Suzanne Topalian’s (Johns Hopkins) responses to interview questions from Tal Behar, Precision World Medicine Conference
1) The single biomarker you’d actually gate treatment on in 2026 (setting + cutoff) — and why.
In my opinion, the single most reliable biomarker for anti-PD-1-based therapy, among three that are currently FDA-approved and many that are still in testing, is MSI-H/dMMR. This marker, based on a cancer’s genetic profile, can reliably identify a small subset of patients (~4–5%) across all solid tumor types for whom anti-PD-1 is likely to confer durable antitumor benefit.
2) What must be true for PD-1 + personalized vaccines to become standard, and which non-melanoma tumor is likeliest to get there first — why.
To enter standard-of-care, a combination of anti-PD-(L)1 plus a personalized vaccine must be shown to be feasible and provide significant clinical benefit compared to anti-PD-(L)1 alone in a randomized trial. The greatest opportunity may be for cancer types that show relatively low or no response to anti-PD-(L)1 monotherapy, for example pancreatic cancer.
3) As personalized cancer vaccines move into combination trials, how do you see immune checkpoint blockade (ICB) evolving to complement these approaches?
Personalized cancer vaccines are most likely to be feasible and effective in the adjuvant (post-surgical) setting, which is the context for most current clinical trials. Vaccine-reactive immune cells typically upregulate immune checkpoint molecules such as PD-1 and others, so combining vaccines with ICB may provide a synergistic antitumor effect.
Several cancer types already have FDA-approved ICB in the adjuvant setting based on relapse-free survival benefit in high-risk populations. This provides a framework for randomized comparisons of vaccine plus ICB versus ICB alone. In other cancers, vaccine plus ICB may lead to new disease indications for ICB in the adjuvant setting.
By interrogating which checkpoint molecules are upregulated in T cells following vaccination, novel vaccine-ICB combinations can be nominated for clinical testing. Finally, recognizing that vaccine-induced immune activation engages checkpoint pathways should enable more effective sequencing of agents in multi-drug combination regimens.
4) What biomarkers or clinical settings will best define which patients benefit most from vaccines, checkpoint inhibitors, or their combination?
The adjuvant (post-surgical) setting is most likely to yield the most informative signals regarding the efficacy of personalized cancer vaccines. Because surgery alone can cure a proportion of patients with early-stage resectable cancers, and adjuvant therapies carry potential toxicity, the risk-benefit ratio must be optimized.
This can be achieved by using accepted clinicopathologic criteria to identify patients at high risk for relapse. Vaccine combinations with ICB should be guided by immune profiling to determine which checkpoint pathways are induced by a given vaccine, and then selectively targeting those pathways with specific inhibitors in rational combination strategies.
