Cancer immunotherapy has revolutionised survival outcomes in patients to the extent that it is now recognised as one of the major modalities of cancer treatment. Technologies leading the charge are immune checkpoint inhibitory antibodies, chimeric antigen receptor T-cells and recombinant bi-specific T-cell engager molecules. It is thought that their workings depend on their effectiveness on specific immune recognition of cancer cells by cytotoxic T lymphocytes. For immune checkpoint inhibitory antibodies, anti-cancer activity results either from generation of new cytotoxic T lymphocytes specificities or re-invigoration of pre-existing intra-tumoral cytotoxic T lymphocytes. For chimeric antigen receptor T-cells and bi-specific T-cell engagers, genetic engineering re-directs anti-cancer activities of either exogenously delivered T cells or endogenous T cells, respectively. Even so, we must acknowledge the enormous complexity of human immunity and our relatively poor understanding of it. Although our current state of knowledge tells us that combination immunotherapies will be most effective, it does not inform us which combinations will optimise clinical benefit. Consequently, empirical clinical testing of cancer immunotherapies will likely continue in tandem with improved understanding of immunobiological mechanisms of action. Here, we aim to describe key principles of cancer immunotherapy and explain the rationale underlying current use of several different kinds of immune-active agents.
The prognosis of patients with metastatic melanoma in Australia has changed dramatically since the introduction of immune checkpoint inhibitors. Ipilimumab, which targets cytotoxic T lymphocyte-associated protein 4 (CTLA-4) was the first agent introduced on the scene. Subsequently nivolumab and pembrolizumab which bind to the programmed death protein 1 (PD-1) have proven to be more effective and less toxic than ipilimumab and form the mainstay of treatment for patients with advanced melanoma. The combination of nivolumab or pembrolizumab with ipilimumab have resulted in improved response rates and survival outcomes with the cost of added immune mediated toxicities. Recently reported trials have shown benefit of adjuvant immunotherapy post resection of high-risk disease. This review will explore the pivotal clinical trial data that has led to regulatory approval for use of these immunotherapy agents in Australia and some of the clinical trial results currently reported for novel combination therapies.
Lung cancer is the leading cause of cancer related mortality and the fifth most common malignancy in Australia. Most tumours are non-small cell histology, with small cell and making up a smaller fraction of newer diagnoses. Until recently, chemotherapy was the mainstay of treatment, with relatively modest benefits seen in progression free survival and overall survival. Immune checkpoint inhibitors including pembrolizumab, nivolumab and atezolizumab are monoclonal antibodies that inhibit the association of programmed death-1 (PD-1) and it’s ligand, which is normally associated with malignancy-induced immunosuppression. There have been positive results in both the first and second line settings in metastatic NSCLC, changing the current treatment paradigm. PD-L1 testing remains a controversial predictive biomarker, used to stratify patients in several randomised phase 3 clinical trials. Current attention has shifted to combining different immune checkpoint inhibitors or in novel multi-modality combination with chemotherapy or radiotherapy. Immunotherapy has also entered into the management of stage 3 disease, and continues to be evaluated in the adjuvant and neoadjuvant settings. Toxicity remains favourable compared with conventional chemotherapy, although clinicians need to remain vigilant for rarer and severe immune related adverse events. It is an exciting time in thoracic oncology with improved and durable survival in this most lethal of malignancies.
Prostate, bladder, kidney, testis and penile cancers cause over 10% of all cancer deaths, and standard treatments are largely palliative in advanced or metastatic disease. Cancer immunotherapy has an established and rapidly expanding role in the management of genitourinary cancers, but the different cancers also give insights across the landscape of immunotherapy.
Renal cancers can often have a well-established immune response, and can be poised for impressive responses to checkpoint immunotherapy. Combination immunotherapy will likely improve these ‘fertile plains’ further. The ‘desert’ of prostate cancer immunotherapy is currently hostile and unappealing, but vaccine strategies to increase immune recognition and novel checkpoint inhibitors are being explored to enrich this territory. Urothelial carcinoma is a veritable ‘jungle’ of therapeutic choices, where treatment individualisation and identification of new pathways to circumvent current pitfalls and improve outcomes. The largely unexplored zones of testicular germ cell and penile cancers suggest novel targets and complementary strategies to improve treatment.
With several immunotherapies in routine clinical use for genitourinary cancer patients, immunotherapy has a solid footing, and many opportunities to explore new ideas and combinations to change the landscape of cancer immunotherapy and open new frontiers.
Haematological malignancies are a heterogenous group of diseases mostly of immunological origin. Immunotherapies such as allogeneic stem cell transplantation and monoclonal antibodies have been an essential part of managing haematological malignancies for decades, though recent understanding of tumour and microenvironment biology has led to the development of highly effective targeted therapies. Inhibiting immune checkpoints such as programmed death-1 (PD-1) and its ligand (PD-L1) have yielded remarkable results in some highly refractory lymphoma subtypes such as relapsed classical Hodgkin Lymphoma. Autologous T-cells with chimeric antigen receptors (CARs) are highly effective in B-lineage acute lymphoblastic leukaemia (B-ALL) and appear promising in diffuse large B cell lymphoma (DLBCL) and myeloma. Bispecific antibodies such as blinatumomab are superior to salvage chemotherapy for relapsed/refractory B-ALL and have become standard of care. However, significant challenges remain in cost, deliverability and manufacture of some of these products. Certain haematological malignancies such as myelodysplastic syndrome and acute myeloid leukaemia remain poorly responsive to current immunotherapy, though new agents show promising pre-clinical data. Immunotherapy is a pillar of management for haematological malignancies and are likely curing a subset of patients previously considered incurable; the clinical challenge is determining how to employ these therapies for maximal benefit and minimal toxicity.
Two of the most common cancers, breast and bowel cancer, seem ‘immune’ to immune therapy – but there are particular molecular subtypes of these cancers that are more responsive. Several types of cancer that occur rarely or uncommonly may also benefit from immune therapy. The rare cancers suffer from under-representation in phase 3 randomised controlled trials, as conducting such large scale studies in the setting of rare cancers is usually not feasible. This in turn affects regulatory approval and access to checkpoint inhibitors for these tumours. Nevertheless, reported activity of these drugs has led oncologists and patients to consider such therapy, particularly where no other active or effective therapy exists. This review article will review the evidence that supports immune therapy for such cancers.
Immune checkpoint inhibitors are an integral part of cancer therapy following the demonstration of substantial responses across multiple tumour types. These agents induce T-cell activation against cancer cells that have achieved immune escape. Tipping the balance of immune homeostasis can however produce undesired autoimmunity, thus giving rise to a myriad of immune-related adverse events (irAEs) that can affect every organ. Although, mostly mild and manageable, potentially life threatening irAEs may occur and require prompt recognition and management.
The incidence and severity of irAEs is likely to increase with combination immunotherapies. Clinical presentations of these irAEs are varied in onset, type and severity, often leading to delays in presentation, diagnosis and appropriate management. As immuno-oncology becomes integrated into the broader anti-cancer treatment paradigm, clinicians will be required to rapidly recognise and manage a wide range of irAEs. We provide a summary of the patterns of onset, key clinical, pathologic and radiologic features of irAEs and management guidelines. Successful management of irAEs requires education for the patient, their carers and other health personnel, good patient-physician communication and multidisciplinary input from the medical oncologist and other specialist.
Immunotherapeutic agents have shown impressive clinical efficacy in a broad range of tumour types, particularly in non-small cell lung cancer and melanoma. An effective predictive biomarker is needed to provide patients with the most effective available treatments, avoid unnecessary toxicity and improve cost effectiveness. While it has been an area of very active research in recent years, the ideal biomarker for predicting response to immune check point inhibitor therapy has not yet been universally agreed upon. Approaches to date have focussed on assessment of tumour related factors such as immunohistochemical expression of programmed death ligand-1 (PD-L1), mutational load and DNA mismatch repair gene or protein status. Alternatively, assessment of the immune microenvironment by techniques such as gene expression profiling or measurement of tumour infiltrating lymphocytes can also be informative. Identifying and validating effective biomarkers is particularly challenging for immunotherapy because the dynamic and multifactorial nature of the interaction between tumours and host immunity. In this review, we discuss the relative advantages and disadvantages of different biomarker approaches in the quest to identify a clinically effective predictive biomarker that can improve the overall utility for immune checkpoint inhibitors.