Recent advances in cancer immunotherapy

Cancer immunotherapy represents a major advance in the cure of cancer following the dramatic advancements in the development and refinement of chemotherapies and radiotherapies. In the recent decades, together with the development of early diagnostic techniques, immunotherapy has significantly contributed to improving the survival of cancer patients. The immune-checkpoint blockade agents have been proven effective in a significant fraction of standard therapy refractory patients. Importantly, recent advances are providing alternative immunotherapeutic tools that could help overcome their limitations. In this mini review, we provide an overview on the main steps of the discovery of classic immune-checkpoint blockade agents and summarise the most recent development of novel immunotherapeutic strategies, such as tumour antigens, bispecific antibodies and TCR-engineered T cells.

Evolution of Cancer Vaccines—Challenges, Achievements and Future Directions

The development of cancer vaccines has been intensively pursued over the past 50 years with modest success. However, recent advancements in the fields of genetics, molecular biology, biochemistry, and immunology have renewed interest in these immunotherapies and allowed the development of promising cancer vaccine candidates. Numerous clinical trials testing the response evoked by tumour antigens, differing in origin and nature, have shed light on the desirable target characteristics capable of inducing strong tumour-specific non-toxic responses with increased potential to bring clinical benefit to patients. Novel delivery methods, ranging from a patient’s autologous dendritic cells to liposome nanoparticles, have exponentially increased the abundance and exposure of the antigenic payloads. Furthermore, growing knowledge of the mechanisms by which tumours evade the immune response has led to new approaches to reverse these roadblocks and to re-invigorate previously suppressed anti-tumour surveillance. The use of new drugs in combination with antigen-based therapies is highly targeted and may represent the future of cancer vaccines. In this review, we address the main antigens and delivery methods used to develop cancer vaccines, their clinical outcomes, and the new directions that the vaccine immunotherapy field is taking.

Novel personalized cancer vaccine platform based on Bacillus Calmette-Guerin

Intratumoural bacillus Calmette-Guerin (BCG) therapy, one of the earliest immunotherapies, can lead to infiltration of immune cells into a treated tumour. Here, we have developed a novel cancer vaccine platform based on BCG that can direct BCG-induced immune responses against tumour antigens. By physically attaching tumour-specific peptides onto the mycobacterial outer membrane, we were able to induce strong systemic and intratumoural T cell-specific immune responses towards the attached tumour antigens. These therapeutic peptides can be attached to the mycobacterial outer membrane using a cell-penetrating peptide sequence derived from human immunodeficiency virus Tat, N-terminally fused to the tumour-specific peptides. Alternatively, therapeutic peptides can be conjugated with a poly-lysine sequence N-terminally fused to the tumour-specific peptides. Using two mouse models of melanoma and a mouse model of colorectal cancer, we observed that the anti-tumour responses of BCG can be significantly improved by coating the BCG with tumour-specific peptides. In addition, by combining this novel cancer vaccine platform with anti-PD-1 immune checkpoint inhibitor therapy, the number of responders to anti-PD-1 immunotherapy can be significantly increased.

PET/CT imaging for tumour response assessment to immunotherapy: current status and future directions

Recent immunotherapeutic approaches have evolved as powerful treatment options with high anti-tumour responses involving the patient’s own immune system. Passive immunotherapy applies agents that enhance existing anti-tumour responses, such as antibodies against immune checkpoints. Active immunotherapy uses agents that direct the immune system to attack tumour cells by targeting tumour antigens. Active cellular-based therapies are on the rise, most notably chimeric antigen receptor T cell therapy, which redirects patient-derived T cells against tumour antigens. Approved treatments are available for a variety of solid malignancies including melanoma, lung cancer and haematologic diseases. These novel immune-related therapeutic approaches can be accompanied by new patterns of response and progression and immune-related side-effects that challenge established imaging-based response assessment criteria, such as Response Evaluation Criteria in Solid tumours (RECIST) 1.1. Hence, new criteria have been developed. Beyond morphological information of computed tomography (CT) and magnetic resonance imaging, positron emission tomography (PET) emerges as a comprehensive imaging modality by assessing (patho-)physiological processes such as glucose metabolism, which enables more comprehensive response assessment in oncological patients. We review the current concepts of response assessment to immunotherapy with particular emphasis on hybrid imaging with 18F-FDG-PET/CT and aims at describing future trends of immunotherapy and additional aspects of molecular imaging within the field of immunotherapy.

HNSCC: Tumour Antigens and Their Targeting by Immunotherapy

Head and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of malignant tumours typically caused by alcohol and tobacco consumption, although an increasing number of HNSCC arise due to persistent infection with high-risk human papilloma virus (HPV). The treatment of HNSCC remains challenging, and the first-line setting is focused on surgery and chemoradiotherapy. A substantial proportion of HNSCC patients die from their disease, especially those with recurrent and metastatic disease. Among factors linked with good outcome, immune cell infiltration appears to have a major role. HPV-driven HNSCC are often T-cell rich, reflecting the presence of HPV antigens that are immunogenic. Tumour-associated antigens that are shared between patients or that are unique to an individual person may also induce varying degrees of immune response; studying these is important for the understanding of the interaction between the host immune system and the cancer. The resulting knowledge is critical for the design of better immunotherapies. Key questions are: Which antigens lead to an adaptive immune response in the tumour? Which of these are exploitable for immunotherapy? Here, we review the current thinking regarding tumour antigens in HNSCC and what has been learned from early phase clinical trials.

Crosstalk between Stress Granules, Exosomes, Tumour Antigens, and Immune Cells: Significance for Cancer Immunity

RNA granules and exosomes produced by tumour cells under various stresses in the microenvironment act as critical determinants of cell survival by promoting angiogenesis, cancer metastasis, chemoresistance, and immunosuppression. Meanwhile, developmental cancer/testis (CT) antigens that are normally sequestered in male germ cells of the testes, but which are overexpressed in malignant tumour cells, can function as tumour antigens triggering immune responses. As CT antigens are potential vaccine candidates for use in cancer immunotherapy, they could be targeted together with crosstalk between stress granules, exosomes, and immune cells for a synergistic effect. In this review, we describe the effects of exosomes and exosomal components presented to the recipient cells under different types of stresses on immune cells and cancer progression. Furthermore, we discuss their significance for cancer immunity, as well as the outlook for their future application.

Paraneoplastic neurological syndromes

Paraneoplastic neurological syndromes are disorders caused by the presence of an underlying tumour, but not due to either direct or metastatic invasion, or to recognized metabolic or endocrine complications. They are thought to arise from an autoimmune response to ‘onconeural’ tumour antigens which are also expressed by cells of the central or peripheral nervous systems. Paraneoplastic neurological syndromes are rare but important because (1) they often develop before the cancer has been identified, (2) serological testing for specific antineuronal (onconeural) antibodies may identify a neurological disorder as paraneoplastic and the results may suggest the location of the underlying tumour and/or predict its prognosis. In some cases, the identity of the antibody predicts an immunotherapy-responsive disease.

CCL21 and Dendritic Cell Suppression in Paediatric B Cell Acute Lymphoblastic Leukaemia

Despite the accumulation of genetic mutations likely to generate antigenic neoepitopes, acute lymphoblastic leukaemia (ALL) cells are poor at eliciting anti-tumour immune responses. Similarly to dendritic cells (DCs), B cells have antigen presenting capacity. In B cell ALL (B-ALL), blast expression of co-stimulatory molecules is down regulated whilst endogenous (tumour) antigens are presented through MHC class I and II[1], thus mimicking the DC peripheral tolerance mechanism. This leads to antigen specific anergy in naïve T cells capable of recognising the malignant cells and an anti-tumour immune response is not mounted. A robust DC response, presenting tumour antigens alongside co-stimulation, should be sufficient to overcome this since no intrinsic T cell defect exists in these patients. However, several studies have reported deficiencies in DC number and function in patients with B-ALL. Maecker et al. demonstrated that paediatric patients with B-ALL have significantly reduced blood DC counts at diagnosis, a reduction not attributable to disease induced bone marrow hypoplasia since blood DC numbers do not correlate with granulocyte or monocyte numbers or haemoglobin[2]. Mami et al. identified that CD34+ peripheral blood mononuclear cells from patients with B-ALL at diagnosis are ineffective at generating functional DCs in vitro suggesting that B-ALL cells, or leukaemia derived factors, may contribute to a block in DC development[3]. In this study, we monitored DCs and plasma cytokines in paediatric patients with B-ALL at diagnosis and throughout remission induction chemotherapy, in peripheral blood (PB) and the bone marrow (BM) tumour microenvironment, to identify on treatment changes in DCs and DC regulatory cytokines. 17 paediatric patients diagnosed with precursor B cell ALL were enrolled in this study. Matched PB and BM aspirate samples were collected at time points co-ordinating with treatment protocol (diagnosis, and induction days 8 and/or 15 and 29). Mononuclear cells and plasma samples were obtained by density gradient centrifugation. DCs were identified by flow cytometry (based on expression of HLA-DR(+), lack of B, T, NK and monocyte markers (CD3-, CD19-, CD56-, CD14-)). Plasma cytokines were analysed by Luminex multi-plex immunoassay. Our study confirmed that blood DCs are low in paediatric patients with B-ALL at diagnosis and that this scenario is mirrored in the BM tumour microenvironment. PB and BM DCs remained low through days 8 and 15 of induction remission chemotherapy however, we identified day 29 of induction chemotherapy as a key time point in the re-establishment of BM DCs, when a significant increase was recorded compared to both earlier time points and day 29 PB samples. Concordantly, high levels of two homeostatic chemokines were recorded in PB and BM plasma samples at diagnosis, CCL19 and CCL21. While CCL19 expression remained consistent throughout induction chemotherapy, CCL21 declined rapidly and was not detectable in any PB or BM day 29 plasma sample, coinciding with the rapid reduction of blasts that occurs during induction therapy. The re-emergence of DCs in the bone marrow and other lymphoid organs may represent the first stages in re-establishment of effective anti-tumour immunosurveillance and contribute to the cure of B-ALL. With overall survival rates greater than 90% it is clear that effective immunosurveillance, capable of maintaining a state of heath post-treatment, is re-established in most patients. When and how this occurs in the treatment process is not yet understood. However, CCL21 may play an important role in mediating immune tolerance to B-ALL, since mouse studies have demonstrated its ability to protect tumours from immune rejection[4]. Here, the re-establishment of BM DCs occurred concordantly to the reduction of CCL21 in the BM tumour microenvironment suggesting that over-expression of CCL21 may contribute to DC suppression in paediatric B-ALL patients. [1] Cardoso et al. (1996) Blood 88(1), 41-48; [2] Meaker et al. (2006) Leukemia 20(4), 645-649; [3] Mami et al. (2004) Br. J. Heamatol. 126(1), 77-80; [4] Sheilds et al. (2010) Science 328, 749-752. Disclosures No relevant conflicts of interest to declare.