Table 5.
Current investigational tissue biomarkers of ICB response
| Marker | Drug | Malignancy | End-point results | References |
|---|---|---|---|---|
| Gene expression | ||||
| IFN- γ, IDO1, CXCL9 | Atezolizumab | Melanoma, NSCLC, RCC |
Pre-treatment tumors—elevated expression of IFN-γ and IFN-γ-inducible genes (e.g., IDO1 and CXCL9) for melanoma only P = 0.024 |
Herbst et al. [145] |
| CCL4, CCL5, CXCL9, CXCL10, CXCL11 | Ipilimumab | Melanoma |
High cytolytic activity, best response—correlated with high expression of such chemokines P = 2.3 × 10−52 |
Ji et al. [166] |
| PD-L1 |
Nivolumab Pembrolizumab Atezolizumab |
Melanoma, NSCLC, GU cancer |
PD-L1 expression is associated with response for these cancer types P < 0.0001 |
Carbognin et al. [167] |
| CD8, CD4, CD3, PD-1, FOXP3, LAG3 |
Nivolumab Ipilimumab |
Melanoma |
Higher level of expression of immune-related biomarkers in responders P < 0.05 |
Chen et al. [168] |
| PD-L2, CTLA-4, Granzyme A, B, Perforin-1 | Ipilimumab | Melanoma | PD-L2 (P = 0.041), CTLA-4 (P = 0.033), granzyme A, B, perforin 1 (P = 0.042)—higher expressed in responders | Van Allen et al. [74] |
| CD40, CD27, HVEM |
Nivolumab Pembrolizumab |
Melanoma |
High expression of HVEM, CD27, CD40 is associated with a better response to ICB P = 0.004 |
Auslander et al. [114] |
| Gene alterations (tumor) | ||||
| EGFR, MDM2, MDM4 | CTLA-4, PD-1/PD-L1 | Lung, bladder, breast tumors | Patients with EGFR aberrations or MDM amplifications were hyper-progressors. EGFR (P = 0.002), MDM2 (P = 0.001), MDM4 (P = 0.03) | Kato et al. [97] |
| ALK, EGFR | PD-1/PD-L1 | NSCLC | EGFR mutations or ALK rearrangements associated with low response rate. P = 0.053 | Gainor et al. [21] |
| KRAS/TP53 | Pembrolizumab | NSCLC | KRAS/TP53 mutations associated with increased expression of PD-L1, highest proportion of PD-L1+ and CD8+ T-cells, increased TMB, better clinical outcome. P < 0.001 | Dong et al. [89] |
| STK11/LKB1 in KRAS tumors | PD-1 or CTLA-4 | LUAC | Low PD-L1 expression, resistance to therapy. P < 0.001 | Skoulidis et al. [90] |
| PBRM1 | PD-1 or CTLA-4 | ccRCC | Clinical benefit for patients with PBRM1 loss of function mutations. P = 0.012 | Miao et al. [91] |
| IFN-gamma pathway genes | Ipilimumab | Melanoma | Non-responders have genomic defects in IFN-gamma genes. P = 0.015 | Gao et al. [92] |
| ATM, POLE, BRCA2, ERCC2, FANCA, MSH6 |
Nivolumab Atezolizumab |
Advanced urothelial cancers | Presence of any DDR alteration was associated with a higher response rate. P < 0.001 | Teo et al. [120] |
| JAK1, JAK2, B2M | Pembrolizumab | Melanoma | JAK1 or JAK2 and beta-2-microglobulin (B2M) truncating mutations associated with acquired resistance to PD-1 blockade | Zaretsky et al. [95] |
| MSH2, MSH6, PMS2, MLH1 | Pembrolizumab | 12 solid tumor types | Objective radiographic responses observed in 53% (95% CI 42–64%) of patients, and complete response in 21% of patients | Le et al. [61] |
| Tumor-infiltrating lymphocytes (TILs) |
Pembrolizumab Ipilimumab |
Melanoma |
High level of CD8+ TILs, expressions in the tumor and at the invasive tumor margin in responders P = 0.005 P = 0.0002 |
Hamid et al. [169] Tumeh et al. [170] |
| Ipilimumab | Melanoma | Association between clinical activity and increased TILs | Hamid et al. [169] | |
| Nivolumab |
Melanoma NSCLC RCC |
P = 0.005 Presence of TILs not sufficient to induce PD-L1 and not an independent factor associated with clinical response |
Taube et al. [171] | |
ccRCC clear cell renal cell carcinoma, LUAC lung adenocarcinoma, NSCLC non-small cell lung carcinoma, SCLC small cell lung carcinoma, RCC renal cell carcinoma, GU genitourinary cancer