Despite strong data favoring pre-surgical systemic therapy, a surgeon argues that many patients will continue to undergo surgery first. This is due to real-world factors like surgeons being the point of diagnosis, urgent symptoms requiring rapid intervention, and patient preferences to have the tumor removed immediately.

A leading hypothesis for why adding immunotherapy to chemoradiation failed is that radiation, particularly for central tumors, destroys the very lymphocytes immunotherapy aims to activate. This biological mechanism suggests the radiation essentially canceled out the drug's intended effect.

Successful immunotherapies like anti-PD-1 work by shifting the battlefield's arithmetic. They enhance the efficiency of each T-cell, allowing one cell to destroy five or ten cancer cells instead of three. This turns the fight into a 'numbers game' that the immune system can finally win.

In adjuvant bladder cancer trials, ctDNA status is both prognostic and predictive. Patients with positive ctDNA after surgery are at high risk of relapse but benefit from immune checkpoint inhibitors. Conversely, ctDNA-negative patients have a lower risk and derive no benefit, making ctDNA a critical tool to avoid unnecessary, toxic therapy.

While immunotherapy was a massive leap forward, Dr. Saav Solanki states the next innovation frontier is combining it with newer modalities. Antibody-drug conjugates (ADCs) and T-cell engagers are being used to recruit the immune system into the tumor microenvironment, helping patients who don't respond to current immunotherapies.

While the field focuses heavily on T-cells and myeloid-derived suppressor cells, Dr. Radvanyi argues that dendritic cells have not received enough attention. Better understanding how to activate these primary antigen-presenting cells is crucial for priming effective and durable anti-tumor immune responses, especially within tertiary lymphoid structures.

Rather than expecting cell therapies (CAR-T, TIL) to eradicate every cancer cell, Dr. Radvanyi reframes them as powerful adjuvants. Their role is to inflict initial damage, kill tumor cells, and release antigens, creating an opportunity to prime a broader, secondary immune response with other modalities like vaccines or checkpoint inhibitors.

Dr. Radvanyi advocates for a paradigm shift: treating almost all cancers with neoadjuvant immunotherapy immediately after diagnosis. This "kickstarts" an immune response before standard treatments like surgery and chemotherapy, which are known to be immunosuppressive, can weaken the patient's natural defenses against the tumor.

The success of new treatments like immunotherapy and ADCs leads to more patients achieving a deep response. This high efficacy makes patients question the necessity of a radical cystectomy, a life-altering surgery, creating an urgent need for data-driven, bladder-sparing protocols.