T-cell receptor (TCR) therapies offer a significant advantage over monoclonal antibodies by targeting intracellular proteins. They recognize peptides presented on the cell surface, effectively unlocking 90% of the proteome and requiring far fewer target molecules (5-10 copies vs. 1000+) to kill a cancer cell.

Even though companies like Moderna (mRNA) and Transgene (viral vector) use different platforms, positive results from any of them help validate the entire individualized neoantigen approach for investors and clinicians. The massive unmet medical need ensures the market is large enough to support multiple successful players.

Dr. Radvanyi emphasizes that foundational discoveries in immunotherapy arose from basic immunology and serendipitous observations, like his own unexpected T-cell proliferation with an anti-CTLA-4 antibody. This highlights the risk of over-prioritizing translational research at the expense of fundamental, curiosity-driven science.

While personalized cancer vaccines require extracting and processing a patient's tumor, Create Medicines' in vivo approach is entirely off-the-shelf. By delivering the programming directly into the body, they enable the patient's own immune system to do the complex, personalized work of attacking the cancer itself.

Despite billions invested over 20 years in targeted and genome-based therapies, the real-world benefit to cancer patients has been minimal, helping only a small fraction of the population. This highlights a profound gap and the urgent need for new paradigms like functional precision oncology.

A sophisticated concern regarding the HIF-2 inhibitor belzutifan is its potential to diminish kidney cancer's antigenicity by reducing human endogenous retrovirus expression. While providing an early benefit, this could theoretically make tumors less responsive to subsequent immunotherapies, negatively impacting long-term outcomes—a critical consideration for sequencing.

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.