Development of immuno-oncology drugs — from CTLA4 to PD1 to the next generations

  title={Development of immuno-oncology drugs — from CTLA4 to PD1 to the next generations},
  author={Axel Hoos},
  journal={Nature Reviews Drug Discovery},
  • A. Hoos
  • Published 1 April 2016
  • Biology, Medicine
  • Nature Reviews Drug Discovery
Since the regulatory approval of ipilimumab in 2011, the field of cancer immunotherapy has been experiencing a renaissance. This success is based on progress in both preclinical and clinical science, including the development of new methods of investigation. Immuno-oncology has become a sub-specialty within oncology owing to its unique science and its potential for substantial and long-term clinical benefit. Immunotherapy agents do not directly attack the tumour but instead mobilize the immune… 
The foundations of immune checkpoint blockade and the ipilimumab approval decennial
The tenth anniversary of the approval of ipilimumab is marked and the foundational scientific history of ICB is discussed, revisiting the history of the discovery, development and elucidation of the mechanism of action of the first generation of drugs targeting the CTLA4 and PD1 pathways.
Oncolytic viruses—immunotherapeutics on the rise
The development of the OV field, why OVs are gaining an increasingly elevated standing as members of the cancer immunotherapy armamentarium, and ongoing clinical studies that are aimed at translating unique OV therapies into approved therapies for aggressive cancers are highlighted.
Leveraging NKG2D Ligands in Immuno-Oncology
It is proposed that combination strategies that target MICA/B with antibodies and strategies aimed at promoting their upregulation on tumor cells or at reprograming TAM into pro-inflammatory macrophages and remodeling of the TME, emerge as frontrunners in immuno-oncology because they may unleash the antitumor effector functions of NK cells and cytotoxic CD8 T cells.
Immuno-Oncology: Emerging Targets and Combination Therapies
The breadth and quality of immunotherapeutic approaches and the types of cancers that can be treated will increase significantly in the foreseeable future.
Trial Watch: Immunostimulatory monoclonal antibodies for oncological indications
The mechanisms of action of these immunostimulatory mAbs, conceived to activate co-stimulatory receptors on immune effector cells, are discussed and recent progress in their preclinical and clinical development is summarized.
Recent advances in the clinical development of immune checkpoint blockade therapy
Preliminary clinical investigations with immune-checkpoint blockers highlight broad opportunities with a high potential to enhance antitumor immunity and, as such, to generate significant clinical responses, and open up new avenues towards efficient therapeutics offered to patients.
Future perspectives in cancer immunotherapy.
Identification of the patients whose tumors are most likely to respond to immunotherapy by the use of appropriate biomarkers will be crucial for the optimal implementation of immunotherapy into the therapeutic armamentarium.
Immunomodulatory Effects of Current Targeted Therapies on Hepatocellular Carcinoma: Implication for the Future of Immunotherapy.
The authors systematically reviewed the pre-clinical evidence of sorafenib and other multikinase inhibitors' immune modulatory effects to explore whether these effects were mediated by angiogenesis inhibition or by other "off-target" effects on the tumor microenvironment.
Trial Watch: Immunomodulatory monoclonal antibodies for oncological indications
Recent advances in the development of checkpoint-blocking mAbs, as well as of immunomodulatory mAbs with distinct mechanisms of action are summarized.
Engineering immunity : enhancing T Cell vaccines and combination immunotherapies for the treatment of cancer
Design criteria for enhancing the immunogenicity of molecular vaccines are defined and essential characteristics of combination immunotherapies capable of curing a majority of tumors in experimental settings typically viewed as intractable are elucidated.


Big opportunities for small molecules in immuno-oncology
Agents aimed at mechanisms — modulation of the immune response, trafficking to the tumour microenvironment and cellular infiltration — are poised to significantly extend the scope of immuno-oncology applications and enhance the opportunities for combination with tumour-targeted agents and biologic immunotherapies.
Immune checkpoint inhibitors in melanoma provide the cornerstones for curative therapies.
In melanoma anti-CTLA-4 (ipilimumab) was approved in 2011 and anti-PD-1 (pembrolimumab) in 2014 and another anti- PD-1 antibody has been recently approved based on phase III trial results in metastatic melanoma without BRAF mutation.
Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy.
Identification of cytotoxic T-lymphocyte antigen-4 (CTLA-4) as a key negative regulator of T-cell activity led to development of the fully human, monoclonal antibody ipilimumab to block CTLA-4 and
Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.
Antibody-mediated blockade of PD-L1 induced durable tumor regression and prolonged stabilization of disease in patients with advanced cancers, including non-small-cell lung cancer, melanoma, and renal-cell cancer.
Immunologic checkpoints blockade in renal cell, prostate, and urothelial malignancies.
Encouraging initial data observed in GU cancers with this new class of agents are reported, which have reinforced the interest of investigating the therapeutic potential of the immune checkpoint modulators in large controlled trials.
Cancer immunotherapy
Going viral with cancer immunotherapy
The ability to engineer OVs that express immune-stimulating 'cargo', the induction of immunogenic tumour cell death by OVs and the selective targeting of OVs to tumour beds suggests that they are the ideal reagents to enhance antitumour immune responses.
Going viral: chimeric antigen receptor T‐cell therapy for hematological malignancies
The concept of chimeric antigen receptor gene‐modified T cells is explained, the extant results in hematologic malignancies are described, and the outlook on where this modality is likely to head in the near future is shared.