Abstract

Cancer treatments often reach a refractory period leading to treatment failure and patients developing disease recurrence. This can be due to tumour cells escaping the immune response and creating an immunosuppressive microenvironment enhancing cancer progression. Immunotherapy has become a promising tool for cancer treatment as it restores the anti-tumour response of the patient’s immune system. Immune checkpoint inhibitors are the most widely studied immunotherapies worldwide and are now approved for multiple cancers. However, chimeric antigen receptor (CAR)-T cell therapy has also shown promise by targeting T lymphocytes that are genetically modified ex vivo to express CARs and this is now approved to treat some haematological cancers. Although immunotherapy has shown successful treatment outcomes in multiple cancers, some patients do not respond to this treatment. Therefore, approaches to enhance the efficacy of immunotherapies are likely to be the key to improve their effectiveness. Therefore, combination therapies of checkpoint inhibitors +/− chemotherapy are at the forefront of current research. Furthermore, biomarkers that predict treatment response are now beginning to emerge. Additionally, utilising nanoparticles as a newly targeted drug delivery system to enhance CAR-T cell therapy may enhance the efficacy of the cells when re-infused within the patient. Even if efficacy is enhanced, severe immune-related adverse events (irAEs) occur that are life-threatening and could lead to therapy being stopped. Therefore, predictive biomarkers for toxicity are also needed to improve both the patient’s quality of life and treatment outcomes. This review will look at the current immunotherapies in clinical trials and discuss how to enhance their efficacy.

Introduction

Cancer therapy is mainly focused on surgery, chemotherapy, radiotherapy, and endocrine therapy [1]. However, these strategies frequently reach a refractory period leading to treatment failure and the patient developing disease recurrence [2,3]. One solution may be to focus on enhancing the patient’s own immune system to attack the tumour; as once cancer is initiated, it can progress as a result of tumour cells escaping from the immune system. Tumour cells can escape the immune response in a variety of ways in order to survive and further progress without being attacked by immune cells [4]. Additionally, tumour cells can prevent immune cell actions, with the support of multiple cell types to create an immunosuppressive microenvironment [5]. Therefore, tumour escape from immunologic control is confirmed as one of the hallmarks of cancer [6].

The immune responses recognise tumour cells and eradicate them by multiple processes involving co-operation of both the innate and adaptive arms [7,8]. This process involves both positive and negative regulators. Positive regulators enhance anti-tumour activity, whereas negative regulators inhibit this killing process and enhance tumour growth instead. Therefore, immunotherapy that targets the negative regulators to enhance the anti-tumour responses could be a promising alternative treatment strategy and may be a powerful tool to treat cancer.

Immunotherapy is now a main focus for many cancer types; it works by restoring the patient’s immune responses to eliminate tumour cells [9,10]. It can be classified as active or passive by assessing the mechanism by which the therapy activates an immune response [11]. Active immunotherapy includes preventive and therapeutic vaccines, immunomodulatory monoclonal antibodies, i.e. immune checkpoint inhibitors, and immunostimulatory cytokines, that stimulate the host’s adaptive immune response in situ. Passive immunotherapy focuses on activating the host’s immune response in vitro and transfers it back to the host known as adoptive cell transfer (ACT) or cell-based therapy, i.e. chimeric antigen receptor (CAR)-T cell therapy.

This review summarises two types of immunotherapies: immune checkpoint inhibitors, and adoptive T-cell transfer in detail within the cancer setting. Immune checkpoint inhibitors focus on anti-programmed cell death-1 (PD-1)/anti-programmed cell death ligand-1 (PD-L1)/anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4); as the mechanism of immune checkpoint proteins on T cells (PD-1, PD-L1, CTLA-4) is to bind to their receptors on tumour cells or antigen-presenting cells (APCs), which causes a negative effect by inhibiting T-cells function. Therefore, blocking the binding of immune checkpoint proteins and their receptors could restore T-cell function to kill tumour cells. Whereas adoptive T-cell transfer or CAR T cells utilise T-cells from patients that are engineered in vitro to express CARs which induce binding to tumour cell antigens and enhance T-cell function, which causes a positive effect to kill tumour cells. The review will also discuss strategies to enhance immunotherapy efficacy and how they relate to the effectiveness of treatment outcomes.

Immune checkpoints and their inhibitors

Active immunotherapy targets the host’s immune response to induce activation and restore anti-tumour function, one example of this is checkpoint inhibitors. Immune checkpoints are negative regulators of the immune system and play a crucial role in limiting anti-tumour immune responses. In the normal anti-cancer immune response; antigens on the surface of tumour cells bind to checkpoint proteins on the surface of T lymphocytes leading to decreased T-cell function. This controls the anti-tumour response and avoids T-cell exhaustion; however, the tumour can hijack this mechanism to suppress anti-tumour functions and promotes tumour progression. Therefore, these immune checkpoints are important immunotherapeutic targets, with checkpoint blockade inhibiting this immune system modulation resulting in increased effector T cells that can co-ordinate an anti-tumour response [12]. Immune checkpoint inhibitors are the most widely studied active immunotherapy in cancer research leading to some having been approved for clinical use [13]. Two types of co-inhibitory proteins that are widely studied are PD-1 and CTLA-4 (Figure 1).

Immune checkpoint interactions that inhibit T-cell functions and their inhibitors

Figure 1
Immune checkpoint interactions that inhibit T-cell functions and their inhibitors

Immune checkpoint, PD-1 on activated T cell binds to specific receptors, PD-L1 and PD-L2, on tumour cells, whereas CTLA-4 on resting T cell binds to B7 on APCs, both to inhibit T-cells function. Immune checkpoint inhibitors, anti-PD-1, anti-PD-L1, and anti-CTLA-4 can block these complexes to restore T-cells function. Abbreviation: PD-L2, programmed cell death ligand-2.

Figure 1
Immune checkpoint interactions that inhibit T-cell functions and their inhibitors

Immune checkpoint, PD-1 on activated T cell binds to specific receptors, PD-L1 and PD-L2, on tumour cells, whereas CTLA-4 on resting T cell binds to B7 on APCs, both to inhibit T-cells function. Immune checkpoint inhibitors, anti-PD-1, anti-PD-L1, and anti-CTLA-4 can block these complexes to restore T-cells function. Abbreviation: PD-L2, programmed cell death ligand-2.

PD-1 and PD-L1

PD-1, known as CD279, is a type I transmembrane protein, a member of the CD28 family which is expressed on activated and exhausted T and B lymphocytes. PD-1 is expressed during the effector phase in peripheral tissue and is up-regulated in many tumours. It binds to specific ligands, called PD-L1 and programmed cell death ligand-2 (PD-L2), on tumour cells.

PD-L1 is expressed on various types of solid tumours, but is not expressed in normal epithelial tissue, where PD-L2 is the dominant form. When PD-1 binds to PD-L1 there is decreased cytokine production and inhibition of T-cells proliferation and function within peripheral tissues and tumours. This plays a key role in negative immune cell regulation resulting in tumour immunity balancing and attenuation of the T-lymphocyte response within the tumour microenvironment [14,15].

CTLA-4

CTLA-4, also known as CD152, is a CD28 homologue membrane glycoprotein on T lymphocyte, found during the priming phase in lymph nodes. CTLA-4 interacts with specific protein (B7) on APCs to produce co-inhibitory signals to decrease T-lymphocyte anti-tumour responses [16]. This was the first pathway for immune checkpoint regulation that was proposed in 1996 by Leach et al. [17].

Immune checkpoint inhibitors block ligand binding to enhance T-cell function

Immune checkpoint interactions can be blocked with anti-PD-1/anti-PD-L1/anti-CTLA-4 antibodies leading to immune cell re-activation and a co-ordinated anti-tumour response of T cells. Currently, three anti-PD-1 immune checkpoint inhibitors, pembrolizumab, nivolumab, and cemiplimab are approved for use within the clinical setting. Three anti-PD-L1 antibodies were also approved; atezolizumab, durvalumab, and avelumab. Ipilimumab is the only anti-CTLA-4 approved for clinical use (Table 1).

Table 1
Summary of immune checkpoint inhibitors approved for multiple cancers
Antibody Drug name Year Approved for Reference studies Phase Response rate References 
Anti-PD-1 Pembrolizumab 2014 Advanced melanoma KEYNOTE-006 (NCT01866319) Phase III 33.7% [18
  2015 Advanced non-small-cell lung cancer (NSCLC) KEYNOTE-001 (NCT01295827) Phase I 19.4% [19
  2016 Recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) KEYNOTE-012 (NCT01848834) Phase II 16.0% [20
  2017 Classical Hodgkin lymphoma (cHL) KEYNOTE-087 (NCT02453594) Phase II 69.0% [22
  2017 Metastatic urothelial carcinoma (mUCC) KEYNOTE-052 (NCT02335424) Phase II 38.0% [23
  2017 Non-resectable or metastatic microsatellite instability-high (MSI-H)/mismatch-repair deficient (dMMR) KEYNOTE-016 (NCT01876511) Phase II  [24
    KEYNOTE-164 (NCT02460198) Phase II  [25
    KEYNOTE-012 (NCT01848834) Phase II 39.6% (Pooled) [20
    KEYNOTE-028 (NCT02054806) Phase Ib  [26
    KEYNOTE-158 (NCT02628067) Phase II  [27
  2017 Gastroesophageal junction (GEJ) carcinoma KEYNOTE-059 (NCT02335411) Phase II 13.3% (MSI-H 57%) [28
  2018 Recurrent or metastatic cervical cancer (RCC) KEYNOTE-158 (NCT02628067) Phase II 13.3% [29
  2018 Large B-cell lymphoma (PMBCL) KEYNOTE-170 (NCT02576990) Phase II 45.0% [30
 Nivolumab 2014 Metastatic melanoma CHECKMATE-037 (NCT01721746) Phase III 32.0% [31
    CHECKMATE-066 (NCT01721772) Phase III 40.0%, [32
  2015 Metastatic NSCLC CHECKMATE-057 (NCT01673867) Phase III 19.2% [33
  2015 Advanced metastatic RCC CHECKMATE-025 (NCT01668784) Phase III 25.0% [34
  2016 Recurrent or metastatic HNSCC CHECKMATE-141 (NCT02105636) Phase III 13.3% [35
 Cemiplimab 2018 Metastatic cutaneous squamous cell carcinoma (CSCC) NCT02383212 Phase I 52.0% [36
Anti-PD-L1 Atezolizumab 2016 Advanced urothelial carcinoma IMVigor210 (NCT02108652) Phase II 23.5% [38
  2016 Metastatic NSCLC OAK (NCT02008227) Phase III 14% [39
    POPLAR (NCT01903993) Phase II 14.3 months [40
 Avelumab 2017 Merkel cell cancer NCT02155647 Phase II 31.0% [41
  2017 Urothelial carcinoma NCT01772004 Phase Ib 16.5% [42
 Durvalumab 2017 mUCC NCT02516241 Phase III 17.8% [43
  2018 Metastatic NSCLC NCT02125461 Random 28.4% [44
Anti-CTLA-4 Ipilimumab 2014 Metastatic melanoma NCT00094653 Phase III 10.9% [46
  2018 Renal cell carcinoma CHECKMATE-214 (NCT02231749) Phase III 42% [47
Antibody Drug name Year Approved for Reference studies Phase Response rate References 
Anti-PD-1 Pembrolizumab 2014 Advanced melanoma KEYNOTE-006 (NCT01866319) Phase III 33.7% [18
  2015 Advanced non-small-cell lung cancer (NSCLC) KEYNOTE-001 (NCT01295827) Phase I 19.4% [19
  2016 Recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) KEYNOTE-012 (NCT01848834) Phase II 16.0% [20
  2017 Classical Hodgkin lymphoma (cHL) KEYNOTE-087 (NCT02453594) Phase II 69.0% [22
  2017 Metastatic urothelial carcinoma (mUCC) KEYNOTE-052 (NCT02335424) Phase II 38.0% [23
  2017 Non-resectable or metastatic microsatellite instability-high (MSI-H)/mismatch-repair deficient (dMMR) KEYNOTE-016 (NCT01876511) Phase II  [24
    KEYNOTE-164 (NCT02460198) Phase II  [25
    KEYNOTE-012 (NCT01848834) Phase II 39.6% (Pooled) [20
    KEYNOTE-028 (NCT02054806) Phase Ib  [26
    KEYNOTE-158 (NCT02628067) Phase II  [27
  2017 Gastroesophageal junction (GEJ) carcinoma KEYNOTE-059 (NCT02335411) Phase II 13.3% (MSI-H 57%) [28
  2018 Recurrent or metastatic cervical cancer (RCC) KEYNOTE-158 (NCT02628067) Phase II 13.3% [29
  2018 Large B-cell lymphoma (PMBCL) KEYNOTE-170 (NCT02576990) Phase II 45.0% [30
 Nivolumab 2014 Metastatic melanoma CHECKMATE-037 (NCT01721746) Phase III 32.0% [31
    CHECKMATE-066 (NCT01721772) Phase III 40.0%, [32
  2015 Metastatic NSCLC CHECKMATE-057 (NCT01673867) Phase III 19.2% [33
  2015 Advanced metastatic RCC CHECKMATE-025 (NCT01668784) Phase III 25.0% [34
  2016 Recurrent or metastatic HNSCC CHECKMATE-141 (NCT02105636) Phase III 13.3% [35
 Cemiplimab 2018 Metastatic cutaneous squamous cell carcinoma (CSCC) NCT02383212 Phase I 52.0% [36
Anti-PD-L1 Atezolizumab 2016 Advanced urothelial carcinoma IMVigor210 (NCT02108652) Phase II 23.5% [38
  2016 Metastatic NSCLC OAK (NCT02008227) Phase III 14% [39
    POPLAR (NCT01903993) Phase II 14.3 months [40
 Avelumab 2017 Merkel cell cancer NCT02155647 Phase II 31.0% [41
  2017 Urothelial carcinoma NCT01772004 Phase Ib 16.5% [42
 Durvalumab 2017 mUCC NCT02516241 Phase III 17.8% [43
  2018 Metastatic NSCLC NCT02125461 Random 28.4% [44
Anti-CTLA-4 Ipilimumab 2014 Metastatic melanoma NCT00094653 Phase III 10.9% [46
  2018 Renal cell carcinoma CHECKMATE-214 (NCT02231749) Phase III 42% [47

Anti-PD-1 (pembrolizumab, nivolumab and cemiplimab)

Pembrolizumab has been studied in multiple solid tumours and has showed anti-tumour activity in clinical trials. As a result, in 2014, it was approved to treat advanced melanoma based on Phase III studies comparing pembrolizumab and the anti-CTLA-4, ipilimumab; pembrolizumab demonstrated prolonged overall survival and less toxicity than ipilimumab [18]. In 2015, pembrolizumab was further approved to treat advanced non-small-cell lung cancer (NSCLC) based on the result that it showed anti-tumour activity with manageable side effects [19]. In 2016, pembrolizumab was approved for recurrent or metastatic head and neck squamous cell carcinoma patients [20]. A study by Seiwert et al. [20] showed that pembrolizumab has efficacy over standard therapy by cetuximab. However, the latest Phase III trial by Merck and Co., showed that this drug did not result in improved overall survival as previously observed [21]. This finding did not affect the previous approval but does show variability in results for this cancer type and suggests that a predictive biomarker is needed to select responsive patients.

Over the past two years, pembrolizumab has been approved for multiple types of cancer including classical Hodgkin lymphoma (cHL), metastatic urothelial carcinoma (mUCC), gastric cancer or gastroesophageal junction (GEJ) adenocarcinoma, and colorectal cancer (CRC). In cHL, pembrolizumab was approved based on a study that treated both adults and pediatric patients with resistance to current therapy. The result showed a 69% overall response rate with 11.1 months of median response duration until reaching unacceptable toxicity [22]. In advanced mUCC, it was approved based on the Phase II trial that compared pembrolizumab with chemotherapy. Pembrolizumab showed a median overall survival of 10.3 months, whereas chemotherapy only showed a median survival of 7.4 months [23]. In the same year, pembrolizumab was also approved for non-resectable or metastatic microsatellite instability-high (MSI-H)/mismatch-repair deficient (dMMR) solid tumours including CRC [20,24–27]. This was the first approval based on the specific biomarkers regardless of the origin of tumour.

In gastric cancer or GEJ adenocarcinoma, pembrolizumab was approved based on the Phase II KEYNOTE-059 study [28]. From 143 patients, the result showed 13.3% objective response rate and response duration of 2.8–19.4 months. MSI-H was observed in seven patients showing a 57% objective response rate and response duration of 5.3–14.1 months suggesting MSI status could predict response to pembrolizumab as seen in other cancers. Recently, pembrolizumab was further approved for treatment of recurrent or metastatic cervical cancer for patients who expressed PD-L1 on tumour cells [29]. In the same month, it was further approved to treat resistant primary mediating large B-cell lymphoma (PMBCL) in adults and paediatrics and showed a 45% response rate [30]. However, 26% of patients did develop serious adverse effects suggesting further work is still needed in the cancer type.

Nivolumab, a second PD-1 inhibitor, has also been investigated in several tumours and shown anti-tumour activity. In 2014, it was approved for metastatic melanoma treatment [31,32], and in 2015, nivolumab was further approved for metastatic NSCLC after a study demonstrated improved overall survival compared with docetaxel therapy [33]. Nivolumab was also approved for use in advanced metastatic renal cell carcinoma (RCC) as it showed improved overall survival over everolimus (Afinitor) [34]. In 2016, nivolumab was approved for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) after a study showed longer overall survival when compared with chemotherapy [35].

Recently, in September 2018, cemiplimab (REGN2810) has been approved to treat patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation [36]. There are also many other anti-PD-1 antibodies, for example pidilizumab (a humanised anti-PD-1), AMP-224, MEDI0680, PDR001, CT-001, in clinical trials for several tumour types [37].

Anti-PD-L1 (atezolizumab, durvalumab and avelumab)

PD-L1 inhibitors have also been approved for use in solid tumours. Atezolizumab was approved for advanced bladder cancer [38] and metastatic NSCLC in 2016 [39,40]. In 2017, avelumab was approved for merkel cell cancer, an aggressive skin cancer, and UCC. In merkel cell cancer, avelumab was the first targeted therapy approved for this disease, the Phase II trial studied avelumab in stage IV chemotherapy refractory disease via an international multicenter trial across North America, Europe, Asia, and Australia [41]. The result showed a 31% response rate and 10.4 months response duration. In UCC, a study in mUCC patients showed 11.4 weeks median response rate. However, almost all patients developed adverse events [42]. Overall, PD-1 and PD-L1 inhibitors have shown good response rates across a variety of cancers but further work is needed to enhance their efficacy and decrease toxicity. In addition, durvalumab was approved for advanced or mUCC in 2017 and NSCLC in 2018 [43,44].

Anti-CTLA-4 (ipilimumab)

The main CTLA-4 inhibitor studied to date is ipilimumab, a monoclonal antibody that was the first checkpoint inhibitor the FDA approved for advanced melanoma in 2014. It was shown to increase T-lymphocyte proliferation and restore the anti-tumour immune response [45]. Based on the Phase III clinical study in unresectable stage III or IV melanoma that divided patients into three treatment groups, ipilimumab plus glycoprotein 100 (gp100) peptide vaccine, ipilimumab alone, and gp100 alone. The result showed that ipilimumab significantly improved patients overall survival compared with the gp100 alone or the combination [46]. Ipilimumab has now also been approved for use in RCC in combination with nivolumab [47].

Tremilimumab, an IgG2 monoclonal antibody, is another anti-CTLA-4 that showed satisfactory result in Phase I/II studies in advance melanoma [48]. However, when tested in a Phase III trial compared with chemotherapy, tremilimumb induced toxicity and showed no survival benefit over chemotherapy [49]. Therefore, tremilimumab was not approved, but further clinical trials are now ongoing to study this drug in combination with current therapies and to assess potential biomarkers to predict treatment response.

Immune checkpoint inhibitors in CRC

Although checkpoint inhibitors have exhibited successful results in other tumours, in CRC, the results for immunotherapy are not as favourable. Initial studies showed some promising results in metastatic CRC patients with dMMR tumours, but not in mismatch repair (MMR) competent patients, which only represents a small proportion of metastatic patients. Therefore, pembrolizumab and nivolumab are only FDA approved for this small group of patients with metastatic dMMR CRC, suggesting that other strategies are required for these inhibitors to be translated to a wider range of CRC tumours.

To address this, immune checkpoint inhibitors are now being trialed in combination with chemotherapy, radiotherapy and other agents that might block factors that suppress the immune response or agents that directly stimulate the immune response, to prime for immunotherapy use [50]. However, there is still a problem with resistance to checkpoint inhibitor due to various factors including signaling pathways which inhibit the anti-tumour activity of immune cells [51]. At the moment, monotherapy or combination therapy to enhance the drug efficacy and reduce this resistance rate in CRC is being considered in parallel to examine new therapeutic targets.

Therefore, a combination of pembrolizumab with azacitidine chemotherapy was performed in MMR competent metastatic CRC. The results observed an enhancement of pembrolizumab anti-tumour activity when combined with this chemotherapy in these patients. The trial is now in Phase II with a cohort of 31 MMR competent metastatic CRC patients receiving 200 mg pembrolizumab every 3 weeks and 100 mg azacitidine daily. However, the results showed a low response rate (3%) and the median overall survival was only 6.2 months. Ten patients did, however, developed rapid stabilisation of tumour progression but treatment-related adverse events occurred in 63% of patients [52]. Therefore, pembrolizumab plus azacitidine showed a low anti-tumour activity for MMR competent metastatic CRC, however, disease stabilisation in some patients may suggest that biomarkers are needed to predict those patients that will achieve disease stabilisation and those that will develop toxicity. Similarly, a combination of nivolumab and ipilimumab was preliminarily studied and showed potential efficacy in the same cohort. The result from 27 patients showed a 41% objective response rate with 78% disease control rate. Tumour-related adverse events occurred in 37% of patients but there was no death due to this therapy [53]. This study is still ongoing to further assess long-term efficacy and analysis of potential predictive biomarkers.

As the PD-L1 inhibitor, atezolizumab, has shown only a partial response in CRC Phase I studies, currently, studies of atezolizumab combined with the vascular endothelial growth factor (VEGF) inhibitor bevacizumab, or atezolizumab plus bevacizumab and FOLFOX in metastatic CRC look promising [54]. Both studies showed significant anti-tumour effects. Many other anti-PD-L1 compounds are also in ongoing studies for combination therapy, i.e. durvalumab and avelumab. Recently, the WNT/β-catenin signaling pathway has been reported to block anti-tumour activity of tumour-infiltrating lymphocytes (TILs) and enhance resistance to anti-PD-1/PD-L1. In addition, immune evasion was further promoted by signal transducer and activator of transcription 3 (STAT3) signaling; BBI608 is an inhibitor that blocks STAT3 and down-regulates WNT/β-catenin signaling. Therefore, combination of pembrolizumab plus BBI608 is currently undergoing assessment for efficacy and safety in a multicenter Phase I/II trial [55].

The trial aims to block WNT/β-catenin and STAT3 signaling in eight patients with MMR competent metastatic CRC, to try to enhance the efficacy of pembrolizumab. In the Phase I trial, patients were divided into two groups: for group 1, five patients received 240 mg BID everyday with 200 mg pembrolizumab; and for group 2, three patients received 480 mg BID everyday with 200 mg pembrolizumab. The result showed that one patient in group 1 developed dose-limiting toxicity and was discontinued, however, the rest of the patients in this group presented no toxicity related symptoms, with no toxicity seen in group 2. Interestingly, one patient in group 2 demonstrated tumour shrinkage over more than 12 weeks with a significant decline in carcinoembryonic antigen (CEA) levels in both lung and lymph node metastases. From these initial results, it suggests this combination might induce anti-tumour activity. This cohort will now continue into a Phase II trial to confirm the efficacy and safety of this combination [56]. These results suggest that for CRC the way forward for immunotherapy is combination with other drugs to prime the immune landscape. Developing predictive biomarkers for treatment response and toxicity may further enhance this.

ACT to enhance T-cell functions

Passive immunotherapy or cell-based therapy is based on immune effector cells that are generated ex vivo and then transferred into the patient known as ACT. ACT is a type of cell-based therapy based on collecting tumour infiltrating or circulating lymphocytes from patients, processing them ex vivo to target a specific neoantigen, and then re-infusion of the cells back into patient (Figure 2). The predominant cell types used are T lymphocytes and natural killer (NK) cells, which both have anti-tumour characteristics, cytolytic actions and produce cytokines to eliminate tumour cells [57].

General principle of CAR-T cell therapy

Figure 2
General principle of CAR-T cell therapy

T lymphocytes from patient’s blood are engineered in vitro to express CAR to enhance T cells’ binding to tumour antigens, after expansion with IL2 they are re-infused into patient to bind to tumour receptors and enhance killing of tumour cells.

Figure 2
General principle of CAR-T cell therapy

T lymphocytes from patient’s blood are engineered in vitro to express CAR to enhance T cells’ binding to tumour antigens, after expansion with IL2 they are re-infused into patient to bind to tumour receptors and enhance killing of tumour cells.

CAR T-cell therapy

Current ACT strategy targets T lymphocytes that are genetically modified to express CAR-T, which is specific to tumour cells. They recognise native tumour antigen on cell surface instead of epitopes presented by human leucocyte antigen (HLA) molecules. Engineered CAR-T cells are linked to the intracellular signalling domain of T lymphocytes by using the antibody-derived single-chain variable fragment (scFv), resulting in T lymphocytes being recognised via surface antigens independent of MHC [58]. After they bind to the tumour antigen, CARs then activate T lymphocytes to kill the tumour. The most important CAR-T cells are generated to target specific tumour cell surface antigens; this avoids unexpected autoimmune diseases. As CARs do not rely on HLA, they can be employed in all patients regardless of HLA haplotype. Currently, CAR-T cell therapy is approved to treat haematologic malignancies, including chronic lymphocytic leukaemia (CLL) and acute lymphocytic leukaemia (ALL) patients and adults with certain types of large B-cell lymphoma [59,60]. Recently, a study reported the potential of CAR-T cells therapy in breast cancer, however, more evidence is needed before the approval of CAR-T cell therapy for this cancer type [61].

CAR-T cells therapy and CRC

In CRC, CAR-T cells are being investigated for metastatic disease. Animal model for CAR-T cells targeting CRC antigens, classic CEA and emerging guanylyl cyclase C (GUCY2C), show therapeutic potential that might translate to clinical use. When targeting CEA, animal experiments suggest that CAR-T cells may induce tumour regression; however, they also cause toxicity due to cytokine release syndrome. In human trials, the initial studies focused on CRC with liver metastasis, and no patients were reported to develop severe adverse effects; however, disease progression was not suppressed, and cancer-specific survival was not improved.

As for targeting GUCY2C, these have only been studies in animal models. Initial results from pulmonary metastasis suggest that CAR-T cells targeting GUCY2C could reduce tumour burden and significantly prolong survival; however, this needs to be confirmed in human studies. Targeting GUCY2C showed no autoimmunity issues and had good safety and efficiency to treat metastatic CRC [62]. From these initial results, CAR-T cells therapy has the potential to be a useful CRC metastasis treatment although further safety testing is required.

Enhancing the efficacy of current immunotherapies

Although immunotherapy has shown satisfactory results in multiple types of cancer, many patients show no response, for example, in MMR competent CRC. Therefore, strategies that enhance the efficacy of immunotherapy are now the focus of many studies. Some approaches to enhance the efficacy of immunotherapy include performing immune checkpoints combination therapy to increase treatment yield, evaluating biomarkers for treatment responses to observe treatment effectiveness, assessing biomarkers for treatment toxicities to reduce treatment failure and investigating new potential targets.

Immune checkpoint inhibitor combination therapy

Currently, combinations of anti-PD-1/PD-L1 and CTLA-4 drugs are in clinical trials, focusing on ipilimumab with nivolumab or pembrolizumab. To date, combination trials in advanced melanoma have shown that a reduced dose of nivolumab combined with the standard dose of ipilimumab showed better response rates than ipilimumab alone, however, it caused more toxicity [63]. Conversely, a Phase I study of standard-dose pembrolizumab combined with low-dose ipilimumab in advanced melanoma showed significant anti-tumour activity and controllable toxicity, therefore, a Phase II trial is now underway [63,64].

Predictive biomarkers for treatment response

Immunotherapy may have shown disappointing results in some tumours because of the genetic variability or differing strengths of the host immune response within each patient. Therefore, specific biomarkers or clinical features that could be used to predict response to treatment are likely to be key in improving the effectiveness of immunotherapy in these patients. This is already suggested with MMR status being used as a predictive marker for pembrolizumab and nivolumab in a variety of cancers. Another potential biomarker candidate for immune checkpoint therapies includes immunological biomarkers, such as intratumoral PD-L1. However, a study from Aguiar et al. [65] showed that PD-L1 negative tumours still respond to checkpoint inhibitor drugs [65]. Suggesting that intratumoural PD-L1 might not be an effective marker for PD-1/PD-L1 inhibitor. Recently, PD-L2 expression was also found to be an independent prognostic factor that may also predict the effectiveness of anti-PD-1 therapy [66,67].

Biomarkers related to clinical responses to anti-PD-1, anti-PD-L1 and anti-CTLA-4 checkpoint inhibitors therapies are currently being studied in both patient’s tumour tissue and blood samples [66,68] (Table 2). In tumour tissues, many biomarkers have been studied, for example, TILs, PD-L1 expression and mutational load. TILs present at the intratumoral site have been shown to be associated with improved clinical benefit for anti-CTLA-4 therapy in advanced melanoma [69]. Also, PD-L1 expression has been shown to associate with improved clinical benefit from anti-PD-1/anti-PD-L1 therapy in multiple cancer types including advanced melanoma and breast cancer [70,71]. Furthermore, mutational load has been performed for both anti-CTLA-4 and anti-PD-1 therapy. In melanoma, it was shown that high mutational load related to improved efficacy for anti-CTLA4 therapy [72]; whereas in NSCLC high mutational load was associated with better efficacy for anti-PD-1 therapy [73]. From these studies, it suggests that assessing treatment responses using various predictive biomarkers may benefit immunotherapy outcomes.

Table 2
Potential biomarkers associated with immune checkpoint inhibitors’ treatment response and toxicity
Samples Biomarkers Antibody References 
Potential biomarkers associated with treatment response    
Tumour tissues TILs Anti-CTLA-4 [60
 PD-L1 expression Anti-PD-1 [61,62
 Mutational load Anti-CTLA-4 [6
  Anti-PD-1 [64
Blood Circulating leucocytes Anti-CTLA-4 [65
 Neutrophil-to-lymphocyte ratio (NLR) Anti-CTLA-4 [66
 Lactate dehydrogenase (LDH) level Anti-CTLA-4 [67
Potential biomarkers associated with treatment toxicity    
Tumour tissues Neutrophil infiltration Anti-CTLA-4 [68,69
Blood Eosinophil level Anti-CTLA-4 [70
Samples Biomarkers Antibody References 
Potential biomarkers associated with treatment response    
Tumour tissues TILs Anti-CTLA-4 [60
 PD-L1 expression Anti-PD-1 [61,62
 Mutational load Anti-CTLA-4 [6
  Anti-PD-1 [64
Blood Circulating leucocytes Anti-CTLA-4 [65
 Neutrophil-to-lymphocyte ratio (NLR) Anti-CTLA-4 [66
 Lactate dehydrogenase (LDH) level Anti-CTLA-4 [67
Potential biomarkers associated with treatment toxicity    
Tumour tissues Neutrophil infiltration Anti-CTLA-4 [68,69
Blood Eosinophil level Anti-CTLA-4 [70

In blood samples, several biomarkers have been studied including circulating leucocytes (lymphocytes, neutrophils, eosinophils and monocytes), myeloid-derived suppressor cells (MDSCs) level and lactate dehydrogenase (LDH) level. For anti-CTLA-4, high lymphocytes level during treatment related to better overall survival on this therapy [74]. Furthermore, the neutrophil-to-lymphocyte ratio (NLR) declined during on-going treatment and this showed association with a higher survival rate [75]. In contrast, high serum LDH level prior to treatment with anti-CTLA-4 therapy was associated with resistance to treatment [76]. Although wide varieties of biomarkers have been investigated in multiple cancers, validation is now required before translation into clinical setting can be achieved.

Predictive biomarkers for toxicity

One issue with checkpoint inhibitors is that the treatment can cause severe immune-related adverse events (irAEs), frequently affecting the skin, intestinal tract, liver and endocrine system. These irAEs occur more frequently with anti-CTLA-4 antibodies than anti-PD-1/anti-PD-L1 antibodies [61]. As these can be life-threatening they often lead to therapy being stopped. Therefore, predictive biomarkers that test for toxicity in patients are also needed to improve both the patient’s quality of life and survival outcomes.

Biomarkers associated with ipilimumab treatment toxicities in melanoma patients have been studied in colon tissue to investigate toxicity within the intestinal tract [77]. The results showed that neutrophil infiltration within the lamina propria of colon biopsies and other markers of digestive dysregulation including histological observation, faecal calprotectin and antibodies for enteric flora were associated with digestive toxicity. This suggests that ipilimumab induces colitis as confirmed by Marthey et al. [78], who then investigated these biomarkers during drug administration and showed they could be of benefit for predicting these adverse effects and improving the quality of life of the patients.

Similarly, another study using blood samples of melanoma patients treated with ipilimumab measured eosinophils level before and after treatment. The result showed that absolute eosinophil counts increased over treatment and were associated with the occurrence of irAEs [79]. To address this further, gene expression profiles of peripheral bloods from advanced melanoma patients treated with ipilimumab, that had developed gastrointestinal tract irAEs, were investigated [80]. The result showed increased expression of neutrophil markers, CD177 and CEA-related cell adhesion molecule 1 (CEACAM1), during treatment supporting the potential role of neutrophil in irAEs of ipilimumab within the gastrointestinal tract. However, further studies from larger cohorts of patients are needed as well as other more specific predictive markers in order for early management of irAEs to occur.

Alternative targets for immunotherapy

At present, apart from targeting PD-1/PD-L1 and CTLA4 pathway, many other immune pathways are being targeted including macrophage targeting therapy, cytokine therapy, toll-like receptor (TLR) agonists, and other checkpoint inhibitors including T-cell membrane protein (TIM-3 or HAVcr2), lymphocyte activation gene (LAG-3 or CD223), B- and T-lymphocyte attenuator (BTLA or CD272), and V-domain Ig suppressor of T-cell activation (VISTA) [64]. As a result, personalised medicine using these targeted immunotherapies is the main focus for future cancer treatments combined with actively seeking predictive biomarkers to increase responsiveness to these treatments.

Novel approaches to immunotherapy are also under investigation including utilising a newly targeted drug delivery system for CD8+ T lymphocytes called nanoparticles that was proposed by Schmid et al. [81]. The study in mice utilised antibody-targeted nanoparticles bound to CD8+ T lymphocytes in blood, lymphoid tissues and the tumour. The result showed the nanoparticles successfully targeted PD-1+ T lymphocytes in the blood and tumour. Using these nanoparticles, a transforming growth factor beta (TGFβ) inhibitor was delivered to PD-1 expressing cells and showed extra survival benefit compared with delivering the inhibitor as a free drug at the same dose. Nanoparticles also modulated the ratio of tumour infiltrating CD8+ T lymphocytes and sensitised tumours to anti-PD-1 therapy [81]. From the results, using nanoparticles targeting specific effector cell’s function to kill tumour cells and inhibit suppressor cells at the same time could potentially change non-responder to responder for immunotherapy.

Other delivery methods are also under development including peptides and antibody-based systems. Furthermore, cellular mechanisms, such as cellular influx, are being investigated to deliver immune regulating compounds to the tumour area [82]. Overall, it is promising time for the use of immunotherapy as a treatment for solid and haematological tumours. Furthermore, enhancing the efficacy of these treatments via combination therapies and utilising biomarkers could expand the treatments prospects.

Conclusion

In conclusion, the immune system plays an essential role in cancer progression through mechanisms regulated by multiple immune cells types in tumour microenvironment. Of these, immune checkpoints, such as PD-1/PD-L1 and CTLA-4, are crucial proteins that inhibit the immune system anti-tumour effects and promote tumour progression. Therefore, immunotherapy targeting immune checkpoints to restore the killing function of immune cells is an alternative treatment strategy. Currently, there are many drugs targeting PD-1/PD-L1 and CTLA-4 that are approved to treat multiple tumour types, with nivolumab and pembrolizumab at the forefront of many clinical trials.

However, not all patients respond to these treatments and this might be due to differences at a genomic or immune level within each patient that is affecting their response to the drug’s action. Therefore, biomarkers that predict response to treatment are also essential for immunotherapies success. As a result, combination therapies of immunotherapy and conventional chemotherapy or radiotherapy are being investigated to see if these can prime the immune system to enhance the efficacy of the immunotherapy. Furthermore, targeting of other checkpoint inhibitors and immune pathways are being investigated to enhance the effectiveness of immunotherapy and move towards a more personalised therapy approach. Additionally, utilising nanoparticles as a newly targeted drug delivery system to target CD8+ T lymphocytes to the tumour is a novel approach to immunotherapy that may enhance adoptive CAR-T cells therapy and is currently a major focus of many clinical trials. Overall, immunotherapy could be a powerful tool to fight multiple cancers; nevertheless, more investigation is needed to enhance efficacy and reduce toxicity within patients.

Competing interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

This work was supported by the Thai Government PhD Scholarship.

Author contribution

J.I. analysed the data and wrote the manuscript. J.E. reviewed the manuscript. A.K.R. devised the study design and reviewed the manuscript.

Abbreviations

     
  • ACT

    adoptive cell transfer

  •  
  • APC

    antigen-presenting cell

  •  
  • CAR

    chimeric antigen receptor

  •  
  • CEA

    carcinoembryonic antigen

  •  
  • cHL

    classical Hodgkin lymphoma

  •  
  • CRC

    colorectal cancer

  •  
  • CSCC

    cutaneous squamous cell carcinoma

  •  
  • CTLA-4

    cytotoxic T-lymphocyte antigen-4

  •  
  • dMMR

    mismatch-repair deficient

  •  
  • GEJ

    gastroesophageal junction

  •  
  • gp100

    glycoprotein 100

  •  
  • GUCY2C

    guanylyl cyclase C

  •  
  • HLA

    human leucocyte antigen

  •  
  • irAE

    immune-related adverse event

  •  
  • LDH

    lactate dehydrogenase

  •  
  • MSI-H

    microsatellite instability-high

  •  
  • MMR

    Mismatch Repair

  •  
  • mUCC

    metastatic urothelial carcinoma

  •  
  • NSCLC

    non-small cell lung cancer

  •  
  • PD-1

    programmed cell death-1

  •  
  • PD-L1

    programmed cell death ligand-1

  •  
  • PD-L2

    programmed cell death ligand-2

  •  
  • RCC

    renal cell carcinoma

  •  
  • scFv

    single-chain variable fragment

  •  
  • STAT3

    Signal transducer and activator of transcription

  •  
  • TGFβ

    Transforming growth factor beta

  •  
  • TIL

    tumour-infiltrating lymphocyte

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