Question 1

How are primary and acquired resistance distinguished in practice?

Accepted Answer

The distinction rests on clinical course: no response at any point indicates primary resistance, while initial benefit followed by progression indicates acquired resistance. Establishing this requires defined response assessment criteria and adequate follow-up. Molecular comparison is only interpretable once the clinical classification is fixed, since the two forms involve largely different mechanisms.

Question 2

Why is paired tissue so important, and how can limited access be handled?

Accepted Answer

Without material from both baseline and progression, a molecular difference between responders and non-responders cannot be separated from pre-existing biology. Where re-biopsy is not feasible, circulating tumour DNA, immune cell profiling in blood, and imaging-derived measures provide partial substitutes whose limitations should be stated rather than glossed over.

Question 3

Which escape mechanisms should be examined first?

Accepted Answer

Loss of antigen presentation components and disruption of interferon response genes account for a substantial share of acquired resistance and are testable with targeted sequencing and staining. Beyond these, suppressive myeloid infiltration, regulatory T cell abundance and other inhibitory checkpoint expression are common. Screening this defined set before broader discovery keeps the project tractable.

Question 4

When are spatial methods preferable to bulk profiling?

Accepted Answer

Whenever the question concerns exclusion rather than absence. A tumour with abundant T cells confined to the stroma looks similar in bulk data to one with infiltrating T cells, yet the biology and the appropriate intervention differ entirely. Spatial imaging or sequencing resolves this, at the cost of throughput and analytical complexity.

Question 5

How much weight should preclinical combination results carry?

Accepted Answer

Transplantable tumour models carry high mutational burden and respond to blockade far more readily than human disease, so combination benefit in these models translates unreliably. Genetically engineered and humanised models are closer but slower. Framing preclinical results as mechanism-supporting rather than efficacy-predicting is the defensible position.

Question 6

What makes a combination rational rather than empirical?

Accepted Answer

A rational combination targets the specific mechanism shown to operate in that resistance setting, with a stated hypothesis about what each agent contributes and in what order. Evidence that the partner agent shifts the identified pathway, measured in the same samples, distinguishes this from adding agents and observing the outcome.

Biotechnology

Biotechnology

Research Frontiers in Checkpoint Inhibitor Resistance Mechanisms