Immune Checkpoint Targeting in Cancer Therapy: Towards Combination Strategies with Curative Potential

By Padmanee Sharma, James P. Allison. Cell, 2015

2,204 citations recorded by the source corpus.

Research in two fronts has enabled the development of therapies that provide significant benefit to cancer patients. One area stems from a detailed knowledge of mutations that activate or inactivate signaling pathways that drive cancer development. This work triggered the development of targeted therapies that lead to clinical responses in the majority of patients bearing the targeted mutation, although responses are often of limited duration. In the second front are the advances in molecular immunology that unveiled the complexity of the mechanisms regulating cellular immune responses. These developments led to the successful targeting of immune checkpoints to unleash anti-tumor T cell responses, resulting in durable long-lasting responses but only in a fraction of patients. In this review we discuss the evolution of research in these two areas and propose that intercrossing them and increasing funding to guide research of combination of agents represent a path forward for the development of curative therapies for the majority of cancer patients.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/258d74a7aa6b74736d1a1c26af6af650a00111b2

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Citations in the corpus

Engineering T cells with Customized Therapeutic Response Programs Using Synthetic Notch Receptors (2016, neutral): “Antibody therapies for cancer that help to elicit an anti-tumor immune response by releasing the breaks on T cells are having unprecedented curative effects in patients with cancers that were otherwise considered terminal (Sharma and Allison, 2015).”
EMERGING BIOLOGICAL PRINCIPLES OF METASTASIS (2017, neutral): “Finally, the clinical and biological impact of various immunotherapies, particularly checkpoint inhibitors (Sharma and Allison, 2015), on metastases is sure to be a continued area of active research, even offering the hope of seeking out and eliminating metastatic deposits.”
Transcriptional Landscape of Human Tissue Lymphocytes Unveils Uniqueness of Tumor-Infiltrating T Regulatory Cells (2016, background): “Therefore, the search for agonists of co-stimulatory complexes or antagonists of inhibitory molecules to potentiate antigen-specific T cell responses is a primary goal of current anti-tumor research (Sharma and Allison, 2015; Zitvogel et al., 2013).”
Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy (2017, background): “Antibodymediated inactivation of inhibitory molecules, such as cytotoxic T lymphocyte–associated protein 4 (CTLA-4) and programmed death-ligand 1 (PD-L1), has produced durable responses in a subset (20 to 30%) of patients with advanced tumors (23).”
Next generation of immune checkpoint therapy in cancer: new developments and challenges (2018, background): “New inhibitory pathways are under investigation, and drugs blocking LAG-3, TIM-3, TIGIT, VISTA, or B7/H3 are being investigated.”
Current state of melanoma diagnosis and treatment (2019, background): “Pembrolizumab has a response rate of ~37–38% in patients with metastatic melanoma, and an overall survival of 74% at 12 months.(118) Treatment with nivolumab showed a ~40% response rate with a 12 month overall survival”