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

Nixon, Andrew B.; Schalper, Kurt A.; Jacobs, Ira; Potluri, Shobha; Wang, I-Ming; Fleener, Catherine

doi:10.1186/s40425-019-0799-2

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?

Indication	Modality	Treatment	Number of patients	Peripheral finding associated with clinical response	Reference
Melanoma	ICI	Anti-PD-1	40	Higher baseline frequency of Bim⁺PD-1⁺CD8 T cells in responders. Levels of Bim decreased after 3 months of treatment	[7] Dronca 2015
Melanoma	ICI	Ipilimumab	137	Higher 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 melanoma	ICI	Ipilumumab/pembrolizumab	30	Low baseline CD45RO⁺ CD8⁺ associated with non-response and poorer OS for ipilimumab, but not pembrolizumab	[9] Tietze 2017
Stage IV melanoma	ICI	Pembrolizumab/prior ipilimumab	29	Clinical outcome related to the ratio of T_ex-cell reinvigoration to tumor burden. Patients with longer PFS had low tumor burden and clustered above the fold-change of T_ex-cell reinvigoration to tumor-burden regression line. Findings supported by independent validation cohort	[3] Huang 2017
Metastatic melanoma	ICI	Ipilimumab/nivolumab	190	Low 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 melanoma	ICI	Anti-PD-1	30	Increased baseline HLA-DR, CLTA-4, CD56, and CD45RO associated with response; elevated CD14⁺CD16b⁻HLA⁻DR^hi identified as potential predictor of response. Findings supported by independent validation cohort	[11] Krieg 2018
Melanoma	ICI	Ipilimumab and anti-PD-1	67	For 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 melanoma	ICI	Ipilimumab and local radiotherapy	22	Higher 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
Melanoma	ICI	Ipilimumab, anti-PD-1 or combination	39	Increases in CD21^lo B cells and in plasmablasts after combination therapy associated with incidence of IRAEs	[14] Das 2018
Melanoma	ICI	Ipilimumab	83	Higher baseline monocytic MDSC associated with shorter OS	[15] Kitano 2014
Melanoma	ICI	Ipilimumab	49	Lower frequency of monocytic MDSC associated with clinical response	[16] Meyer 2014
Advanced melanoma	ICI	Neoadjuvant ipilimumab	35	On treatment decrease in MDSC and increase in Treg associated with improved PFS	[17] Tarhini 2014
Metastatic melanoma NSCLC	ICI	Nivolumab, pembrolizumab; nivolumab/ipilimumab combination	29	On-treatment decreases in serum IL-8 between baseline and best response, which increased on progression	[18] Sanmamed 2017
Stage 1B-IIIA NSCLC	ICI	Ipilimumab, neoadjuvant chemotherapy, paclitaxel	24	Increased T cell ICOS, HLA-DR, CTLA-4, and PD-1 after ipilimumab, but no association with response	[19] Yi 2017
Urothelial	ICI	Ipilimumab	6	Increased on-treatment ICOS⁺ CD4⁺ and NY-ESO-1 responsive T cells (correlation with clinical outcome not reported)	[20] Liakou 2008
ER⁺/PR⁺ breast cancer	ICI	Tremelimumab and exemestane	26	Compared 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, Melanoma	ICI	Nivolumab	83	Longer PFS in patients with high T cell CM/effector ratio associated with inflammatory gene transcripts in tumor at baseline	[22] Manjarrez-Orduno 2018
Advanced NSCLC	ICI	Pembrolizumab, nivolumab, or atezolizumab	29	Early on-treatment proliferative responses in PD-1⁺ CD8⁺ T cells associated with PR or SD	[23] Kamphorst 2017
Various	ICI	Pembrolizumab or nivolumab	25	On 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 ascites	Bispecific Ab	Catumaxomab (EpCAM/CD3 bispecific)	258	Higher 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
ALL	Bispecific Ab	Blinatumomab (CD19 BiTE)	42	High baseline Treg predictive of non-response	[26] Duell 2017
Melanoma	Cancer vaccine	Multi-epitope peptide vaccine	37	Ability 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
mCRPC	Cancer vaccine	DCvac and docetaxel	43	On-treatment decreases in peripheral MDSCs were associated with improved survival	[28] Kongsted 2017
CRPC	Cancer vaccine	DNA vaccine encoding prostatic acid phosphatase	38	Non-immune responder patients tended to have higher antigen-specific IL-10 secretion prior to vaccination	[29] Johnson 2017
CRPC	Cancer vaccine	Personalized peptide vaccine	40	4-gene classifier (LRRN3, PCDH17, HIST1H4C, and PGLYRP1) and elevated baseline IL-6 associated with shorter survival	[30] Komatsu 2012
mCRPC	Cancer vaccine	PROSTVAC and ipilimumab	30	Lower baseline PD-1⁺Tim-3^NEG CD4_EM, and higher baseline PD-1^NEGTIM-3⁺CD8 and CTLA4^NEG Treg associated with improved OS. An increase in Tim-3⁺ NK cells post- vs. pre-vaccination associated with longer OS	[31] Jochems 2014
CRPC	Cancer vaccine	Prostate GVAX and ipilimumab	28	Baseline 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 NSCLC	Cancer vaccine	TG4010 and gemcitabine/cisplatin	148	Normal baseline levels of CD16⁺CD56⁺CD69⁺ lymphocytes associated with better clinical outcome compared with chemotherapy alone	[34] Quoix 2011
NSCLC	Cancer vaccine	RNActive®CV9201	22	On-treatment transcriptional modules associated with T and NK cells correlated with prolonged PFS; confirmed correlation by flow cytometry	[35] Hong 2016
Pancreatic cancer	Cancer vaccine	3 therapeutic epitope peptides and gemcitabine	63	Lower PD-1⁺ CD4 and 8 T cells and Tim-3⁺CD8⁺ T cells associated with longer survival	[36] Shindo 2017
MUC1⁺ advanced / recurrent NSCLC	Cancer vaccine	MUC1 peptide loaded dendritic cell-based vaccine	40	irAEs and higher baseline lymphocyte count were predictive of response	[37] Teramoto 2017
CLL	CAR-T	CTL019	41	Peripheral 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, CLL	CAR-T	Autologous CD19 CAR-T	15	Baseline 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, TFL	CAR-T	Axicabtagene ciloleucel	111	CAR-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-ALL	CAR-T	CD19 CAR-T with defined CD4/8 ratio	29	Loss of CD19 target antigen or development of CD8⁺ immunity to CAR product associated with relapse	[41] Turtle 2016
mCRC	CAR-T	Anti-CEA CAR-T	6	Increases 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, MCL	CAR-T	Autologous CD19 CAR-T	22	Pre-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

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

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