In Vitro-Transcribed mRNA Chimeric Antigen Receptor T Cell (IVT mRNA CAR T) Therapy in Hematologic and Solid Tumor Management: A Preclinical Update
Abstract
:1. Introduction
2. Effect of IVT mRNA CAR T Cells in Preclinical Studies Related to Hematologic Malignancies
2.1. Chronic Lymphocytic Leukemia (CLL)
2.2. Acute Lymphoblastic Leukemia (ALL)
2.3. Acute Myeloid Leukemia (AML)
3. Effect of IVT mRNA CAR T Cells in Preclinical Studies Related to Solid Malignancies
3.1. Mesothelioma and Colon Cancers
3.2. Ovarian and Breast Cancers
3.3. Neuroblastoma and Glioblastoma Multiforme
3.4. Melanoma
4. IVT mRNA-Based Clinical Trials in Hematologic and Solid Tumors
5. Future Directions
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
CAR T | Chimeric antigen receptor T cell |
IVT mRNA CAR T | in vitro transcribed anti-mRNA-based CAR T cells |
TCR | T cell receptor |
CAR | Chimeric antigen receptor |
scFv | Single-chain variable fragment |
TAA | Tumor-associated antigen |
EGFR | Epidermal growth factor receptor |
CEA | Carcinoembryonic antigen |
ERBB2 | Epidermal growth factor receptor 2 |
PSMA | Prostate-specific membrane antigen |
B-CLL | B cell chronic lymphocytic leukemia |
B-NHL | B cell non-Hodgkin’s lymphoma |
FcγR | Fragment c gamma receptor |
BiTEs | Bispecific T cell engager |
AML | Acute myeloid leukemia |
NKG2D | Natural killer group 2D |
ESFT | Ewing’s sarcoma family of tumors |
TGFβRIImut | Transforming growth factor β receptor II frameshift mutation |
GM-CSF | Granulocyte–macrophage colony Stimulating factor |
FRα | Folate receptor alpha |
EpCAM | Epithelial cell adhesion molecule |
GBM | Glioblastoma multiforme |
gp100 | Glycoprotein 100 |
TRP-1 | Tyrosinase-related protein 1 |
TRP-2 | Tyrosinase-related protein 2 |
GD2 | Disialoganglioside 2 |
L1-CAM | L1 cell adhesion molecule |
MCSP | Melanoma-associated chondroitin sulfate proteoglycan |
TETARs | T cells expressing two additional receptors |
CSPG4 | Chondroitin sulfate proteoglycan 4 |
NKT | Natural killer T |
VEGFR2 | Vascular endothelial growth factor receptor 2 |
CARTmeso cells | CAR T cells redirected for mesothelin |
IgG | Immunoglobulin G |
PD1 | Programmed cell death protein 1 |
PDL1 | Programmed death ligand 1 |
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Type of Study | Target | Dose and Administration | Tumor Type | Results | Reference |
---|---|---|---|---|---|
in vitro | CD19 | - | Leukemia, lymphoma | Cytotoxicity | [10] |
in vivo | CD19 | Multiple doses 5 × 106; i.p. | lymphoma | Tumor growth inhibition | [11] |
in vitro | CD19 | - | Leukemia, lymphoma | Degranulation and IFN-γ secretion | [12] |
In vitro and in vivo | CD37 | Multiple doses 107; intratumorally | Lymphoma | Cytotoxicity; tumor growth reduction | [13] |
in vivo | Canine CD20-ζ | 2.4 ×108, 5.4 × 107, 1.1 × 108 cells i.v.; 1.16 × 108 cells i.n. | Lymphoma | Antitumor activity | [14] |
In vitro and in vivo | CD19 | 5 × 106, 1 × 107, or 2.5 × 107 cells; i.v. | Leukemia | Cytotoxicity | [15] |
in vivo | CD19 | Multiple doses 1 × 107 or 2 × 107, 5 × 106 and 5 × 106; i.v. | Acute lymphoblastic leukemia | Increased cytotoxicity with split doses | [16] |
in vivo | CD19 | 20 × 106 or 10 × 106; i.v. | Acute lymphoblastic leukemia | Abrogation of CD19-based cytotoxicity due to the presence of IgG1-CH2CH3 spacer in CAR construct | [17] |
in vivo | CD19 | 2 × 107; i.v. | Acute lymphoblastic leukemia | Cytotoxicity | [23] |
In vitro and in vivo | CD33 | 5 × 106; i.v. | Acute myeloid leukemia | Cytotoxicity; tumor growth reduction | [21] |
in vivo | CD123 | 1 × 107; i.v. | Acute myeloid leukemia | Cytotoxicity | [22] |
Type of Study | Target | Dose and Administration | Tumor Type | Results | Reference |
---|---|---|---|---|---|
in vivo | Mesothelin | 10–15 × 106; intratumorally | Mesothelioma | Tumor growth reduction | [26] |
in vitro | NKG2D | - | Ewing’s sarcoma family of tumors | Short-lived expression of mRNA | [27] |
in vitro and in vivo | Her2 | 5 × 106; intratumorally or i.p. | Ovarian cancer | Cytotoxicity; tumor growth reduction | [29] |
in vitro and in vivo | FRα | Multiple doses 107; i.p. | Ovarian cancer | Tumor growth inhibition | [30] |
in vitro and in vivo | Mesothelin | 1 × 107 or 1 × 108; i.p. | Ovarian cancer | Tumor growth inhibition | [31] |
in vivo | Epithelial cell adhesion molecule | 1 × 107; i.p. | Ovarian and colorectal cancer | Tumor growth inhibition | [32] |
in vitro and in vivo | c-Met | 2 × 107; i.p. | Breast and ovarian cancer | Cytotoxicity; tumor growth inhibition | [33] |
in vivo | Disialoganglioside GD2 | 5 × 106; intratumorally | Neuroblastoma | Cytotoxicity | [35] |
in vitro | EGFR | - | Glioblastoma | Cytotoxicity | [36] |
in vitro and in vivo | MCSP | Melanoma | Cytotoxicity | [38] | |
in vitro | gp100/HLA-A2 or MCSP | - | Melanoma | Cytotoxicity | [39] |
in vitro | gp100 and MCSP | - | Melanoma | Cytotoxicity | [40] |
in vitro | gp100 and CSPG4 | - | Melanoma | Cytotoxicity | [41] |
in vitro | CSPG4 | - | Melanoma | Cytotoxicity | [43] |
in vivo | VEGFR2 | 5 × 106; i.v. | Melanoma | Tumor growth reduction | [45] |
Phase | National Clinical Trial (NCT) No. | Target | Dose and Administration | Tumor Type | Results | Reference |
---|---|---|---|---|---|---|
Early Phase 1 | NCT02623582 | CD123 | 3 or 6 doses 4 × 106cells/kg; i.v. | Relapsed/refractory acute myeloid leukemia | Safe method; no antitumor effects | [46] |
Early Phase 1 | NCT02277522 (adult); NCT02624258 (pediatric) | CD19 | 6 doses in the range 7.46 × 105–2.11 × 106; i.v. | Hodgkin’s lymphoma | No severe toxicity | [47] |
Phase 1 | NCT01355965 | Mesothelin | Cohort 1: 1 × 108 and 1 × 109; Extended cohort: 3 doses of 1 × 108 cells followed by 3 doses of 1 × 109; i.v. | Malignant pleural mesothelioma | Severe anaphylaxis in one patient; partial antitumor response | [48,50] |
Phase 1 | NCT01897415 | Mesothelin | 3 doses weekly 1–3 × 108/m2; i.v. | Metastatic pancreatic ductal adenocarcinoma | Increased expression of antitumor antibodies | [51] |
Phase 0 | NCT01837602 | c-Met | 3 × 107 or 3 × 108; intratumoral | Metastatic breast cancer | Anti-cancer effects | [33] |
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Soundara Rajan, T.; Gugliandolo, A.; Bramanti, P.; Mazzon, E. In Vitro-Transcribed mRNA Chimeric Antigen Receptor T Cell (IVT mRNA CAR T) Therapy in Hematologic and Solid Tumor Management: A Preclinical Update. Int. J. Mol. Sci. 2020, 21, 6514. https://doi.org/10.3390/ijms21186514
Soundara Rajan T, Gugliandolo A, Bramanti P, Mazzon E. In Vitro-Transcribed mRNA Chimeric Antigen Receptor T Cell (IVT mRNA CAR T) Therapy in Hematologic and Solid Tumor Management: A Preclinical Update. International Journal of Molecular Sciences. 2020; 21(18):6514. https://doi.org/10.3390/ijms21186514
Chicago/Turabian StyleSoundara Rajan, Thangavelu, Agnese Gugliandolo, Placido Bramanti, and Emanuela Mazzon. 2020. "In Vitro-Transcribed mRNA Chimeric Antigen Receptor T Cell (IVT mRNA CAR T) Therapy in Hematologic and Solid Tumor Management: A Preclinical Update" International Journal of Molecular Sciences 21, no. 18: 6514. https://doi.org/10.3390/ijms21186514