES
[1] Dunn GP1, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004 Aug;21(2):137-48.
[2] Inman BA, Sebo TJ, Frigola X, Dong H, Bergstralh EJ, Frank I, Fradet Y, Lacombe L, Kwon ED. PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer. 2007 Apr 15;109(8):1499-505.
[3] Boorjian SA, Sheinin Y, Crispen PL, Farmer SA, Lohse CM, Kuntz SM, Leibovich BC, Kwon ED, Frank I. T-cell coregulatory molecule expression in urothelial cell carcinoma: clinicopathologic correlations and association with survival. Clin Cancer Res. 2008 Aug 1;14(15):4800-8. doi: 10.1158/1078-0432.CCR-08-0731.