Context.— Cancer immunotherapy provides unprecedented rates of durable clinical benefit to late-stage cancer patients across many tumor types, but there remains a critical need for biomarkers to accurately predict clinical response. Although some cancer immunotherapy tests are associated with approved therapies and considered validated, other biomarkers are still emerging and at various states of clinical and translational exploration. Objective.— To provide pathologists with a current and practical update on the evolving field of cancer immunotherapy testing. The scientific background, clinical data, and testing methodology for the following cancer immunotherapy biomarkers are reviewed: programmed death ligand-1 (PD-L1), mismatch repair, microsatellite instability, tumor mutational burden, polymerase δ and ε mutations, cancer neoantigens, tumor-infiltrating lymphocytes, transcriptional signatures of immune responsiveness, cancer immunotherapy resistance biomarkers, and the microbiome. Data Sources.— Selected scientific publications and clinical trial data representing the current field of cancer immunotherapy. Conclusions.— The cancer immunotherapy field, including the use of biomarker testing to predict patient response, is still in evolution. PD-L1, mismatch repair, and microsatellite instability testing are helping to guide the use of US Food and Drug Administration–approved therapies, but there remains a need for better predictors of response and resistance. Several categories of tumor and patient characteristics underlying immune responsiveness are emerging and may represent the next generation of cancer immunotherapy predictive biomarkers. Pathologists have important roles and responsibilities as the field of cancer immunotherapy continues to develop, including leadership of translational studies, exploration of novel biomarkers, and the accurate and timely implementation of newly approved and validated companion diagnostics.

Myeloid leukemia in children with Down syndrome (ML-DS) is associated with young age and somatic GATA1 mutations. Due to high event-free survival (EFS) and hypersensitivity of the leukemic blasts to chemotherapy, the prior Children's Oncology Group protocol ML-DS protocol (AAML0431), reduced overall treatment intensity but lacking risk stratification, retained the high-dose cytarabine course (HD-AraC), which was highly associated with infectious morbidity. Despite high EFS of ML-DS, survival for those who relapse is rare. AAML1531 introduced therapeutic risk stratification based on the previously identified prognostic factor, measurable residual disease (MRD) at the end of the first induction course. Standard risk (SR) patients were identified by negative MRD using flow cytometry (<0.05%) and did not receive the historically administered HD-AraC course. Interim analysis of 114 SR patients revealed a 2-year EFS of 85.6% (95% confidence interval (CI), 75.7-95.5%), which was significantly lower than for MRD-negative patients treated with HD-AraC on AAML0431 (p=0.0002). Overall survival at 2 years was 91.0% (95% CI 83.8%-95.0%). Twelve SR patients relapsed, mostly within one year from study entry and had a 1-year OS of 16.7% (95% CI 2.7% - 41.3%). Complex karyotypes were more frequent in SR patients who relapsed compared to those who did not (36% vs. 9%; p=0.0248). MRD by error-corrected sequencing of GATA1 mutations was piloted in 18 SR patients and detectable in 60% who relapsed vs. 23% who did not (p=0.2682). Patients with SR ML-DS had worse outcomes without HD-AraC after risk classification based on flow cytometric MRD. ClinicalTrials.gov NCT02521493

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