Biomarker | Study | Tumor | Findings |
Tumor-related | |||
High TMB | Lauss et al28; n=27 | MM | Significant correlation with PFS and OS. |
Levi et al29; n=152 | MM | Significantly higher TMB in ACT responders. | |
High neoantigen load | Lauss et al28; n=27 | MM | Significant association with PFS and OS. |
Creasy et al31; n=64 | MM |
| |
Favorable transcriptome and epigenome | Lauss et al28; n=25 | MM |
|
Cascone et al39; n=19 | MM | Significantly higher expression of glycolytic genes (GPI, PGAM4) in non-responders. | |
Creasy et al31; n=64 | MM |
| |
Patient-related | |||
Baseline LDH levels | Rosenberg et al7; n=93 | MM | No significant differences in ORR according to LDH levels. |
Besser et al33; n=57 | MM | Negative correlation with response. | |
Goff et al10; n=101 | MM | ||
Forget et al32; n=74 | MM | Strong negative effect on OS. | |
Seitter et al35; n=226 | MM | Negative correlation with response. | |
Chesney et al34; n=153 | MM | ||
Rohaan et al13; n=168 (Phase III) | MM | No significant differences in PFS (vs ipilimumab) according to LDH levels in a subgroup analysis. | |
Less prior exposure to systemic therapies | Rosenberg et al7; n=93 | MM | No influence of prior therapies (ipilimumab, IL-2, chemotherapy) on response rates or OS. |
Besser et al33; n=57 | MM | Previous ipilimumab did not correlate with response. | |
Andersen et al9; n=25 | MM | No significant difference between responding and not responding patients according to prior therapies (IL-2, ipilimumab). | |
Goff et al10; n=101 | MM | No significant difference in response rates according to prior anti-CTLA-4 (n=31); anti-PD-1 (n=3); or both (n=8). | |
Forget et al32; n=74 | MM | Potential negative impact of previous anti-CTLA-4 on OS was found inconclusive after a multivariable analysis. Non-significant decrease in ORR and DOR in anti-CTLA-4-exposed patients. | |
Borch et al41; n=55 | MM |
| |
Seitter et al35; n=226 | MM |
| |
Levi et al29; n=181 | MM |
| |
Rohaan et al13; n=168 (Phase III) | MM | No influence in PFS of prior anti-PD-1 treatment. | |
Chesney et al34; n=153 | MM | Responses to LN-144 regardless of anti-CTLA-4 exposure (anti-PD-1 refractory population). | |
Baseline immune-stimulating cytokines | Forget et al32; n=74 | MM | High baseline IL-9 levels significantly associated with response. |
Borch et al41; n=12 | MM | Lower mean levels of IL-6, IL-8, IL-10, and TNF in patients with longer PFS. | |
Treatment and TIL-related | |||
Short ex vivo culture time of TIL | Aebersold et al51; n=67 | MM | Significantly less days of TIL culture for responders. |
Schwartzentruber et al 52; n=41 | MM | Shorter culture duration and TIL doubling time in responders. | |
Besser et al46; n=20 | MM | Lower median TIL age in responders (13.2 days vs 18.6 days). | |
Itzhaki et al47; n=31 | MM | Significantly younger TIL in responders (median age 13.2 vs 19.7 days), TIL age at infusion <20 days in all the responders. | |
Zhou et al54; n=27 | MM | Correlation between telomere length and clinical responses. | |
Rosenberg et al7; n=93 | MM | ||
High total number of TIL infused | Besser et al46; n=20 | MM | Higher number of TIL and higher REP expansion rate in responders. |
Ellebaeck et al8; n=6 | MM | More than 80-fold higher number of CD8+ cells in responders. | |
Andersen et al9; n=25 | MM | No significant difference in total number or percentage of CD8+ or CD4+ TIL between responders and non-responders. | |
Forget et al32; n=74 | MM | Higher number of CD8+ TIL in responders (possibly stronger predictive value in anti-CTLA-4-naïve). | |
Dafni et al12; n=122 (meta-analysis) | MM | Higher number of infused cells in responders (11 CR, 36 PR). | |
Zhou et al21; n=60 | Osteosarcoma | Better outcomes for cell products with ≥5×109 cells (ORR: 20/35) than those with <5×109 cells (ORR: 2/25). | |
Itzhaki et al47; n=31 | MM | Higher median number of total TIL and CD8+ TIL in responders. | |
Radvanyi et al61; n=31 | MM | ||
Rohaan et al13; n=78 (Phase III) | MM | ||
High CD8:CD4 ratio | Itzhaki et al47; n=31 | MM | Higher percentage of CD8+ T cells in responders (72.1% vs 53%). |
Radvanyi et al61; n=31 | MM | Higher percentage of CD4+ TIL in non-responders. | |
TCR structure | Andersen et al9; n=25 | MM | Trend toward a higher number of γδ T cells in non-responders. |
Expression of exhaustion markers | Gros et al79; n=6 | MM | Higher expression of exhaustion markers on CD8+ reactive TIL. |
Lauss et al28; n=27 | MM | Trend toward upregulation of exhaustion markers in responders. | |
Zhou et al21; n=60 | Osteosarcoma | Higher percentage of PD-1+ TIL in non-responders. | |
Radvanyi et al61; n=31 | MM | Higher percentage of BTLA+CD8+ TIL in responders. | |
Stoltenborg et al62; n=80 | MM | ||
Expression of immunosuppressive molecules | Rosenberg et al7; n=93 | MM | Higher percentage of CD4+FoxP3+ TIL in non-responders. |
Zhou et al21; n=60 | Osteosarcoma | ||
Yao et al85; n=154 | MM | ||
Costimulatory signals and phenotypic differentiation | Hernandez-Chacon et al86; n=NA | MM | Correlation between levels of CD137 in CD8+ TIL and cytotoxicity against melanoma cells in vitro. |
Rosenberg et al7; n=93 | MM | Correlation between CD27/CD28 expression and clinical efficacy. | |
Radvanyi et al61; n=31 | MM | Better clinical outcomes with CD27− Teff than CD27+ TM cells. | |
Ye et al87; n=NA | Ovarian cancer | Higher expression of CD137 in TIL than in circulating T cells, and better antitumor effects for CD137+ vs CD137− TIL. | |
Krishna et al88; n=16 | MM | Correlation between stem-like CD39−CD69− TIL and responses. | |
Stoltenborg et al 62; n=80 | MM | Higher expression of CD27/CD28 and CD39 in TIL from responders. | |
Broad scope of target antigens | Creelan et al15; n=13 | NSCLC | Correlation between polyclonal T cell reactivity and responses. |
Kristensen et al71; n=26 | MM | Higher number of neoepitope-specific infused CD8+ TIL in responders. | |
Persistence of tumor-reactive cells | Rosenberg et al7; n=93 | MM | Correlation between detection of tumor-reactive CD8+ TIL 1 month after infusion and durable responses. |
Forget et al32; n=74 | MM | High levels of CD8+ TIL and NK cell-related markers (ULBP-1, NKG2D ligand) 3 months after infusion in responders. | |
Stevanović et al18; n=29 | HPV-related | Correlation between persistent tumor-reactive TIL and clinical responses. | |
Creelan et al15; n=13 | NSCLC |
ACT, adoptive cell therapy; BRAF/MEKi, BRAF and MEK inhibitors; CRR, complete response rate; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DOR, duration of response; FoxP3, Forkhead box P3; HPV, human papillomavirus; IL, interleukin; LDH, lactate dehydrogenase; MM, metastatic melanoma; MSS, melanoma-specific survival; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PD-1, programmed cell death protein-1; PFS, progression-free survival; REP, rapid expansion protocol; Teff, effector T cell; TIL, tumor-infiltrating lymphocyte; TM, memory T cell; TMB, tumor mutation burden; TNF, tumor necrosis factor; ULBP-1, UL16 binding protein 1.