Article Text
Abstract
Cancer immunotherapy and in particular monoclonal antibodies blocking the inhibitory programed cell death 1 pathway (PD-1/PD-L1) have made a significant impact on the treatment of cancer patients in recent years. However, despite the remarkable clinical efficacy of these agents in a number of malignancies, it has become clear that they are not sufficiently active for many patients. Initial evidence, for example with combined inhibition of PD-1 and CTLA-4 in melanoma and non-small cell lung cancer (NSCLC), has highlighted the potential to further enhance the clinical benefits of monotherapies by combining agents with synergistic mechanisms of action. In order to address the current progress and consider challenges associated with these novel approaches, the Society for Immunotherapy of Cancer (SITC) convened a Combination Immunotherapy Task Force. This Task Force was charged with identifying and prioritizing the most promising prospects for combinatorial approaches as well as addressing the challenges associated with developing these strategies. As a result of the extensive clinical benefit and tolerable side effects demonstrated with agents inhibiting the PD-1 pathway, an overview of current evidence to support its promising potential for use as a backbone in combination strategies is presented. In addition, key issues in the development of these strategies including preclinical modeling, patient safety and toxicity considerations, clinical trial design, and endpoints are also discussed. Overall, the goal of this manuscript is to provide a summary of the current status and potential challenges associated with the development and clinical implementation of these strategies.
- Immunotherapy
- Combination
- Checkpoint inhibitors
- Preclinical models
- Clinical trial
- Endpoints
- 4-HT
- 4-hydroxytamoxifen
- AE
- Adverse events
- CAR
- Chimeric-antigen receptor
- CRS
- Cytokine release syndrome
- CTLA-4
- Cytotoxic T lymphocyte associated protein 4
- DC
- Dendritic cell
- DLT
- Dose-limiting toxicity
- DMBA
- 7,12-dimethylbenz[a]anthracene
- DRR
- Durable response rate
- DT
- Diphtheria toxin
- FOXN1
- Forkhead box protein N1
- GEMM
- Genetically engineered mouse model
- GITR
- Glucocorticoid-induced tumor necrosis factor receptor-related protein
- GVHD
- Graft-versus-host disease
- IDO
- Indoleamine 2,3-dioxgenase
- IL
- Interleukin
- irAE
- Immune-related adverse event
- IRB
- Institutional review board
- irRC
- Immune-related response criteria
- MAD
- Maximum administered dose
- MBED
- Maximum biologically-effective dose
- MCA
- Methylcholanthrene
- MDSC
- Myeloid derived suppressor cells
- MSI
- Microsatellite instability
- MT
- Metallothionein-I
- MTD
- Maximum tolerated dose
- mWHO
- Modified World Health Organization
- NK
- Natural killer cell
- NKT
- Natural killer T cell
- NSCLC
- Non-small cell lung cancer
- ORR
- Objective response rate
- OS
- Overall survival
- PD-1
- Programed cell death 1
- PD-L1
- Programed cell death ligand 1
- PFS
- Progression-free survival
- PyMT
- Polyoma middle T antigen
- RAG-1
- Recombination activation gene
- RECIST
- Response evaluation criteria in solid tumors
- SCID
- Severe combined immunodeficiencies
- SITC
- Society for Immunotherapy of Cancer
- SV40
- Simian virus 40
- TPA
- 12-O-tetradecanoylphorbol-13-acetate
- Treg
- Regulatory T cell
- T-VEC
- Talimogene laherparepvec
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