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Table 2 Immunotherapy modalities and key peripheral findings associated with response

From: Peripheral immune-based biomarkers in cancer immunotherapy: can we realize their predictive potential?

IndicationModalityTreatmentNumber of patientsPeripheral finding associated with clinical responseReference
MelanomaICIAnti-PD-140Higher baseline frequency of Bim+PD-1+CD8 T cells in responders. Levels of Bim decreased after 3 months of treatment[7] Dronca 2015
MelanomaICIIpilimumab137Higher frequency of baseline CD8 EM1, trend for lower TEMRA, and on treatment decreases in PD-1 associated with improved BOR and OS[8] Wistuba-Hamprecht 2017
Metastatic melanomaICIIpilumumab/pembrolizumab30Low baseline CD45RO+ CD8+ associated with non-response and poorer OS for ipilimumab, but not pembrolizumab[9] Tietze 2017
Stage IV melanomaICIPembrolizumab/prior ipilimumab29Clinical outcome related to the ratio of Tex-cell reinvigoration to tumor burden. Patients with longer PFS had low tumor burden and clustered above the fold-change of Tex-cell reinvigoration to tumor-burden regression line. Findings supported by independent validation cohort[3] Huang 2017
Metastatic melanomaICIIpilimumab/nivolumab190Low PD-L1 on CD4/8+ T cells prognostic for greater OS/PFS; CD137+ CD8 T cells predicted lack of relapse to ipilimumab + nivolumab combination[10] Jacquelot 2017
Metastatic melanomaICIAnti-PD-130Increased baseline HLA-DR, CLTA-4, CD56, and CD45RO associated with response; elevated CD14+CD16bHLADRhi identified as potential predictor of response.
Findings supported by independent validation cohort
[11] Krieg 2018
MelanomaICIIpilimumab and anti-PD-167For ipilimumab, lower levels of baseline memory (CD45RA+) T cells associated with response; for anti-PD-1, increased CD69+ NK cells in PMA/ionomycin stimulated PBMCs in responders[12] Subrahmanyam 2018
Stage IV melanomaICIIpilimumab and local radiotherapy22Higher baseline CD8 CM cells, transient on-treatment increases in MIP-1α and β, and sustained increases in IP-10 and MIG associated with CR/PR[13] Hiniker 2016
MelanomaICIIpilimumab, anti-PD-1 or combination39Increases in CD21lo B cells and in plasmablasts after combination therapy associated with incidence of IRAEs[14] Das 2018
MelanomaICIIpilimumab83Higher baseline monocytic MDSC associated with shorter OS[15] Kitano 2014
MelanomaICIIpilimumab49Lower frequency of monocytic MDSC associated with clinical response[16] Meyer 2014
Advanced melanomaICINeoadjuvant ipilimumab35On treatment decrease in MDSC and increase in Treg associated with improved PFS[17] Tarhini 2014
Metastatic melanoma
ICINivolumab, pembrolizumab; nivolumab/ipilimumab combination29On-treatment decreases in serum IL-8 between baseline and best response, which increased on progression[18] Sanmamed 2017
Stage 1B-IIIA NSCLCICIIpilimumab, neoadjuvant chemotherapy, paclitaxel24Increased T cell ICOS, HLA-DR, CTLA-4, and PD-1 after ipilimumab, but no association with response[19] Yi 2017
UrothelialICIIpilimumab6Increased on-treatment ICOS+ CD4+ and NY-ESO-1 responsive T cells (correlation with clinical outcome not reported)[20] Liakou 2008
ER+/PR+ breast cancerICITremelimumab and exemestane26Compared with PD, patients with SD had greater increase in ICOS on T cells and an increase in the ratio of ICOS+ T cells to Treg in blood[21] Vonderheide 2010
NSCLC, MelanomaICINivolumab83Longer PFS in patients with high T cell CM/effector ratio associated with inflammatory gene transcripts in tumor at baseline[22] Manjarrez-Orduno 2018
Advanced NSCLCICIPembrolizumab, nivolumab, or atezolizumab29Early on-treatment proliferative responses in PD-1+ CD8+ T cells associated with PR or SD[23] Kamphorst 2017
VariousICIPembrolizumab or nivolumab25On treatment increases in PD-1 on CD4+ and NK cells in responders; decreases in GITR+ on NK cells, CD4+, CD8+ T cells; decreases in CTLA-4 on NK cells and OX40 on CD4+ T cells[24] Du 2018
Ovarian, gastric cancer ascitesBispecific AbCatumaxomab (EpCAM/CD3 bispecific)258Higher relative lymphocyte count pre-treatment associated with longer OS. On-treatment HAMA associated with greater puncture-free survival, OS, and time to next therapeutic paracentesis[25] Heiss 2014
ALLBispecific AbBlinatumomab
(CD19 BiTE)
42High baseline Treg predictive of non-response[26] Duell 2017
MelanomaCancer vaccineMulti-epitope peptide vaccine37Ability of CD8+ T cells to produce IFN-γ after ex vivo stimulation with the vaccinating melanoma peptides correlated with clinical responses to the vaccine[27] Schaefer 2015
mCRPCCancer vaccineDCvac and docetaxel43On-treatment decreases in peripheral MDSCs were associated with improved survival[28] Kongsted 2017
CRPCCancer vaccineDNA vaccine encoding prostatic acid phosphatase38Non-immune responder patients tended to have higher antigen-specific IL-10 secretion prior to vaccination[29] Johnson 2017
CRPCCancer vaccinePersonalized peptide vaccine404-gene classifier (LRRN3, PCDH17, HIST1H4C, and PGLYRP1) and elevated baseline IL-6 associated with shorter survival[30] Komatsu 2012
mCRPCCancer vaccinePROSTVAC and ipilimumab30Lower baseline PD-1+Tim-3NEG CD4EM, and higher baseline PD-1NEGTIM-3+CD8 and CTLA4NEG Treg associated with improved OS. An increase in Tim-3+ NK cells post- vs. pre-vaccination associated with longer OS[31] Jochems 2014
CRPCCancer vaccineProstate GVAX and ipilimumab28Baseline elevated CD4+CTLA-4+ predicted survival. High pre-treatment levels of CD14+HLA-DR monocytic MDSC were associated with reduced OS[32, 33] Santegoets 2013, 2014
Advanced NSCLCCancer vaccineTG4010 and gemcitabine/cisplatin148Normal baseline levels of CD16+CD56+CD69+ lymphocytes associated with better clinical outcome compared with chemotherapy alone[34] Quoix 2011
NSCLCCancer vaccineRNActive®CV920122On-treatment transcriptional modules associated with T and NK cells correlated with prolonged PFS; confirmed correlation by flow cytometry[35] Hong 2016
Pancreatic cancerCancer vaccine3 therapeutic epitope peptides and gemcitabine63Lower PD-1+ CD4 and 8 T cells and Tim-3+CD8+ T cells associated with longer survival[36] Shindo 2017
MUC1+ advanced / recurrent NSCLCCancer vaccineMUC1 peptide loaded dendritic cell-based vaccine40irAEs and higher baseline lymphocyte count were predictive of response[37] Teramoto 2017
CLLCAR-TCTL01941Peripheral expansion of T cells in CTL019 product associated with response; elevated on treatment IL-15, IL-7, and IL-6 in CR and a subset of PR[38] Fraietta 2018
DLBCL, MCL, ALL, FL, CLLCAR-TAutologous CD19 CAR-T15Baseline Th1 immune fitness, low monocytic MDSC correlated with response; high baseline or increasing on-treatment monocytic MDSC, high IL-6, IL-8, NAP-3, PD-L1, and PD-L2 correlated with poorer survival[39] Enblad 2018
DLBCL, PMBCL, TFLCAR-TAxicabtagene ciloleucel111CAR-T expansion (higher AUC to day 28) correlated with response. Elevated serum IL-6, IL-10, IL-15, IL-2Rα associated with neurological events and CRS[40] Neelapu 2017
Relapsed or refractory CD19+ B-ALLCAR-TCD19 CAR-T with defined CD4/8 ratio29Loss of CD19 target antigen or development of CD8+ immunity to CAR product associated with relapse[41] Turtle 2016
mCRCCAR-TAnti-CEA CAR-T6Increases in NLR and serum IL-6 positively correlated with response; lower NLR fold-change correlated with serological decreases in CEA[42] Saied 2014
DLBCL, FL, MCLCAR-TAutologous CD19 CAR-T22Pre-infusion polyfunctional T cells in drug product, CAR-T expansion, and baseline serum IL-15 associated with response. Antitumor efficacy associated with polyfunctional IL-17A producing T cells[43] Rossi 2018
  1. Ab Antibody, ALL Acute lymphoblastic leukemia, AUC Area under the curve, BiTE Bispecific T-cell engager, BOR Best overall response, CAR Chimeric antigen receptor, CAR T CAR T cell, CC Cholangiocarcinoma, CEA Carcinoembryonic antigen, CLL Chronic lymphocytic leukemia, CM Central memory, CPRC Castrate-resistant prostate cancer, CR Complete response, CRS Cytokine-release syndrome, CTLA-4 Cytotoxic T-lymphocyte-associated protein 4, DCvac Dendritic cell vaccination, DLBCL Diffuse large B-cell lymphoma, EM Effector memory, ER Estrogen receptor, FL Follicular lymphoma, GC Gastric cancer, GITR Glucocorticoid-induced TNFR-related protein, HAMA Human anti-mouse antibody, ICI Immune checkpoint inhibitor, IL Interleukin, irAE Immune-related adverse event, MCL Mantle cell lymphoma, mCRC Metastatic colorectal cancer, mCRPC Metastatic castration-resistant prostate cancer, MDSC Myeloid-derived suppressor cell, MIG Monokine induced by interferon-gamma, MIP Macrophage inflammatory protein, MUC1 Mucin 1, N/A Not applicable, NK Natural killer, NLR Neutrophil-to-lymphocyte ratio, NSCLC Non-small cell lung carcinoma, OS Overall survival, PBMC Peripheral blood mononuclear cell, PD Progressive disease, PD-1 Programmed cell death 1, PD-L1 Programmed death ligand 1, PD-L2 programmed death ligand 2, PFS Progression-free survival, PMBCL Primary mediastinal large B-cell lymphoma, PR Partial response, PR+ Progesterone receptor positive, RCC Renal cell carcinoma, SCLC Small cell lung cancer, SD Stable disease, TEMRA Terminally differentiated effector-memory T cells, TFL Transformed follicular lymphoma, TNFR Tumor necrosis factor receptor, Treg Regulatory T cell