Immune Checkpoints and CAR-T Cells: The Pioneers in Future Cancer Therapies?
Abstract
:1. Introduction
2. Immune Checkpoints Inhibitors: The Pioneering Immunotherapy
2.1. Mechanisms of CTLA-4 Blockade for Cancer Treatment
2.2. Mechanisms of PD-1/PD-L1 Blockade for Cancer Therapy
3. Beyond CTLA-4 and PD-1/PD-L1 Inhibition: New Immune-Landscape to Break Cancer
3.1. LAG-3
3.2. TIM-3
3.3. TIGIT
3.4. VISTA
3.5. B7-H3
3.6. BTLA
4. Bispecific T-Cell Engager (BiTE) Molecules
5. Cell Therapy with Chimeric Antigen Receptor T (CAR-T)-Based Strategies
6. Allogeneic CAR-T
6.1. CAR-T Cell Manufacturing from A Stem Cell Transplant Donor
6.2. Virus-Specific CAR-T Cells
6.3. Gene Editing
7. Overcoming CAR-T Cell-Based Approaches Boundaries
8. Future Immune Checkpoints Candidates: Boosting CAR-T Therapy Effectiveness
9. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Cancer Type | FDA Approved Drug | FDA Approval Year |
---|---|---|
Melanoma | Ipilimumab | 2011 |
Nivolumab | 2014 | |
Pembrolizumab | 2014 | |
Nivolumab + Ipilimumab | 2015 | |
Pediatric Melanoma | Ipilimumab | 2017 |
Adjuvant (pre-surgical) treatment for stage III Melanoma | Pembrolizumab | 2019 |
NSCLC | Pembrolizumab | 2015 |
Nivolumab | 2015 | |
Atezolizumab | 2016 | |
Durvalumab | 2018 | |
First-line treatment of patients with stage III NSCLC | Pembrolizumab | 2019 |
NSCLC | Atezolizumab (in combination with chemotherapy) | 2019 |
Hodgkin lymphoma | Nivolumab | 2016 |
Hodgkin lymphoma (adult and pediatric patients) | Pembrolizumab | 2017 |
Urothelial carcinoma | Atezolizumab | 2016 |
Nivolumab | 2017 | |
Durvalumab | 2017 | |
Avelumab | 2017 | |
Pembrolizumab | 2017 | |
HNSCC | Pembrolizumab | 2016 |
Nivolumab | 2016 | |
First-line treatment of patients with metastatic or recurrent HNSCC | Pembrolizumab | 2019 |
Merkel cell carcinoma | Avelumab | 2017 |
Pembrolizumab | 2018 | |
MSI-HI solid tumors | Pembrolizumab | 2017 |
Nivolumab + Ipilimumab | 2018 | |
MSI-HI CRC | Nivolumab | 2017 |
HCC | Nivolumab | 2017 |
Pembrolizumab | 2018 | |
Gastric and gastroesophageal carcinoma | Pembrolizumab | 2017 |
Advanced ESCC | Pembrolizumab | 2019 |
Renal cell carcinoma | Nivolumab | 2015 |
Nivolumab + Ipilimumab | 2018 | |
Avelumab | 2019 | |
Cervical cancer | Pembrolizumab | 2018 |
PMBCL | Pembrolizumab | 2018 |
SCLC | Nivolumab | 2018 |
Pembrolizumab | 2019 | |
Extensive-stage SCLC | Atezolizumab | 2019 |
CSCC | Cemiplimab | 2018 |
TNBC | Atezolizumab | 2019 |
Endometrial carcinoma | Pembrolizumab | 2019 |
NMIBC | Pembrolizumab | 2020 |
Advanced HCC | Nivolumab + Ipilimumab | 2020 |
Extensive-stage SCLC | Durvalumab (in combination with chemotherapy) | 2020 |
Metastatic NSCLC | Nivolumab + Ipilimumab | 2020 |
Metastatic or recurrent NSCLC | Nivolumab + Ipilimumab (in combination with chemotherapy) | 2020 |
Untreated HCC | Atezolizumab (in combination with Bevacizumab, an anti-VEGF-A) | 2020 |
Unresectable advanced, recurrent or metastatic ESCC | Nivolumab | 2020 |
Unresectable or metastatic TMB-H solid tumors | Pembrolizumab | 2020 |
Recurrent or metastatic CSCC | Pembrolizumab | 2020 |
MSI-H or dMMR CRC | Pembrolizumab | 2020 |
BRAF V600 mutation-positive advanced melanoma | Atezolizumab (plus cobimetinib and vemurafenib) | 2020 |
Molecules | Ligands | Receptor Expression | Function | Drugs | References |
---|---|---|---|---|---|
CTLA-4 | B7-1(CD80), B7-2(CD86) | Activated T cells, Tregs | Co-inhibition | Ipilimumab *, Tremelimumab | [33,34,41] |
PD-1 | PD-L1,PD-L2 | TILs, B cells, Effector T cells, Tregs NK cells macrophages, subsets of DC | Co-inhibition | Nivolumab *, Pembrolizumab * Cemiplimab * | [49,50,51,52] |
PD-L1 | PD-1, B7-1 | DCs, T cells monocytes, macrophages, mast cells, B cells, NK cells | Attenuate development of T cells in inflamed tissues | Atezolizumab *, Avelumab *, Durvalumab * | [49,50,51,52] |
LAG3(CD22) | MHC-II, LSECtin, Galectin-3 | Activated T cells, B cells, Tregs, NK cells, DCs | Negative regulation of T-cell expansion, DC activation | IMP321/Eftilagimod alpha, Relatlimab /BMS- 986016, LAG525, MK-4280, Sym022, REGN3767, TSR-033 | [53,54,55,56,57] |
TIM3 (HAVCR2) | Galectin9, PtdSer, HMGB1, CEACAM-1 | Activated T cells, NK cells, DCs, B cells, Tregs, monocytes | Maintaining peripheral tolerance | TSR-022, MBG453, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, | [22,58,59,60] |
TIGIT (WUCAM/ Vstm3/Vsig) | CD155, CD112 | NK Cells, T cells | Negative regulation of T cells activity, DC tolerization | MK-7684, Etigilimab /OMP-313 M32, AB-154, Tiragolumab/ MTIG7192A/RG-6058, BMS-986207, ASP-8374 | [31,60,61,62,63] |
VISTA (PD-1H/ DD1α/Gi24/ Dies1/B7-H5) | VSIG-3 | T Cells, Myeloid cells | T-cell negative regulation; CD4 + T cells suppression | JNJ-61610588 CA-170 | [22,31,64,65,66,67] |
B7-H3 (CD276) | Unknow | Activated T cells, DCs, NK cells, tumor tissue monocytes | Co-inhibition | Enoblituzumab /MGA271, MGD009, 8H9 | [68,69,70,71,72] |
BTLA (CD272) | HVEM | Mature B cells, Tregs, T cells, DCs, macrophages | Co-inhibition | TAB004/JS004 | [31,73,74,75] |
Interventions | Mechanism of Action | Cancer | Clinical Trial Phase | Study Start Date | The Status | ClinicalTrials.gov Identifier |
---|---|---|---|---|---|---|
Anti-GD2, PSMA, Muc1, or Mesothelin | Recognition of the tumor-related antigens via ex vivo training of T-cell with GD2, mesothelin, PSMA, and Muc-1 | Cervical cancer | Phase I/II | 2017 | Recruiting | NCT03356795 |
huCART-meso cells | ex vivo training of T-cell and depletion of lymphocytes | Pancreatic cancer | Phase I | 2017 | Active, not recruiting | NCT03323944 |
Anti-TM4SF1 and EpCAM CAR-T therapy | Recognition of the tumor-related antigens via ex vivo training of T-cell with TM4SF1 and EpCAM | Advanced solid neoplasia | Not Applicable | 2019 | Not yet recruiting | NCT04151186 |
Anti-meso CAR-T cells in combination with Fludarabine and Cyclophosphamide | ex vivo training of T-cell to identify mesothelin. DNA synthesis inhibition. Protein synthesis inhibition | Ovarian cancer | Phase I | 2019 | Recruiting | NCT03799913 |
Anti-CD19, CD20, CD22, CD30, CD38, CD70, and CD123 4th generation CAR-T cells | ex vivo training of T-cell to identify CD19, CD20, CD22, CD30, CD38, CD70, and CD123 | B cell malignancies | Phase I/II | 2017 | Recruiting | NCT03125577 |
Anti-VEGFR2 CAR-T cells therapy in combination with cyclophosphamide, Aldesleukin, and Fludarabine | ex vivo training of T-cell against VEGFR2, inhibiting tumor growth, upregulating T cell production, and suppression of tumor growth, respectively | Metastatic cancers, metastatic melanoma, and renal cancer | Phase I/II | 2010 | Terminated (no objective responses) | NCT01218867 |
Anti-CEA CAR-T cells | Recognition of the tumor-related antigen via ex vivo training of T-cell with the carcinoembryonic antigens | Liver metastases and pancreatic cancer | Phase I | 2017 | Active, not recruiting | NCT02850536 |
Anti-CEA CAR-T cells | Recognition of the tumor-related antigen via ex vivo training of T-cell with the carcinoembryonic antigens | Peritoneal carcinomatosis, Peritoneal metastases, Colorectal cancer, Gastric cancer, Breast cancer, Pancreas cancer | Phase I | 2018 | Active, not recruiting | NCT03682744 |
Anti-CD147 CAR-T cell | Recognition of the tumor-related antigen via ex vivo training of T-cell with the CD147 | Advanced hepatocellular carcinoma | Phase I | 2019 | Recruiting | NCT03993743 |
Anti-CD147 CAR-T cell | Recognition of the tumor-related antigen via ex vivo training of T-cell with the CD147 | Recurrent glioblastoma | Early Phase I | 2019 | Recruiting | NCT04045847 |
Anti-EGFR806 CAR-T cell | Recognition of the tumor-related antigen via ex vivo training of T-cell with the EGFR806 | Central nervous system tumor, Pediatric glioma, Ependymoma, Medulloblastoma, Germ cell tumor, Atypical teratoid/rhabdoid tumor, Primitive, Neuroectodermal tumor, Choroid plexus carcinoma, Pineoblastoma | Phase I | 2019 | Recruiting | NCT03638167 |
Anti-Muc-1 CAR-T cells | Recognition of the tumor-related antigens via ex vivo training of T-cell with Muc-1 | Intrahepatic cholangiocarcinoma | Phase I/II | 2018 | Recruiting | NCT03633773 |
Anti-EpCAM CAR-T cells | Recognition of the tumor-related antigens via ex vivo training of EpCAM | Nasopharyngeal carcinoma, Breast Cancer | Phase I | 2016 | Recruiting | NCT02915445 |
Anti-mesothelin CAR-T cells | ex vivo training of T-cell to recognize mesothelin. | Pancreatic cancer | Phase I | 2017 | Active, not recruiting | NCT03323944 |
Anti-GPC3 CAR-T cell | CAR-T cells against Glypican-3 positive hepatocellular tumor cells | Hepatocellular carcinoma | Phase I | 2016 | Recruiting | NCT02905188 |
NCT Number | Type of Malignancy | Status | Location | Summary of Study |
---|---|---|---|---|
NCT03287817 | -DLBCL -Relapse/Refractory DLBCL | Recruiting | USA | A phase I/II study aiming to evaluate the efficacy of AUTO3 (anti CD19, CD22 CAR-T cell) followed by anti PD-1 antibody for limited time |
NCT04213469 | B cell lymphoma | Recruiting | China | Evaluating the efficacy of PD-1 knockout CD19-directed CAR-T cell |
NCT02650999 | -DLBCL -Follicular lymphomas -Mantle cell lymphomas | Active, not recruiting | USA | Phase I/II study of pembrolizumab in patients with relapsed/refractory lymphoma after CTL019 |
NCT03298828 | -Acute lymphoblastic leukemia -Burkitt Lymphoma | Not yet recruiting | China | A phase I study determining the efficacy of CD19 CAR and PD-1 knockout engineered T cells |
NCT03932955 | Relapsed/refractory B cell lymphoma | Recruiting | China | A phase I study evaluating the efficacy and safety of MC-19PD-1 CAR-T cells |
NCT03208556 | Relapsed/refractory B cell lymphoma | Unknown | China | A phase I study determining the efficacy and safety of iPD-1 CD19-CAR-T cells |
NCT03540303 | Relapsed non-Hodgkin lymphoma | Unknown | China | A phase I study assessing the efficacy and safety of Cytoplasmic activated PD-1 CAR-T cells |
NCT04163302 | Relapsed/refractory B cell lymphoma | Recruiting | China | A phase II study determining the efficacy and safety of CD19-PD-1 CAR-T cells |
NCT04162119 | Relapsed/refractory Multiple myeloma | Recruiting | China | A phase II study evaluating the safety and efficacy of BCMA-PD1-CART cells |
NCT04134325 | Relapsed/refractory Hodgkin lymphoma | Recruiting | USA | An early phase I study determining the efficacy of Nivolumab and Pembrolizumab after anti-CD30 CAR-T cell therapy |
ChiCTR-OIC-17011310 | Refractory/aggressive non-Hodgkin lymphoma | Recruiting | China | A phase I/II study determining the efficacy of dPD-1 hCD19CAR-T cells |
ChiCTR1800020306 | Relapsed/refractory B cell lymphoma | Recruiting | China | A phase II study assessing the efficacy and safety of PD-1 knockdown engineered anti-CD19 CAR-T cells |
ChiCTR1800018713 | Relapsed/refractory non-Hodgkin lymphoma | Recruiting | China | Evaluating the efficacy and safety of PD-1 knock out CD19/CD20/CD22/CD30 directed CAR-T cells |
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Hosseinkhani, N.; Derakhshani, A.; Kooshkaki, O.; Abdoli Shadbad, M.; Hajiasgharzadeh, K.; Baghbanzadeh, A.; Safarpour, H.; Mokhtarzadeh, A.; Brunetti, O.; Yue, S.C.; et al. Immune Checkpoints and CAR-T Cells: The Pioneers in Future Cancer Therapies? Int. J. Mol. Sci. 2020, 21, 8305. https://doi.org/10.3390/ijms21218305
Hosseinkhani N, Derakhshani A, Kooshkaki O, Abdoli Shadbad M, Hajiasgharzadeh K, Baghbanzadeh A, Safarpour H, Mokhtarzadeh A, Brunetti O, Yue SC, et al. Immune Checkpoints and CAR-T Cells: The Pioneers in Future Cancer Therapies? International Journal of Molecular Sciences. 2020; 21(21):8305. https://doi.org/10.3390/ijms21218305
Chicago/Turabian StyleHosseinkhani, Negar, Afshin Derakhshani, Omid Kooshkaki, Mahdi Abdoli Shadbad, Khalil Hajiasgharzadeh, Amir Baghbanzadeh, Hossein Safarpour, Ahad Mokhtarzadeh, Oronzo Brunetti, Simon C. Yue, and et al. 2020. "Immune Checkpoints and CAR-T Cells: The Pioneers in Future Cancer Therapies?" International Journal of Molecular Sciences 21, no. 21: 8305. https://doi.org/10.3390/ijms21218305