San Antonio, Texas USA (UroToday.com) The role of immunotherapy for non-muscle invasive bladder cancer (NMIBC) is particularly apt for discussion, as it has now been 40 years since the first publication of the use of BCG for the treatment of NMIBC. What we have learned since the initial introduction of BCG is that there is a complex cancer immunity cycle that affects the response of tumor cells to immune manipulation.
There is a well-defined pathway that has been elucidated: Release of tumor antigens, antigen presentation by antigen-presenting cells, priming/activation of T cells, trafficking of T cells to tumors, infiltration of T cells toward tumor cells, recognition of cancer cells by T cells, and finally, killing of cancer cells.
BCG has been a remarkably effective treatment for NMIBC, but large gaps still exist for patients that are under-responsive or non-responsive to intravesical BCG. This does not mean these patients cannot be treated with immune therapy, but it does mean we need to be cleverer in activating the immune system to combat these cells.
One approach is the “BCG-plus” concept. The use of intravesicle BCG + interferon has shown some benefit for improving the immune response related to treatment. We also know that different strains of BCG have different therapeutic efficacy, and with the announcement by Sanofi that they will halt production of the most commonly used BCG strain, research into other viable strains will be imminently important. We will hopefully have good evidence for a new strain via the SWOG 1602 trial that is introducing the Tokyo BCG strain to study efficacy vs. the TICE BCG strain. Researchers are also attempting to enhance and re-tool BCG strains in a way to improve treatment efficacy by anchoring surface antigens, causing expression of caspases or IL 15, or by cloning genes into the strain to secrete listeriolysin (listeria toxin), a molecule that pokes holes in tumor cell membranes and induces cytotosic T cell responses. This is being studied by a Phase II trial now underway in Switzerland.
Another approach is via vaccinations. The idea is to vaccinate patients with BCG prior to treatment to prime immune system. Studies have shown that patients that have been primed and are subsequently PPD positive prior to intravesical treatment with BCG may have improved survival after treatment. Priming is a promising approach, and the aforementioned SWOG 1062 trial will also have a 3rd arm to prime the immune system prior to giving Tokyo BCG. The HS410 Vesigenurtacel-L tumor cell line has been engineered to express gp96, which causes a specific targeting of tumor cells; a Phase II trial is looking at the combination of BCG plus HS-410 immunization, and these results will also be interesting to see.
Other vaccination approaches include using an IL 15 superagonist complex that tags IL 15 to an IgG backbone. Since IL 15 is such a potent immunomodulatory, it may potentiate treatment effects of BCG. Indeed, ramping up the immune system with these agents may also lead to combination therapies with PD-1 inhibitors to affect the T-cell response directed at tumor cells.
Viruses are another approach to charging the immune system against NMIBC. There is a currently a Phase III trial using an oncolytic virus in BCG-unresponsive NMIBC. Lastly, but perhaps most promisingly, there is a new world of checkpoint inhibitors that are demonstrating excellent treatment efficacy in MIBC and in other solid-organ GU tumors. Two examples of current studies evaluating the use of checkpoint inhibitors are the S1605 Phase II SWOG trial of atezolizumab in BCG-unresponsive high risk NMIBC and the KEYNOTE-057 Phase II trial of Pembrolizuma. There is a great deal of anticipation for the findings of these studies.
As Dr. Black concludes, the future of treatment of NMIBC will be determined by combining agents and using multiarm trials to find the most effective combinations and sequences of agents within the correct patient populations. We should continue to build on the overwhelming successes of immune therapy via intravesical BCG. Ongoing trials with novel new concepts and agents will hopefully make a for a better future in the treatment of NMIBC.
Presented By: Peter C. Black, MD, University of British Columbia
Written By: Shreyas Joshi, MD, Fox Chase Cancer Center
17th Annual Meeting of the Society of Urologic Oncology - November 30 -December 2, 2016 – San Antonio, Texas USA