The future of immune checkpoint therapy

  title={The future of immune checkpoint therapy},
  author={Padmanee Sharma and James P. Allison},
  pages={56 - 61}
Immune checkpoint therapy, which targets regulatory pathways in T cells to enhance antitumor immune responses, has led to important clinical advances and provided a new weapon against cancer. This therapy has elicited durable clinical responses and, in a fraction of patients, long-term remissions where patients exhibit no clinical signs of cancer for many years. The way forward for this class of novel agents lies in our ability to understand human immune responses in the tumor microenvironment… 
Alternative Checkpoints as Targets for Immunotherapy
Alternative checkpoints that can be targeted to improve cytotoxic lymphocyte function while harnessing other components of the immune system are discussed.
Immune Checkpoint Therapy and the Search for Predictive Biomarkers
More work is needed to provide a better understanding of the mechanisms that elicit tumor rejection, which will enable identification of appropriate biomarkers, reveal new targets, provide data to guide combination studies, and eventually dictate a platform that allows more patients to derive clinical benefit with immune checkpoint therapy.
Lessons learned from the blockade of immune checkpoints in cancer immunotherapy
The current understanding of the mechanisms by which resistance to checkpoint blockade immunotherapy occurs is summarized, and how actionable combination strategies may be derived to improve clinical outcomes for patients is outlined.
Reinstating endogenous antitumor immunity: The concept of therapeutic management of cancer
By understanding the immune tumor microenvironment, this work can now target key pathways that suppress endogenous antitumor responses, thereby re-instating such immune responses and identifying novel targets for immune therapies.
Regulation of Cancer Immune Checkpoints: Molecular and Cellular Mechanisms and Therapy
In this work, insights are gained into the molecular control of immune checkpoint receptors and ligands, which extended knowledge on the immune system and provided alternative strategies for developing checkpoint inhibitors.
Current Strategies to Enhance Anti-Tumour Immunity
This review summarizes the recent advances in immune therapies and discusses the importance of combination therapies in the treatment of cancers.
T Lymphocyte-Based Cancer Immunotherapeutics.
Immune cell therapy for hepatocellular carcinoma
This review focuses on hepatocellular carcinoma among other solid tumors and discusses the current status and future of immune cell therapy in cancer immunotherapy.


Combining Radiation and Immunotherapy: A New Systemic Therapy for Solid Tumors?
A comprehensive overview of the early clinical and preclinical evidence behind the combination of immunomodulating agents with radiation to induce a phenomenon known as the abscopal effect, whereby localized radiation results in immune-mediated tumor regression in disease sites well outside of the radiation field.
The blockade of immune checkpoints in cancer immunotherapy
  • D. Pardoll
  • Biology, Medicine
    Nature Reviews Cancer
  • 2012
Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
Novel cancer immunotherapy agents with survival benefit: recent successes and next steps
The following next steps are necessary: first, the development of immune-monitoring strategies for the identification of relevant biomarkers; second, the establishment of guidelines for the assessment of clinical end points; and third, the evaluation of combination therapy strategies to improve clinical benefit.
Cancer immunotherapy: moving beyond current vaccines
Results in cancer vaccine trials are considered and alternate strategies that mediate cancer regression in preclinical and clinical models are highlighted.
Enhancement of Antitumor Immunity by CTLA-4 Blockade
In vivo administration of antibodies to CTLA-4 resulted in the rejection of tumors, including preestablished tumors, and this rejection resulted in immunity to a secondary exposure to tumor cells, suggesting that blockade of the inhibitory effects of CTLA4 can allow for, and potentiate, effective immune responses against tumor cells.
CTLA-4 blockade increases IFNγ-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients
It is found that CD4 T cells from peripheral blood and tumor tissues of all treated patients had markedly increased expression of inducible costimulator (ICOS), which are the first immunologic changes reported in both tumor tissues and peripheral blood as a result of treatment with anti-CTLA-4 antibody.
PD-1 blockade induces responses by inhibiting adaptive immune resistance
It is shown that pre-existing CD8+ T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy.
Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients
It is shown that periodic infusions of anti-CTLA-4 antibodies after vaccination with irradiated, autologous tumor cells engineered to secrete GM-CSF (GVAX) generate clinically meaningful antitumor immunity without grade 3 or 4 toxicity in a majority of metastatic melanoma patients.
Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer
Treatment efficacy was associated with a higher number of mutations in the tumors, and a tumor-specific T cell response paralleled tumor regression in one patient, suggesting that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.
Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape.
A strong synergy between the PD-1 and LAG-3 inhibitory pathways in tolerance to both self and tumor antigens is defined and it is argued strongly that dual blockade of these molecules represents a promising combinatorial strategy for cancer.