Epitranscriptomic Approach: To Improve the Efficacy of ICB Therapy by Co-Targeting Intracellular Checkpoint CISH
Abstract
:1. Introduction
1.1. Connotation of Immune Checkpoint Markers
1.2. ICB Drug-Resistance and Toxicities
2. Milestones in ICB therapeutics
2.1. Discovery of ICB Therapy
2.2. Mechanism of ICB/ICI-Therapeutics
2.3. Strategies to Overcome ICB Drug-Resistance
3. Epitranscriptomics in ICB-Therapeutics
3.1. Editors (Writers):
3.1.1. Mettl-3/14 in Anti-PD-1 Resistance (Colorectal Cancer)
3.1.2. Mettl-3 in Anti-PD-1 Resistance (Lung Metastasis)
3.2. Erasers (Removers):
3.2.1. FTO in Anti-PD1 Resistance (Melanoma):
3.2.2. FTO in Anti-PD-1 Resistance (Colon Cancer)
3.2.3. ALKBH5 in Anti-PD-1 Resistance (Melanoma)
3.3. Effectors (Readers):
3.3.1. YTHDF1 in Anti-PD1 Resistance (Solid Tumors)
3.3.2. YTHDF2 in Anti-PD1 Resistance (Brain Tumors)
4. Immune Cells: Targeting Intracellular Checkpoint ‘CISH’ in Combination with ICB-Therapeutics and Recent Clinical Trials
4.1. NK-Cells Targeting CISH in ICB Therapeutics
4.2. T-cells Targeting CISH in ICB Therapeutics
4.3. Dendritic Cells Targeting SOCS-1/CISH in ICB-Therapeutics
5. MicroRNAs and Epigenetic Modifiers (DNA and Histone Proteins) in ICB-Therapy
5.1. MicroRNAs in ICB-Therapeutics
5.2. Epigenetic Modifiers (DNA and Histone Proteins) in ICB-Therapeutics
6. Biopharmaceutical Companies Developing Personalized Medicines: Targeting Intracellular Checkpoint ‘CISH’ in Combination with ICB-Therapeutics and Recent Clinical Trials
6.1. ONK Therapeutics Limited
6.2. Intima Bioscience, Inc.
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- NK-cells targeting intracellular checkpoint CISH: ONK therapeutics, Ireland, estimated to conduct Phase-I clinical trial (ONKT102, ONKT103 and ONKT104) by 2021𠄲2022 for the treatment of haematological malignancies (multiple myeloma and AML) and solid tumors (ovarian, NSCLC and breast cancers) [135].
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- ■
7. Conclusions
8. Future Prospective
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AIA | Ag-induced arthritis |
ALKBH5 | alpha-ketoglutarate-dependent hydroxylase |
CAND1 | Cullin-associated NEDD8-dissociated protein 1 |
EZH2 | Enhancer of zeste 2 polycomb repressive complex-2 subunit |
EBF-1 | Early B-cell factor-1 |
FTO | Fat Mass and Obesity Associated Protein |
MPM | Malignant pleural mesothelioma |
Spred2 | Sprouty related EVH1 domain containing protein-2 |
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RNA (m6A)-Modifiers (Editors/Erasers/Effectors) | |||||
---|---|---|---|---|---|
RNA Modifiers | Disease Condition | Target | Disease Mechanism | Therapeutic Strategies | Ref. |
Writers Mettl3/14 | up-regulated in colorectal cancer and melanoma | IFNγ, STAT1, IRF1, Cxcl-9 and Cxcl-10 | By reducing CD8+T-cells infiltrations in TME | CRISPR/cas9 silencing of Mettl3/14 via YTHDF2 | [8] |
Mettl-3 | down-regulated in M1/M2-med. lung metastasis | Spred-2 | By recruiting immunosuppresive T-reg and MDSCs | Overexpressing Mettl3 via polarizing M1/M2-macrophages | [9] |
m6A | m6A-mediated regulation of PD-L1 in HNSCC | G2M checkpoint and PI3K/AKT/ mTOR signaling | Analysed via cancer genome atlas TCGA and GSE65858 cohort | By targeting m6A regulatated signature genes | [10] |
Erasers FTO | up-regulated in melanoma | PD-1, CXCR4 and SOX10 | Impairs anti-PD1 effect by reducing target gene expressions | Selective inhibition of FTO to enhance anti-PD1 effects | [11] |
FTO | up-regulated in colon cancer | PD-L1 | Up-regulates PD-L1 expression in IFNγ signaling-independent manner | Selective inhibition of FTO inhibits PD-L1 to control colon cancer | [12] |
ALKBH5 | up-regulated in melanoma | Mct4/Slc16a3 | By recruiting immunosuppresive T-reg and MDSCs | Anti-ALKBH5 enhances the effect of anti-PD1 therapy. | [13] |
Readers YTHDF1 | up-regulated in solid tumors | Lysosomal cathepsins | Degrade neo-antigen and impair dendritic cell presentation | Anti-YTHDF1 suppress cathepsins and enhance DC cross-presentation | [14] |
YTHDF2 | up-regulated in LGG (brain tumor) and several other immune cells | PD-1, CTLA4, TIM3 | Impair immune checkpoint signalling | Anti-YTHDF2 in combination with immunecheckpoint immunotherapy | [15,16] |
DNA and Histone Modifiers in ICB-Therapeutics | |||||
Epigenetic Regulators | Disease Condition | Target | Mechanism | Therapeutic Strategies | Ref. |
DNA methylation | down-ragulates CTLA4 in HNSCC | CTLA4, CD28, CD80/86, ICOS | DNA methylation affects HNSCC | Selective DNA (DNMTs) inhibitors | [17] |
DNA methylation | down-regulates PD-L1 in melanoma | Interfron signalling | cpG DNA methylation regulate melanoma | [18] | |
DNA methylation | up-regulates PD-1 & CTLA4 in NSCLC | PD-1 (PDCD-1) CTLA4 | Hypo-methylation increases PD-1, CTLA4 expression in NSCLC | Selective DNA (5hmC) inhibitors | [19] |
DNA methylation | up-regulates PD-L1 & PD-L2 in HNSCC | PD-L1 (CD274) PD-L2 (PDCD1LG2) | Hypo-methylation increases PD-L1 & PD-L2 expression | Combining DNA inh. with Nivolumab and Pembrolizumab | [20] |
DNA methylation | up-regulates PD-L1 in CRC | PD-L1 (CD274) | DNA-methylation control PD-L1 exp. | Selective DNA (TETs) inhibitors | [21] |
HDAC | up-ragulates CTLA4 in B-cell associated function | CTLA4 and LAG3 | Tcf1 regulate CTLA4 expression in TFH-cells | HDACi control CTLA4-mediated B-cell help | [22] |
HDAC6 | up-regulates PD-L1 in melanoma | PD-L1 (CD274) STAT3 | HDAC6 increase PD-L1 expression by recruiting STAT3 | HDAC6-inhibitor decreases PD-L1 by de-activating STAT3 | [23] |
Active H3K4me3 | up-regulates PD-L1 in breast cancer | EMT-induced PD-L1 expression | Active H3K4me3 modifications in Breast cancer | Selective histone inhi. enhance the efficacy of ICB-Abs | [24] |
Active H3K4me3 | up-regulates PD-L1 in pancreatic cancer | PD-L1 (CD274) | MLL1 catalyzed H3K4me3 to bind with PD-L1 promoter and increase its expression | MLL1 inhibitor in combination with anti-PD-L1,anti-PD-1 improves efficacy | [25] |
Repressive H3K27me3 | down-regulates PD-L1 in HCC | PD-L1, IRF1 | EZH2 negatively regulate PD-L1 exp. by recruiting repressive H3K27me3 in HCC | Selective H3K27me3 inhibitor could enhance ICB efficacy | [26] |
HDACi (Belinostat) | up-regulates PD-L1 & CTLA4 in HCC | Increase IFN-γ & reduce T-reg populations | Belinostat treatment increase anti-tumor immunity against HCC | Combining belinostat enhances the efficacy of ICB therapy | [27] |
SAHA | Increases CTLA4 and Foxp3 exp. cardiac transplant | Foxp3 CTLA4 | SAHA increases suppressive function of T-reg to prolong allograft survival | SAHA (HDACi) couls be a promissing immunosuppressive agent with CNI drug | [28] |
H3Ac | up-regulates PD-L1 in drug resistant cancer cell | H3Ac enhance PD-L1 exp. | drug resistant issues in cancer cells | HDACi in combination with anti-PD-L1 | [29] |
MicroRNAs in ICB-Therapeutics | |||||
miRNAs | Disease Condition | Target | Mechanism | Therapeutic Strategies | Ref. |
miR-15a,b miR-16, miR-193a-3p | down-regulated in MPM | Direct target of PD-L1 | miR-15a, miR-16 and miR-193a-3p (−)vely regulates PD-L1 | Respective miRNA mimics combined ICB-therapeutics | [30] |
miR-17-5p | down-regulated in melanoma | Directly binds 3′-UTR PD-L1 | miR-17-5p (−)vely regulates PD-L1 | miR-17-5p mimics with anti-PD-L1 Abs | [31] |
miR-18a (miR-140, 142, 340, 383) | up-regulated in cervical cancer | PI3K/AKT, WNK2, SOX6, p53 PTEN, MEK | miR-18a (+)vely and miR-140, 142, 340, 383 (−)ly regulates PD-L1 | Respective miRNA antagomiR & mimics with ICB-therapy | [32] |
miR-20b-21-130b | up-regulated in colorectal cancer | PTEN, B7-H1 (PD-1) | miRs (+)vely regulates B7-H1 (PD-1) exp. | Respective miRNAs AntagomiRs in combination with ICB-therapeutics | [33] |
miR-21 (CD4+T-cells) | up-regulated in arthritis and GC | PDCD4, Th17, STAT5, T-reg | miR-21 (−)vely regulates PDCD4, PD-1 | [34,35] | |
miR-23a-3p | up-regulated in (MΦ) liver cancer | PTEN, AKT pathways | miR-23a-3p (+)vely regulates PD-L1 exp. | Anti-miR-23a-3p (antagomiR therapy) with anti-PD-L1 Abs | [36] |
miR-25-93- 106b cluster | down-regulated in pancreatic cancer | CXCL12, PD-L1 | miR-25-93- 106b−/− mice increases PD-L1 | miR-93, miR-106b mimics with BET inh. | [37] |
miR-28 | melanoma | PD-1 | miR-28 (−)vely regulates PD-1 | miR-28 mimics | [38] |
miR-33a | down-regulated in Lung A. carcinoma | PD-L1,CTLA4, PD-1, CAND1 | miR-33a (−)vely regulates PD-1/PD-L1 | miR-33a mimics with combined ICB-Abs | [39] |
miR-34a | down-regulated in AML, lymphoma | EBF-1 and 3′-UTR PD-L1 | miR-34a (−)vely regulates PD-L1 exp. | ICB therapy combined miRNA | [40,41,42,43,44] |
miR-138-5p | down-regulated in CRC | Target 3′-UTR PD-L1 | miR-138-5p (−)vely regulatesPD-L1 exp. | miR-138-5p mimics combined ICB-Abs | [45] |
miR-140 | down-regulated in NSCLC | miR-140/ PD-L1/cyclinE pathways | miR-140 target 3′-UTR PD-L1 (−)vely regulates its exp. | miR-140 mimics with anti-PD-L1 therapy | [46] |
miR-142-5p | down-regulated in pancreatic cancer | miR-142-5p target 3′-UTR PD-L1 | miR-142-5p (−)vely regulates PD-L1 exp. | miR-142-5p mimics + anti-PD-L1 therapy | [47] |
miR-145 | down-regulated in ovarian carcinoma | Cisplatin cMYc (TcF) | miR-145 (−)vely regulates PD-L1 exp. | miR-145 mimic (restoration therapy) with anti-PD-L1 Abs | [48] |
miR-146a | up-regulated in melanoma | STAT1-IFNγ axis | miR-146a (+)vely regulates PD-L1 exp. | miR-146a antagomiR with anti-PD-L1 Abs | [49] |
miR-148a -3p | down-regulated in dMMR/MSI-H CRC | miR-148a-3p binds to 3′-UTR PD-L1 | miR-148a-3p (−)vely regulates PD-L1 exp. | Respective miRNA mimics with anti-PD-L1 therapy | [50] |
miR-155 | up-regulated in B-cell lymphoma | AKT and ERK | miR-155 (+)vely regulates PD-L1 exp. | miR-155 antagomiR + PD-L1 antagonists | [51] |
miR-191-5p | down-regulated in colon-adenocarcinoma | PD-L1 | miR-191-5p (−)vely regulates PD-L1 exp. | miR-191-5p mimics | [52] |
miR-195 | down-regulated in PC and DLBCL | PD-L1 | miR-191-5p (−)vely regulates PD-L1 exp. | miR-191 mimics | [53,54] |
miR-197 | down-regulated in NSCLC | CKS1B/STAT3 (Bcl-2, c-Myc, CyclinD1) | miR-197 (−)vely regulates PD-L1 exp. | miR-193 mimics (replacement therapy) + ICB-therapeutics | [55] |
miR-200b, miR-152 | down-regulated in gastric cancer (GC) | B7-H1 (PD-1) | miR-200b and miR-152 (−)vely regulates B7-H1 | Respective miRNA mimics combined PD-L1 antagonists | [43,56,57] |
miR-214 | down-regulated in B-cell lymphoma (DLBCL) | miR-214 atrget 3′-UTR PD-L1 | miR-214 (−)vely regulates PD-L1 exp. | miR-214 mimic in combination with anti-PD-L1 Abs | [58] |
miR-217 | down-regulated in laryngeal cancer | AEG-1 and PD-L1 | miR-217 (−)vely regulates PD-L1 exp | miR-217 mimics with anti-PD-L1 therapy | [59] |
miR-324-5p miR-338-5p | downregulated in Mycobateria-responsive hedgehog sign | PD-L1, SHH signaling | (−)vely regulate PD-L1 | miRNA mimics | [60] |
miR-340 | down-regulated in Cervical cancer | PD-L1 | miR-340 (−)vely regulates PD-L1 exp. | miR-340 mimics | [61] |
miR-375 | down-regulated in HNSCC | JAK2 | Inhibits JAK2-STAT1 axis suppressing PD-L1 exp. | miR-375 mimics | [62] |
miR-424 (322) | down-regulated in ovarian cancer | PD-1/PD-L1, CD80/CTLA4 | miR-424 (322) (−)vely regulates PD-1/PD-L1, CD80/CTLA4 exp. | miR-424 (322) mimics (restoration therapy) + ICB-therapeutics | [63] |
up-regulated in Colon cancer | CD28, CD80 and CD86 | up regulated miR-424 impairs anti-tumor immunity | modified tumor-secreted EVs with miR-424 knocked down | [64] | |
miR-497-5p | down-regulated in RCC (ccRCC) | Cell proliferation | miR-497-5p (−)vely regulates PD-L1 exp. | miR-497-5p mimic with anti-PD-L1 Abs | [65] |
miR-513 | cholangiocytes in response to C. parvum infection | B7-H1 (PD-1) | miR-513 (−)vely regulates PD-1 exp. | miR-513 mimics | [66] |
miR-570 | down-regulated in gastric cancer | B7-H1 (PD-1) | SNP (polymorphism) disrupts miR-570- B7-H1 interactions | Restoration therapy combined ICB-Abs | [43,67] |
miR-873 | down-regulated in breast cancer | PI3K/Akt, ERK1/2 pathways | miR-873 (−)vely regulates PD-L1 by binding to 3′-UTR | miR-873 mimics with PD-1/PD-L1 inhibitor | [68] |
miR-3127-5p | up-regulated in NSCLC | pSTAT3 | Upregulates PD-L1 by suppressing p-STAT3 | Anti-miR-3127-5p (antagomiR therapy) | [69] |
miR-3609 | down-regulated in breast cancer | PD-L1 | miR-3609 (−)vely regulates PD-L1 exp. | miR-3609 mimics | [70] |
miR-4717 | down-regulated in HBV | PD-1 | miR-4717 (−)vely regulates PD-1 exp. | miR-4717 mimics | [71] |
Immune Cell Targeted Antibodies (Anti-PD-1 Therapy) | ||||||
---|---|---|---|---|---|---|
Company | Antibody FDA Approval | Brand/ Other Name | Combination | Disease | Clinical Trial | Ref. |
Bristol-Meyers Squibb | Nivolumab (Human IgG4) 2014 | Opdivo®, BMS-936558, MDX-1106 ONO-4538 | LAG3 (BMS-986016), B7-H3 (Enoblituzumab), KIR (Lirilumab), 4-1BB (Urelumab), ICOS (JTX-2011), CD27 (Varlilumab), GM.CD40L (vaccine for lung NSCLC) | Broad range of tumor types and Lymphomas | NCT01968109 NCT02817633 NCT01714739 NCT02253992 NCT02904226 NCT02335918 NCT02466568 NCT01673867 | [83,84] |
Medimmune | MEDI0680 (AMP-514) | - | NCT02118337 Phase I | [85,86] | ||
Regeneron/ Sanofi | REGN2810 | - | Phase I/II NCT02383212 NCT02760498 | |||
Novartis | PDR001 | GITR (GWN323) | NCT02740270 | [87] | ||
Merck | Pembrolizumab (Humanized IgG4k) 2014 | Keytruda® MK-3475, lambrolizumab | B7-H3 (Enoblituzumab), Multi-kinase inhibitor (Sunitinib) | Melanoma, Lung, NSCLC, HNC, cervical, thyroid cancer | NCT02475213 NCT02599779 NCT01295827 | [83,88] |
Cure Tech | Pidilizumab (Humanized IgG1k) | CT-011 | Pidilizumab (formerly CT-011), anti-delta like-1 (DLL1), anti-PD-1 | Malignant gliomas | Phase I/ II NCT01952769 | |
Sanofi | Cemiplimab 2018 | Libtayo® | Cervical cancer CSCC | Phase III | [83] | |
Immune Cell Targeted Antibodies (Anti-CTLA4 Therapy) | ||||||
Medarex/ Bristol-Meyers Squibb | Ipilimumab (IgG1 isotype) 2011 | Yervoy® (BMS-734016, MDX-010, MDX-101) | Nivolumab, Gemcitabine, Cisplatin | Melanoma, SCLC, Bladder, prostate cancer | NCT00527735 NCT01524991 NCT00323882 | [83,89,90,91,92] |
Pfizer/ AstraZeneca | Tremolimumab (IgG2 isotype) 2015 | Orphan drug approval, CP-675, 206 | Metastatic melanoma, Solid Tumor | Phase III NCT02527434 NCT03703297 | [93,94,95,96,97] | |
Tumor Cell/APC-Targeted Antibodies (Anti-PD-L1/L2 Therapy) | ||||||
Roche/ Genentech | Anti-PD-L1 Atezolizumab (Humanized IgG1k), 2016 | Tecentriq®, MPDL3280A, RG7446, RO5541267 | CD27 (Varlilumab), VEGF inhibitors (Bevacizumab cediranib) | Ovarian, Urothelial, Lung Cancer, HNCLC | NCT02543645 NCT02659384 | [83] |
Merck, EMD, Serono/Pfizer | Avelumab 2017 | Bavencio® MSB0010718C | Metastatic MCC | Urothelial, RCC, Merkel | NCT02603432 | [83,98] |
Medimmune/ AstraZeneca | Anti-PD-L1 Durvalumab (Human IgG1k), 2017 | Imfinzi® MEDI4736 | Osimertinib, Olaparib and Sunitinib | NSCLC, Solid Tumor, urothelial carcinoma | Reference [70] NCT02221960 NCT02484404 | [99,100,101] |
Bristol-Meyers Squibb | Anti-PD-L1 (Human IgG4) | BMS-936559 (MDX1105) | - | HIV-1, Sepsis, NSCLC | Phase I NCT02028403 | [102,103,104] |
Amplimmune/ Glaxo Smith Klein | Anti-PD-L2 | AMP-224 | - | MCC | NCT02298946 | [105] |
Anti-PD-L2 AMP-514 (fusion protein) | MEDI0680 | - | kidney cancer, melanoma | Phase I NCT02013804 | [86] |
Biopharmaceutical Company/University | Target | Combined Therapeutic Approach | Clinical Trial | Indication | Ref. |
---|---|---|---|---|---|
Natural Killer Cells (NK-cells) Clinicaltrials.gov, accessed on 15 July 2021 | |||||
ONK therapeutics (Ireland) 2015 www.onktherapeutics.com | CISH−/− NK-cells NK-cells | CISH−/− NK-cells in combination with ICB-antibodies | ONK102 ONK103 ONK104 | M. Myeloma NSCLC AML | [135] |
Fate Therapeutics San Diego, USA | iPSC-derived NK Cells (FT500) | Nivolumab (anti-PD-1) Pembrolizumab (anti-PD-1) Atezolizumab (anti-PD-L1) Interleukin-2 (IL-2) | NCT03841110 NCT04106167 (Phase-I) | Advanced solid tumors and lymphoma | [136,137,138,139,140] |
Innate Pharma S. A | NK cell (NKG2A) | Durvalumab (Phase-I/II) Nivolumab (Phase-I) Ipilimumab (Phase-I) Nivolumab + 5-Aza (Ph-I) | NCT02671435 NCT01592370 NCT01750580 NCT02599649 | Metastatic Cancer | [141,142] |
Altor Biosciences corporation | IL-15 super agonist mediated NK-cells | Nivolumab (anti-PD-1) | NCT02523469 (Phase-I/II) | NSCLC | [142] |
ImmunityBio, Inc. | High-affinity Natural Killer (haNK) Cell | Avelumab (Bavencio®) (anti-PD-L1) | NCT03387085 (Phase-I/II) | Triple Negative Breast Cancer | - |
SignalRX Pharmaceuticals, Inc. | SF1126 (dual inhibitor of PI3K and BRD4) | Nivolumab (anti-PD-1) | NCT03059147 | Advanced HCC | [83] |
Effector Therapeutics | Tomivosertib (eFT-508) | Pembrolizumab (anti-PD-1) | NCT03616834 Phase-II Completed 2021 | Solid tumors and NSCLC | [83] |
NantKwest Inc., and Chan Soon-Shiong Institute for Medicine, USA | CD16-targeted NK-cell (haNKTM) with N-803 (IL-15 superagonist) | Avelumab (Bavencio®) (anti-PD-L1) | NCT03853317 (Phase-II) | Merkel cell carcinoma | [139,143] |
National Cancer Institute, Naples | NK-cells (Tregs and NKs) | Nivolumab (anti-PD-1) | NCT03891485 | Renal cell carcinoma | [144] |
Gachon University & Severance hospital, Republic of Korea | Allogeneic NK-Cells (SMT-NK) | Pembrolizumab (anti-PD-1) Keytruda | NCT03937895 (Phase-I/II) | Biliary tract cancer | [139] |
Fox Chase Cancer Center, USA | NK-cells and T-cells | Pembrolizumab (anti-PD-1) | NCT02535247 (Phase-I/II) | Lymphoma | [144,145,146] |
Jilin University Hospital, China | NK-cells | PD-1 Ab | NCT03958097 (Phase-II) | Non-small cell lung cancer | [139] |
MD Anderson Cancer Center, USA | DF1001 (a new molecule targeting NK-cell activations) | Drug: DF1001 Pembrolizumab (anti-PD-1) | NCT04143711 (Phase-I/II) | Advanced Solid Tumors | [139,144] |
T-Cells: Tumor-Infiltrating Lymphocytes (TILs) | |||||
Intima Bioscience, Inc. with University of Minnesota | CISH-deleted Tumor-Infiltrating Lymphocytes (TIL) | CISH checkpoint-deleted TILs combined with Cyclophosphamide, Fludarabine, Aldesleukin and ICB-therapeutics | NCT04426669 (Phase-I/II) | Solid tumors & gastro-intestinal cancers | [1,147] |
CISH−/− T-cells (TILs) | NCT03538613 (Phase-I/II) | Gastro-intestinal cancers | [2,5] | ||
Hangzhou Cancer Hospital in collabration with Anhui Kedgene Biotechnology Co.,Ltd | PD-1 Knockout T-Cells | CRISPR/Cas9-deleted PD-1 in T-Cells with hydrocortisone | NCT03081715 (Phase-I) Completed, 2018 | Advanced Esophageal Squamous Cell Carcinoma | [2,144] |
Sichuan University in collabration with Chengdu MedGenCell | PD-1 Knockout T-Cells | CRISPR/Cas9-deleted PD-1 in T-Cells with Cyclophosphamide | NCT02793856 (Phase-I) Completed, 2020 | Metastatic Non-small Cell Lung Cancer | [2,144,148] |
Peking University and (Cell Biotech) | PD-1 Knockout Engineered T Cells | PD-1-KO-T-cells with IL-2 and Cyclophosphamide | NCT02863913 NCT02867345 NCT02867332 (Phase-I) | Bladder, Prostate and Renal Cell Carcinoma | [2,5] |
University of Pennsylvania, with Tmunity Therapeutics | NY-ESO-1 redirected autologous T cells | TCR-deleted and PD-1-deleted T cells | NCT03399448 | Myeloma, melanoma and several cancers | [2,5,149] |
Nanjing University Medical School | PD-1 Knockout EBV-CTLs | PD-1-KO-EBV-CTL with IL-2, Fludarabine and Cyclophosphamide | NCT03044743 (Phase-I/II) | EBV associated Malignancies | [2,5] |
Dendritic Cells (DCs) | |||||
H. Lee Moffitt Cancer Center, BMS and MultiVir, Inc. | DC-based p53 Vaccine | Ipilimumab (anti-CTLA4) Nivolumab (anti-PD-1) | NCT03406715 (Phase-II) | Small Cell Lung Cancer | [137] |
Allife Medical Sc. and Technology Co., Ltd. | DC-NK YNYY-01 (DC-NK Cells) | Pembrolizumab (anti-PD-1) Keytruda | NCT03815084 (Phase-I) | Solid tumors | [144,150] |
Bristol-Myers Squibb and Duke Cancer Inst. | DC Vaccines | Nivolumab (anti-PD-1) | NCT02529072 NCT02775292 (Phase-I) | Recurrent Brain Tumors | |
Northwest Biotherapeutics, BMS and JCCC | Autologous DCs pulsed with tumor lysate | Nivolumab (anti-PD-1) | NCT03014804 (Phase-II) | Recurrent Glioblastoma | |
University of Pennsylvania | Autologous DC pulsed peptide | Pembrolizumab (anti-PD-1) | NCT03092453 (Phase-I) | Advanced Melanoma | |
Mayo Clinic in collabration with National Cancer Inst. | Autologous DC pulsed tumor Ags | Pembrolizumab (anti-PD-1) | NCT03035331 (Phase-I/II) | Aggressive Non-Hodgkin Lymphoma | |
Oslo University Hospital in collabration with NCS and MSDC | Autologous DC | Pembrolizumab (anti-PD-1) Rituximab, GM-CSF and anti-TNF-alpha therapy | NCT02677155 (Phase-II) | Follicular Lymphoma | |
Capital Medical Univ. in collabration with Duke Univ. | Autologous DC-CIK cell | Pembrolizumab Anti-PD-1 + DC-CIK (Ph-I) Anti-PD-1 alone (Ph-II) | NCT03190811 NCT03360630 | Advanced Solid Tumors and NSCLC | |
Sun Yat-sen University | DC-CIK cell (Cytokine-induced Killer Cell) | Anti-PD-1 antibody | NCT02886897 (Phase-I) Completed, 2019 | Refractory Solid Tumors | |
Beth Israel Deaconess Medical Center | Dendritic Cell Fusion Vaccine | Pidilizumab (anti-PD-1) | NCT01067287 (Phase-I) | Multiple Myeloma | |
Cancer Insight in collabration with Elios Therapeutics, LLC | Autologous DC (TLPLDC Vaccine) | Checkpoint Inhibitor | NCT02678741 (Phase-I/II) | Metastatic Melanoma | |
Grupo Espanol Multidisciplinario del Cancer Digestivo | Autologous DC Vaccine (AVEVAC) | Avelumab (Bavencio®) (anti-PD-L1) | NCT03152565 (Phase-I/II) Completed, 2020 | Metastatic Colorectal Carcinoma | |
Dana-Farber Cancer Institute in collabration with Celgene | DC/AML Fusion Vaccine | Durvalumab (Imfinzi®) (anti-PD-L1) | NCT03059485 (Phase-II) | Acute Myelogenous Leukemia | |
Radboud University in collabration with Dutch Cancer Society | MiHA-loaded PD-L1/L2 silenced DC Vaccination | PD-L1/L2-silenced DC (siRNA silenced) | NCT02528682 (Phase-I/II) Completed, 2021 | Hematological Malignancies | |
Johns Hopkins University, USA | TLR3 agonist enhace DC activation | Anti-PD-1 in combination with DCs | - | Glioblastoma | [16] |
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Kumar, S.; Sarthi, P.; Mani, I.; Ashraf, M.U.; Kang, M.-H.; Kumar, V.; Bae, Y.-S. Epitranscriptomic Approach: To Improve the Efficacy of ICB Therapy by Co-Targeting Intracellular Checkpoint CISH. Cells 2021, 10, 2250. https://doi.org/10.3390/cells10092250
Kumar S, Sarthi P, Mani I, Ashraf MU, Kang M-H, Kumar V, Bae Y-S. Epitranscriptomic Approach: To Improve the Efficacy of ICB Therapy by Co-Targeting Intracellular Checkpoint CISH. Cells. 2021; 10(9):2250. https://doi.org/10.3390/cells10092250
Chicago/Turabian StyleKumar, Sunil, Parth Sarthi, Indra Mani, Muhammad Umer Ashraf, Myeong-Ho Kang, Vishal Kumar, and Yong-Soo Bae. 2021. "Epitranscriptomic Approach: To Improve the Efficacy of ICB Therapy by Co-Targeting Intracellular Checkpoint CISH" Cells 10, no. 9: 2250. https://doi.org/10.3390/cells10092250