Nobel Prize in Physiology or Medicine 2018

Insights into the effects of targeted therapies, conventional chemotherapy and radiation therapy, on the induction of antitumour immunity will help to advance the design of combination strategies that increase the rate of complete and durable clinical responses in patients.

Patients receiving anticancer therapies based on immune-checkpoint blockade (ICB) often experience clinical benefits from such treatments, but unconventional patterns of response can be observed, emphasizing the importance of using a specific approach to evaluating responses to immunotherapy. Herein, the authors review the biological mechanisms underlying the response patterns associated with ICB, describe strategies for the assessments of such responses, and highlight the ongoing efforts to identify biomarkers to guide treatment with ICB.

Immuno-oncology has become the fastest-growing area in the pharmaceutical industry. In this Perspective, Hoos provides an overview of the history of immuno-oncology and investigates the factors that have led to its success. Moreover, he discusses the three generations of immunotherapies that have been developed since 2011 and provides an outlook to the future directions of drug discovery and development in immuno-oncology.

This Timeline looks back at the past 60 years of fundamental research into the mechanisms of T cell-mediated cytotoxicity, which has culminated in recent interest in the therapeutic manipulation of cytotoxic T cell responses for cancer immunotherapy.

Prostate cancer is refractory to anti-CTLA-4 therapy, but the reason why is unclear. Padmanee Sharma and colleagues report that the inhibitory molecule VISTA, which negatively regulates T cells, is upregulated on macrophages in prostate tumors that have been treated with anti-CTLA-4 and may play a role in resistance to this immunotherapy.

By targeting the surgical bed and circulating tumour cells, platelets conjugated with an antibody against an immune checkpoint protein prevent tumour recurrence and metastasis following resection of the primary tumour.

Immune checkpoint blockade with anti-PD-1 or anti-PD-L1 agents produces a high response rate in patients with desmoplastic melanoma.

Among many populations of blood cells, high dimensional analysis using mass cytometry reveals classical monocyte frequency as strong predictors of response to PD-1 blockade therapy of melanoma.

Successful translation of modern molecular immunology into effective cancer immunotherapy is threatened by regulatory barriers and challenges to the development of novel agents and combinatorial strategies through effective public-private partnerships. For its promise to be fully realized, both the National Cancer Institute and Food and Drug Administration must take active steps to help academic investigators and companies jointly navigate the pathways from laboratory to clinic.

The US Food and Drug Administration (FDA) recently approved the immunotherapy agents sipuleucel-T and ipilimumab for the treatment of metastatic prostate cancer and melanoma, respectively. This Opinion article discusses how immunotherapy might be improved by understanding the mechanisms that are responsible for clinical benefit, identifying biomarkers that predict response or toxicity and developing combination therapies.

Programmed Death ligand-1 (PD-L1) protein mediates immune suppression in cancer. Here, the authors show that in breast cancer, PD-L1 expression can be up regulated post-translationally by glycosylation, which in turn acts through inhibiting GSK3β-mediated PD-L1 degradation.

Combination therapy with α-CTLA-4 and α-PD-1 is showing improved therapeutic effects in clinical trials. Here, the authors report that mechanistically in bladder cancer such effect depends upon an upregulation of T cell activity mediated by the IL-7/IL-7R and IFN-γ/IFN-γR signalling pathways.

Oncolytic viruses induce a variety of immune targets in the infected tumours. Here, the authors show that Newcastle Disease Virus (NDV) upregulates the inducible co-stimulator (ICOS) on T cells and that intratumoral targeting of ICOS with engineered NDV in combination with CTLA-4 blockade induces systemic anti-tumour immunity in mice.

The functional significance of T-cell infiltration in pancreatic ductal adenocarcinoma in relation to desmoplastic stroma is unclear. Here the authors develop a method to spatially resolve tumour stroma composition and find that spatial T-cell infiltration correlates with patient prognosis regardless of desmoplasia.

Many patients fail to respond to T cell based immunotherapies. Here, the authors, through a high-throughput screening, identify HSP90 inhibitors as a class of preferred drugs for treatment combination with immunotherapy.

A carcinogen-induced mouse tumour model is used here to show that mutant tumour-specific antigens are targets for CD8⁺ T-cell responses, mediating tumour regression after checkpoint blockade immunotherapy, and that these antigens can be used effectively in therapeutic vaccines; this advance potentially opens the door to personalized cancer vaccines.

The dynamics of T-cell responses are investigated in tumour tissue from patients with advanced melanoma who were treated with a PD-1-blocking monoclonal antibody, revealing that clinical efficacy of the treatment correlates with increased frequencies of pre-existing CD8⁺ T cells and PD-1 and PD-L1 expression.

Clinical and correlative biomarker results from a phase 1 clinical trial in patients with different solid tumours are presented; the findings indicate that PD-L1 expression on tumour-infiltrating immune cells is associated with clinical response to MPDL3280A (anti-PD-L1).

The results of a clinical phase I study in metastatic urothelial bladder cancer treated with the MPDL3280A antibody show that expression of PD-L1 on tumour-infiltrating immune cells is relevant for the therapeutic response.

A combination of TGFβ inhibition and checkpoint-inhibition therapy provokes a potent cytotoxic response against metastatic tumours derived from colorectal cancers in mice.

In humans, TGFβ signalling is associated with lack of response to immunotherapy in immune-excluded tumours; in mouse models of this immune phenotype, robust tumour infiltration by T cells and tumour regression are observed only when checkpoint inhibition is combined with inhibition of TGFβ signalling.

An exploratory randomized controlled clinical trial of renal cell carcinoma identifies molecular patterns distinguishing responders to immune checkpoint blockade alone or combined with angiogenesis inhibitor versus angiogenesis inhibitor alone.

A blood-based DNA sequencing assay to infer tumor mutational burden in the absence of tumor biopsy predicts response to PD-L1 blockade in patients with non-small-cell lung cancer.

High-density lipoprotein nanodiscs loaded with immunostimulatory biomolecules can target draining lymph nodes for cancer vaccination.

Nanoparticles can be utilized to capture tumour antigens and improve their presentation, which in turn improves the efficacy of cancer immunotherapy.

A multivalent bi-specific nanoconjugate can promote immune cells to recognize and eradicate cancer cells in a receptor targeted manner, leading to the generation of potent and durable anti-tumour immunity.

STING-activating nanoparticle vaccines achieve robust activation of tumour-specific T cells for cancer immunotherapy.

Magnetic fucoidan-based nanoparticles conjugated with T-cell activators and checkpoint inhibitors can be directed to tumours via magnetic navigation for improving therapeutic efficacy and reducing systemic side effects.

The clinical management of metastatic melanoma requires predictors of the response to checkpoint blockade. Here, the authors use immunological assays to identify potential prognostic/predictive biomarkers in circulating blood cells and in tumor-infiltrating lymphocytes from patients with resected stage III melanoma.

A subset of cancer patients treated with immune checkpoint blockade develops colitis. Here the authors show that lower abundance of Bacteroidetes and vitamin B biosynthetic modules in fecal samples of melanoma patients can predict their susceptibility to colitis following anti-CTLA-4 treatment.

Photothermal therapy can induce an anti-tumour immune response by producing tumour-associated antigens. Here, the authors design a nanoparticle that simultaneously acts as a photothermal agent and an immune-adjuvant and demonstrate the anti-tumour efficacy in combination with anti-CTLA4 therapy in preclinical murine cancer models.

Acquired resistance is a major problem in cancer immunotherapy. Here the authors report a study of two patients with Merkel cell carcinoma under immunotherapy treatment who develop resistance after deep responses for >1 year and identified a novel mechanism of acquired, gene-specific transcriptional suppression of HLAs.

Blocking immune checkpoints is a promising strategy to treat lung cancer, but patients often become resistant to the therapy. Here, the authors analyse resistance in mouse models of lung cancer and show in mice and two patients, an increase in the expression of TIM3, which is also involved in the immune response to cancer.

PD-L1 accumulates on cancer stem cells and favours immune evasion but the mechanism underlying this accumulation are unknown. Here the authors show that epithelial-mesenchymal transition induces glycosylation and stabilisation of PD-L1; antagonising this process renders cancer cells sensitive to anti-Tim3-therapy.

Immune checkpoints blockade (ICB) is a viable anti-cancer strategy. Here the authors show that nuclear receptor NR2F6 acts as an immune checkpoint in T cells and, using mouse models and human T cells, they show NR2F6 inhibition might improve current ICB therapy or work as an alternative therapeutic strategy.

Antitumor T cells can be inhibited by a TGFβ rich tumor microenvironment. The authors develop bifunctional proteins comprising CTLA-4 or PD-L1 immune checkpoint-targeted antibodies fused to a “TGFβ trap” and show that they counteract tumor immune tolerance and enhance the efficacy of these antibodies.

Many patients have now received various types of immunotherapy, so we asked three scientists to give their views on whether acquired resistance to immunotherapy exists in patients and the future challenges posed by immunotherapy.

The aim of immunotherapy is to treat cancer by enabling the immune system to attack the tumour. In the past decade, remarkable results have been obtained in clinical trials with immunotherapy for patients with advanced-stage cancer. Two types of immunotherapy have been used in the majority of trials conducted in the past decade: immune cell-targeted antibody therapy and adoptive cellular therapy. Herein, the latest advances in both modalities are discussed, including settings for which testing combination strategies and 'armoured' CAR T cells are recommended.

The tumor immune microenvironment influences tumor progression and response to immunotherapy; its further characterization will improve therapeutic outcome.

In this Review, the authors detail the complex expression patterns and regulation of programmed cell death protein 1 (PD1) and its ligands. The authors focus on the importance of understanding these pathways in order to optimize the efficiency and safety of immune checkpoint blockade in patients.

Recent clinical trials have shown that blocking immune checkpoint molecules can boost antitumour immune responses. In this Review, the authors consider whether targeting these pathways could also be used to combat a range of infectious diseases, such as malaria, tuberculosis and chronic viral infections.

Urothelial bladder cancer is one of the most common, and most deadly, malignant diseases worldwide. This Primer summarizes the current epidemiological and outcome data of patients with this disease, as well as describing how new molecular subtyping strategies might improve patient care in the future.

Renal cell carcinoma (RCC) is a neoplasm of the renal epithelium and accounts for >90% of kidney cancers. Cancer genomic studies have identified numerous molecular events that lead to RCC and marked intra-tumour heterogeneity, which have prognostic and therapeutic relevance. In this Primer, the authors describe these advances, as well as highlight the considerable advances in the systemic treatment of metastatic RCC.

Immunotherapies have shown significant promise in cancer treatment. This Review discusses how a range of materials have been employed to enhance the effectiveness of these therapies by mediating their delivery and immunomodulatory activity.

Multiple methods exist to induce liver disease and hepatocellular carcinoma formation in mice. This Review provides an overview of different mouse models of hepatocellular carcinoma, discussing approaches to help choose an appropriate model and highlighting specific concepts for immunotherapy research.

Immune checkpoint inhibitors are a novel approach to cancer immunotherapy. However, they are associated with substantial risk of immune-related adverse events, including gastrointestinal toxicity. This Review explores the manifestations of gastrointestinal toxicity with immune checkpoint inhibitor use and insights into its management.

Hepatocellular carcinoma (HCC) is an antigenic lesion infiltrated by T cells, but factors within the tumour and its microenvironment dampen the immune response and prevent effective antitumour immunity. The stepwise elucidation of the various immunosuppressive mechanisms at play in HCC has exposed new therapeutic options. This Review gives a comprehensive overview of the different immunotherapeutic modalities applicable in HCC, including vaccines, adoptive T-cell therapy, cytokines, gene therapy and immune checkpoint inhibitors.

Several immune checkpoint inhibitors have been approved for use in metastatic urothelial carcinoma and could be clinically useful alone or in combination. However, they are associated with various immune-related adverse events and specific immune-related patterns of response. In this Review, the authors discuss the data supporting the use of checkpoint inhibition and consider how to optimize therapy to reduce and manage the effects of these therapies.

Lee and Gujar review the potential of virotherapy to increase the effectiveness of immunotherapies in prostate cancer. They discuss how oncolytic viruses can improve anticancer immunological responses and strategies for combining virotherapy with other immunotherapies to obtain improved patient outcomes.

Felsenstein and Theodorescu discuss advances in therapy response prediction in patients with bladder cancer based on tumour genomics. They summarize current clinical approaches and future requirements in personalized precision medicine including targeted as well as immunotherapeutic strategies.

This Review provides an overview of the molecular determinants of renal cell carcinoma, how understanding the underlying mechanisms of disease has fuelled the development of targeted therapies, and tools to assess the value of these agents.

Immune checkpoint inhibitors (ICIs) have led to a paradigm shift in cancer therapy; however, these agents can induce immune-related adverse events (irAEs) in off-target organs. This Review describes the mechanism of action of ICI therapies and how these agents induce irAEs in the kidney and heart.

Targeting the immune system in tumour cells has become a central therapy for cancer treatment, but such drugs can lead to adverse effects. In this Review, the authors describe the immune-related endocrinopathies, such as hypophysitis, thyroid dysfunction and the development of diabetes mellitus that can result from cancer immunotherapy.

Although anaplastic thyroid carcinoma (ATC) is a rare form of thyroid cancer, the limited efficacy of conventional treatment options and challenges in histological diagnosis make this an almost invariably lethal disease. In this Review, the authors describe the clinical and pathological features of ATC, highlight recent advances in uncovering the genetics and molecular biology of this disease, and discuss both conventional and future treatment modalities.

Cancer can be successfully treated by blocking inhibitory immune checkpoint receptors, but in some patients these treatments cause immune-related adverse effects that can resemble autoimmune responses. This Review discusses what rheumatologists can learn from these observations and summarizes progress in therapeutically targeting inhibitory receptors in autoimmune diseases.

Cancer immunotherapies that function as checkpoint inhibitors are an exciting development but are associated with immune-related adverse events that can occur in almost any organ. Among these events are complications that mirror established rheumatic diseases, so oncologists and rheumatologists must work together.

Activating immune cells to destroy tumours is an effective strategy for treating an advanced lung cancer — but only for some people. Evidence that this approach has potential in early disease and as a combination therapy has now emerged.

This article analyses the huge volume of clinical trial activity for immune checkpoint inhibitors, and discusses the development of the market and strategic trends for immuno-oncology therapies in general.

Immune-checkpoint inhibitors (ICIs) are transforming oncology, but the mounting costs of cancer care necessitate concerns regarding economic sustainability. Here, several strategies that clinicians could use to exercise economically prudent administration of ICIs are discussed. These include better appraisal of the cost-effectiveness literature, judicious patient selection, separating statistical from clinical significance, and careful patient counselling.

Nanoscale metal–organic frameworks carrying an immunotherapy payload and administered into tumours alongside a low dose of radiotherapy enhance local and systemic antitumour immunity in mouse models of breast cancer and colorectal cancer.