Background
The tumor microenvironment
Cells of the tumor microenvironment
Immune cells - T lymphocytes
B lymphocytes
Natural killer cells
Dendritic cells
Tertiary lymphoid structures
Macrophages
Neutrophils
Myeloid-derived suppressor cells
Cancer associated fibroblasts
The immunosuppressive TME: ECM, hypoxia and metabolism
Cancer immunotherapy
Drugs stimulating the host immune response
Monoclonal antibodies
Immune checkpoint inhibitors
Drugs promoting immune cell recruitment into the tumor
Oncolytic viruses
Cytokines
Cancer vaccines
Vaccine and antigen | Indication | Key observations |
---|---|---|
GM-CSF–IL-4 DCs with or without HLA-A*0201-restricted peptides or peptides alone | Metastatic prostate cancer | One of the first studies that tested the immunogenicity of DCs |
GM-CSF–IL-4 DCs with peptides, tumour lysates or autologous tumour-eluted peptides | Stage IV melanoma, renal cell carcinoma and malignant glioma | Loading DCs with complex antigen preparations; Objective clinical responses |
Blood DCs and idiotype antigens | Multiple myeloma | Immunogenicity of DCs; Tumour regression |
Mature GM-CSF–IL-4 DCs and peptides | Stage IV melanoma | Well-controlled and validated vaccine manufacture process; Testing mature DCs; Immunogenicity; Objective clinical responses |
CD34+ HPC-derived DCs and peptides | Stage IV melanoma | One of the first studies to test CD34+ HPC-derived DCs; Loading vaccines with a mixture of well-defined peptides; Durable immune responses in long-term survivors; Objective clinical responses |
FLT3 ligand-expanded blood DCs and altered peptides | Advanced CEA+ cancer | Immunogenicity; Objective clinical responses |
Immature GM-CSF–IL-4 DCs | Healthy volunteers | Antigen-specific inhibition of effector T cell function after injection of immature DCs |
GM-CSF–IL-4 DCs and tumour lysates | Refractory pediatric solid tumors | Immunogenicity; Objective clinical responses |
Mature cryopreserved GM-CSF–IL-4 DCs | Stage IV melanoma | Immunogenicity |
DCs loaded with autologous tumour RNA | Colon cancer | Feasibility; Immunogenicity |
DCs loaded with killed allogeneic tumour cells | Stage IV melanoma | Immunogenicity; Durable objective clinical responses; Long-term survival |
Monocyte-derived DCs loaded with the NK T cell ligand α-galactosylceramide | Advanced cancer | Adjuvant effect of NK cell activation on CD8+ T cell-mediated immune response |
Monocyte-derived DCs | Melanoma | In vivo identification of antigen-specific immune response by PET imaging in patients |
Comparative study of CD34+ HPC-derived Langerhans cells versus monocyte-derived DCs | Melanoma | Langerhans cell-based vaccines stimulated significantly greater tyrosinase-HLA-A*0201 tetramer reactivity than the monocyte-derived DC vaccines |
Type 1-polarized monocyte-derived DCs | Glioma | Combination of DC vaccination with polyICLC to trigger systemic inflammation driven by type I interferon family members |
Drugs inducing metabolic changes in the tumor microenvironment
Cellular therapy of cancer
Other new immunotherapy drugs and unmet requirements
Targets and radiopharmaceuticals for imaging tumor-infiltrating cells
Cell labelling strategies
Ex vivo labelling
In vivo labelling
Imaging tumor-infiltrating lymphocytes
Ex vivo labelling
In vivo labelling
Imaging tumor-infiltrating NK cells
Ex vivo labelling
In vivo labelling
Imaging tumor-associated macrophages
Ex vivo labelling
In vivo labelling
Indirect labelling
Conclusion
Drug | Target | Clinical use | Mechanism of action | Labelling agent |
---|---|---|---|---|
Rituximab | CD20 | B-Cell non-Hodgkin lymphoma, Chronic lymphocytic leukemia. | Direct induction of apoptosis. | 99mTc |
Ipilimumab/ Tremelimumab | CTLA-4 | Metastatic melanoma, renal cell carcinoma, hepatocellular carcinoma. | Inhibition of CTLA-4 signaling | 64Cu-DOTA |
Pembrolizumab/ Nivolumab | PD-1 | Melanoma, non-small-cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, squamous cell carcinoma of the head and neck, gastric cancer, cervical cancer, urothelial carcinoma, colorectal cancer with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer. | Inhibition of PD-1 (expressed in lymphocytes), induction of tumor-specific T cell CD8+ activation against cancer | 64Cu-DOTA; 89Zr-DFO; 111In-DTPA |
Atezolizumab | PD-L1 | Urothelial cancer, non-small cell lung cancer, small cell lung cancer, triple negative breast cancer. | Inhibition of PD-L1 (expressed in tumor cells), induction of tumor-specific T cell CD8+ activation against cancer | 89Zr-DFO; 111In-DTPA |
Durvalumab | PD-L1 | Urothelial carcinoma, non-small cell lung cancer. | Inhibition of PD-L1 (expressed in tumor cells), induction of tumor-specific T cell CD8+ activation against cancer | 89Zr-DFO |
Avelumab | PD-L1 | Merkel -cell carcinoma, renal cell carcinoma, urothelial carcinoma. | Inhibition of PD-L1 (expressed in tumor cells), induction of tumor-specific T cell CD8+ activation against cancer | 89Zr-DFO |
Interleukin-2 | IL2 receptors | Metastatic renal cell carcinoma and metastatic melanoma | T cell activation and expansion | 123I; 99mTc; 18F |
Interferon alfa-2B | INF- α receptors | Hairy cell leukemia, Malignant melanoma, follicular lymphoma, AIDS related Kaposi Sarcoma. | Immunomodulating activities, including cytotoxicity of lymphocytes. Upregulation of Th1 T-helper cell subsets | 131I |
Compound | Labelling agent | Target/Mechanism | Application |
---|---|---|---|
T lymphocytes | 111In-oxine | Tumor infiltration/Cytokine production | Evaluation of immunotherapy/adoptive cell transfer efficacy |
89Zr-oxine | |||
[18F]FDG | |||
64Cu-gold nanoparticles | |||
SPIO | |||
19F-Perfluorcarbon | |||
mAb-TCR-complex | 64Cu | Tumor infiltration | T cell homing |
Interleukin-2 | 123I | Interleukin-2 receptors on activated lymphocytes | Evaluation of immunotherapy/adoptive cell transfer efficacy |
99mTc | |||
18F | |||
Anti-CD8 cys diabody | 89Zr | CD8 on activated T cells | Evaluation of immunotherapy efficacy |
NK cells | 111In-oxine | NK cell infiltration | Evaluation of adoptive cell transfer efficacy – NK cell homing |
89Zr-oxine | |||
[18F]FDG | |||
SPIO | |||
Anti-CD56 mAb | 99mTc | CD56 on NK cells | Evaluation of adoptive cell transfer efficacy – NK cell homing |
Macrophages | 111In-oxine | Tumor infiltration by macrophages | Pre-clinical evaluation of TAMs |
89Zr-Nanoparticles | |||
[18F]FDG | |||
19F-Nanoparticles | |||
SPIO | |||
(R)PK11195 | 11C | translocator protein (TSPO) expressed by TAMs | Pre-clinical evaluation of TAMs |
Anti-Mannose receptor nanobody | 99mTc | Mannose receptor on TAMs | Pre-clinical evaluation of TAMs |
18F |