SPECIAL

Immuno-oncology combinations: rationale and clinical implications in melanoma, renal cell carcinoma and lung cancer

ABSTRACT

Over the past years, immune checkpoint inhibitors have been widely used for the treatment of a broad range of malignancies. Unfortunately, only a proportion of patients derives long-term benefit from these therapeutics. In fact, a majority of patients fails to respond to immune checkpoint inhibition, while others relapse after a certain time. In an attempt to increase the response rate of tumours to these drugs, investigators have looked into the potential of combining different immunotherapeutic agents. Since inhibitors of the immune checkpoints CTLA-4 and PD-(L)1 have different modes of action and given the fact that blocking one of both pathways results in an upregulation of the other, provide a theoretical rationale to combine these agents. This review provides an overview of clinical studies evaluating combinations of CTLA-4 and PD-(L)1 inhibitors in the treatment of melanoma, renal cell carcinoma and non-small-cell lung cancer.

Chimeric antigen receptor T-cells: is the success in haematological malignancies translatable to solid tumours?

SUMMARY

Chimeric antigen receptor (CAR) T-cell therapy is a new cancer immunotherapy targeting specific cell surface antigens. This type of adoptive cell immunotherapy has been a breakthrough in the treatment of aggressive B-cell lymphoma and B-cell precursor acute lymphoblastic leukaemia (ALL) and is currently being studied in other cancer types, including multiple myeloma and chronic lymphocytic leukaemia. With the unprecedented success of CAR T cells in haematological malignancies, a growing number of (pre)clinical studies are focusing on translating this treatment to solid tumours. However, response rates to CAR T-cell therapy have so far been much less favourable in non-haematologic malignancies, mainly due to a paucity of unique tumour target antigens, limited CAR T-cell trafficking to tumour sites, tumour heterogeneity, antigen loss, the presence of an immune suppressive tumour microenvironment and recognition of normal cells expressing the targeted antigen. A broad range of strategies is currently being explored to overcome these hurdles. For example, TCR-CAR-T hybrids have been developed that can also target intracellular antigens which broadens the potential scope of the CAR-T cell strategy. This article reviews completed and ongoing CAR T-cell trials in solid tumours and discusses the strategies to improve the efficacy of this treatment modality in solid tumours, including accelerated production flows. CAR-T’s might very well be the upcoming major advance in cancer treatment.

Role of immune checkpoint inhibitors in small cell lung cancer treatment

In recent years, the potential of several immune checkpoint (ICP) inhibitors in small cell lung cancer (SCLC) has been increasingly investigated. Despite the fact that in some trials the benefit of the addition of ICP inhibitors was only modest, results of the CheckMate-032 and Keynote-028 and 158 have led to the FDA approval of nivolumab and pembrolizumab as third-line treatment options for patients with extensive disease (ED)-SCLC. More recently, results of IMpower 133 formed the basis for the EMA approval of atezolizumab in combination with chemotherapy as a first-line treatment option for ED-SCLC. In addition, several ongoing first-line trials in ED-SCLC patients will report their results in the near future. Also in limited disease (LD) SCLC patients, several trials are examining the interactive effects of concurrent tumour irradiation with chemo- and immunotherapy. Until now, unfortunately, there are no validated biomarkers to identify those SCLC patients who might derive the best long-term survival benefit from chemo-immunotherapy.

Radiotherapy in the lung cancer immuno-oncology era

ABSTRACT

Radiotherapy not only allows us to selectively target the tumour, it also interacts with the tumor microenvironment and consequently the host’s immune system. Theoretically this can lead to an in situ vaccination and trigger so-called abscopal responses, away from the irradiated site. Unfortunately, these are rarely seen the clinic. Over the past years, both preclinical and clinical studies demonstrated synergistic effects of radiation in combination with several types of immunotherapy. However, the optimal dose and fractionation of radiation therapy as well as the optimal combination and sequence of radiotherapy and immunotherapy still needs to be determined.

Immune-modulating antibodies in head and neck cancer: past, present, and future

Squamous cell carcinoma of the head and neck (SCCHN) has recently expanded the growing range of oncologic diseases successfully treated with immune-modulating agents. With the origins dating back to the nineteenth century, the concept of immunotherapy was repeatedly revisited and refined but also rejected and criticized. Currently, its armamentarium comprises tumour-specific antibodies, cancer vaccines, cytokines, adoptive T-cell transfer, and immune-modulating antibodies. Among these approaches it has been the latter one drawing major attention from healthcare professionals. Nivolumab and pembrolizumab are monoclonal immunoglobulins directed against programmed cell death protein-1 (PD-1), an immune-checkpoint negatively regulating T-cells. In second-line recurrent and/or metastatic SCCHN, two phase III studies demonstrated meaningful clinical benefit achieved by these drugs, dubbed checkpoint inhibitors, compared with standard monotherapy (methotrexate, docetaxel, or cetuximab). In the CheckMate-141 trial, nivolumab significantly improved median overall survival (OS) from 5.1 to 7.5 months. A similar benefit achieved by pembrolizumab in KEYNOTE-040 fell short of statistical significance (8.4 vs. 6.9 months), probably due to post-study immune-checkpoint therapy leading to a better-than-expected survival in the control arm. However, the classical outcome measures do not fully capture the exceptional activity of these agents. Apart from low frequency of severe adverse events (13% vs. 35% with standard therapy), these antibodies can induce durable tumour responses and retain activity even after several previous chemotherapy lines. With their advent in first-line palliative regimens and protocols for locally advanced disease, further progress is expected. Reliable predictive biomarkers are urgently needed, and several candidates are being evaluated. Among them, tumour mutational burden and gut microbiota offer an innovative approach to biomarker-enrichment strategies.

Immune-modulating antibodies in head and neck cancer: past, present, and future

Squamous cell carcinoma of the head and neck (SCCHN) has recently expanded the growing range of oncologic diseases successfully treated with immune-modulating agents. With the origins dating back to the nineteenth century, the concept of immunotherapy was repeatedly revisited and refined but also rejected and criticized. Currently, its armamentarium comprises tumour-specific antibodies, cancer vaccines, cytokines, adoptive T-cell transfer, and immune-modulating antibodies. Among these approaches it has been the latter one drawing major attention from healthcare professionals. Nivolumab and pembrolizumab are monoclonal immunoglobulins directed against programmed cell death protein-1 (PD-1), an immune-checkpoint negatively regulating T-cells. In second-line recurrent and/or metastatic SCCHN, two phase III studies demonstrated meaningful clinical benefit achieved by these drugs, dubbed checkpoint inhibitors, compared with standard monotherapy (methotrexate, docetaxel, or cetuximab). In the CheckMate-141 trial, nivolumab significantly improved median overall survival (OS) from 5.1 to 7.5 months. A similar benefit achieved by pembrolizumab in KEYNOTE-040 fell short of statistical significance (8.4 vs. 6.9 months), probably due to post-study immune-checkpoint therapy leading to a better-than-expected survival in the control arm. However, the classical outcome measures do not fully capture the exceptional activity of these agents. Apart from low frequency of severe adverse events (13% vs. 35% with standard therapy), these antibodies can induce durable tumour responses and retain activity even after several previous chemotherapy lines. With their advent in first-line palliative regimens and protocols for locally advanced disease, further progress is expected. Reliable predictive biomarkers are urgently needed, and several candidates are being evaluated. Among them, tumour mutational burden and gut microbiota offer an innovative approach to biomarker-enrichment strategies.

What can the tumour microenvironment tell us?

Nowadays, PD-L1/PD-1 immune checkpoint inhibitors have become a key part of the clinical management of cancer. Improving our understanding of anti-cancer immune response, which is influenced by a complex set of tumour, host and environment factors, will further broaden the clinical applicability of these treatments. In this review, we discuss several approaches to evaluate the tumour microenvironment (TME) in clinical practice as well as a view on future predictive biomarkers for cancer immunotherapy.