Abstract

Increased understanding of cellular and molecular tumour immunology over the past two decades has enabled the identification of new and innovative ways to manipulate the immune response to cancer, with recent phase III trials in patients with metastatic melanoma and hormone-resistant prostate cancer providing proof-of-principle that immunotherapies can improve survival. Based on these successes, many new immunotherapies are being developed, including vaccines and other agents that prime or boost the immune system, T-cell modulatory agents, agents that enhance innate immunity and agents designed to inhibit immunosuppression within the tumour microenvironment. Current experience suggests that immunotherapies are a promising foundation to build treatment regimens for a variety of tumour types. Because many approaches target the immune system and not the cancer, immunotherapies are being evaluated in almost every tumour type, including those that were not previously considered likely to respond to immune manipulation. Immunotherapies also have potential for durable and adaptable cancer control at different stages of disease, including those with early-stage disease and low tumour burdens. To maximise benefits, however, it is likely that combination regimens with conventional cancer treatments or other immunotherapies will be necessary. In addition, the identification of biomarkers will allow further optimisation from a mechanistic and a patient selection perspective. Further advances in research will necessitate multidisciplinary collaboration among physicians, basic and translational researchers and the pharmaceutical industry to ensure that immuno-oncology becomes a cornerstone element in the development of cancer therapy.

introduction

The idea that the immune system might respond to cancer was first theorised in the late 19th century, when, upon noting that feverish infections were associated with tumour regression in some patients with cancer, William Coley began injecting cancer patients with a bacterial toxin, achieving a cure rate of over 10%. In 1909, Paul Ehrlich suggested that cancers may occur at an ‘overwhelming frequency’ were it not for the immune system, and in the 1960s Frank Burnet proposed that lymphocytes were continually patrolling tissues and eliminating tumour cells, presumably via recognition of tumour-associated antigens (TAA), a process he termed as ‘immunosurveillance’ (reviewed in [1]). However, this concept was not widely accepted until a report characterising the first human TAA recognised by lymphocytes from a melanoma patient, referred to as MAGE-A1, was published in 1991 [2]. Subsequently, data regarding human TAA continued to increase, with different categories of TAA being identified. Many TAA are expressed in human tumours of different histological origin [3].

Recognition of TAA as nonself initiates an immune response that can keep the growth of tumours in check; however, in some individuals the equilibrium between immunity and tumour growth is disrupted. In these cases, immunoselection for tumour cells that are able to avoid, resist or suppress the natural immune response occurs, resulting in the emergence of malignant tumours that are often resistant to elimination by the immune system [4–6].

The field of immuno-oncology involves the development of therapies that can harness or potentiate the body's intrinsic potential for generating an effective immune response against cancer. In 1985, the observation that treating cancer patients with interleukin-2 (IL-2), a cytokine that stimulates the growth, differentiation and survival of antigen-selected cytotoxic T cells, resulted in durable antitumour responses [7] represented the first demonstration that manipulation of the immune system could reproducibly lead to tumour regression. These data ultimately led to the Food and Drug Administration (FDA) approval of IL-2 for the treatment of patients with metastatic renal cell carcinoma in 1992 and with metastatic melanoma in 1998 [8].

When a new therapeutic modality is discovered, however, its use is accompanied by increased understanding of both toxic effect and limitations of treatment efficacy [9]. Indeed, until recently, confidence in using immunotherapies to modulate the immune system was tempered by disappointing results from clinical trials with cancer vaccines and biochemotherapy regimens, and by the low response rates and high toxic effect associated with cytokines like IL-2 [10].

Despite the initial lack of clinical success, extensive immuno-oncology research over the past two decades has enabled the identification of new and innovative ways to manipulate the immune response to cancer. As a result, we now have proof-of-principle that immunotherapies can prolong the survival of patients with advanced cancer. Data from a phase III trial with ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) showing substantial improvements in overall survival (OS) [11], resulted in ipilimumab 3 mg/kg receiving marketing authorisation from both the FDA (for all patients with metastatic melanoma) and European Commission (for pretreated patients only) in 2011 and sipuleucel-T recently became the first approved therapeutic vaccine for any type of cancer following its FDA approval in 2010 for the treatment of patients with hormone-resistant prostate cancer [12].

Reinvigorated by these successes and our improved understanding of tumour immunology, many new immunotherapies are being developed, representing an alternative strategic approach to cancer treatment that will hopefully compliment both conventional cytotoxic approaches and molecularly targeted therapies currently in development.

Not only is the range of therapies in development exciting, but also the number of patients that may benefit. While recent successes have been limited to a number of patients with advanced melanoma and prostate cancer, immunotherapies are being evaluated in almost every type of cancer, including those that were not previously considered likely to respond to immune manipulation.

can immuno-oncology change our approach to cancer treatment?

In 2000, Hanahan and Weinberg suggested that the malignant growth of cancer cells resulted from six physiological changes, collectively termed ‘hallmarks’ of cancer. These comprised an independence from exogenous growth signals, insensitivity to signals that block proliferation, evasion of apoptosis, limitless replicative potential, sustained angiogenesis and tissue invasion and metastasis [13]. In 2011, prompted by increased understanding of the complexities of cancer, Hanahan and Weinberg revisited the original hallmarks, and added a further two emerging hallmark capabilities to the list. The first involved changes in energy metabolism in order to fuel cell growth and division. The second considers active evasion by cancer cells from attack and elimination by immune cells. In addition, they noted that rather than tumours merely being a collection of proliferating cancer cells, they are in fact complex tissues composed of multiple distinct cell types; therefore, to fully understand tumour biology it is necessary to also consider the role of the tumour microenvironment [14].

Imbalances in the tumour microenvironment, resulting from changes in antigen-presenting-cell (APC) subsets, co-stimulatory and co-inhibitory molecules, tumour-derived growth factors and the ratio of effector T cells and regulatory T cells (Treg), result in immune tolerance, whereby cancer cells and host immune cells interact to create an immunosuppressive network that promotes tumour growth and protects the tumour from immune attack [15, 16]. These findings point to daunting complexity within tumours, and suggest that rather than focusing on one component, a systems-biology approach may be necessary to account for the interaction between immune cells, tumour cells, stromal cells and the extracellular matrix. They also suggest that using therapies that target the stromal compartment or immune response directly, including those that challenge immune tolerance within the tumour, is a viable therapeutic approach.

The immune system can be leveraged to fight cancer via four broad, overlapping strategies, comprising priming/boosting of the immune system, T-cell modulation, reducing immunosuppression in the tumour microenvironment and enhancing adaptive immunity [16–19].

One example of T-cell modulation is to use monoclonal antibodies that block CTLA-4 which, together with its homologous counterpart CD28, acts to keep the stimulation and inhibition of T-cell proliferation and activation in balance. CTLA-4, which has a much greater binding affinity for the B7 surface molecules found on APCs than CD28, is a negative regulator of T-cell activity. By contrast, CD28 stimulates T-cell activity. Inhibition of CTLA-4, therefore, prevents binding to B7 molecules, allowing CD28 to function unopposed. This tips the balance towards immune stimulation and the breaking of immune tolerance [20].

Alternatively, cancer vaccines can be used to prime/boost the immune system by generating or amplifying antigen-specific immune responses to proteins differentially expressed by tumour cells. Vaccines activate immune system components, including dendritic cells, antibodies and T cells. The resultant antitumour T-cell response abrogates established mechanisms of immune tolerance, potentially resulting in tumour eradication [21, 22].

Immuno-oncology research involves preclinical and clinical studies to improve our understanding on each of these strategies, and concomitantly identify, understand and validate targets for therapeutic compound development.

potential for combination therapy

As immunotherapies function by distinct mechanisms, it is possible that their combination with other treatment modalities may be synergistic. For example, distinct types of cell death are thought to induce different types of immune responses, with physiological cell death (apoptosis) intrinsically tolerogenic and pathological cell death (necrosis) inherently immunogenic [23, 24]. However, although chemotherapy mostly triggers cell death with an apoptotic morphology, the therapy-induced, and therefore nonphysiological, cell death can result in a series of changes that allow innate immune effector cells to engulf portions of the stressed and dying tumour cells and present tumour-derived antigenic peptides to T cells, thus stimulating a tumour-specific T-cell response. Of note, chemotherapeutic agents differ in their capacity to induce immunogenic tumour cell death [23, 24], which will have implications on the choice of chemotherapeutic combination partner. Similarly, radiation therapy has mechanistic elements that result in the acquisition of tumour-specific immunity able to attack both the original tumour site and the sites of metastases [25], and induction of cell death following treatment with molecularly targeted inhibitors may also result in the release of tumour antigens that prime an immune response [26]. Because all of these immune-potentiating mechanisms could potentially be enhanced with immunotherapy, the scope for immunotherapy-based combination approaches is vast. However, the types of agents used, together with issues of dosing and timing, will require careful consideration in early phase clinical trials (see the supplementary article by Charles Drake).

how is immunotherapy evolving?

Because the immune system has the capacity to induce an antitumour immune response against any cancer and is common to all patients, developing agents that augment the immune response does not rely on understanding the genetic make-up of the tumour. In addition, although it may require further boosting, the immune system is not affected by specific mutations. In essence, immunotherapies are designed to enhance the immune response to the tumour while the natural, inbuilt ability of the immune system does the rest. As a result, immunotherapies have the advantage of being potentially effective for all tumours in all patients or, at the very least, most tumours in most patients. Although melanoma remains the most advanced model tumour for immuno-oncology research (see the supplementary article by Michele Maio), treatments designed to enhance the inherent antitumour capabilities of the immune system are being evaluated in almost every type of cancer (Table 1), including those that were not previously considered likely to respond to immune manipulation such as haematological malignancies, head and neck (H&N) cancer, breast cancer and colorectal cancer (CRC).

Table 1.

Immunotherapies in phase III development

Vaccines
 
Other
 
Name Indication Name MOA Indication 
Algenpantucel-L (HyperAcute®) Pancreatic cancer Girentuximab (adjuvant) (Rencarex®) ADCC Renal 
Astuprotimut-R (ASCI) Melanoma/NSCLC    
Biovest (BiovacID®) Follicular lymphoma Leukocyte interleukin (Multikine®) Combination ITx H&N 
Belagenpumatucel-L (Lucanix®) NSCLC    
CaPVAX (DCVax®-Prostate) Prostate MGN1703 TLR-9 agonist CRC 
Emepepimut-S (Stimuvax®) NSCLC Mycobacterial cell wall–DNA complex (Prostacidin™; Urocidin™) Immunostimulant Bladder/prostate 
IMA901 Renal Naptumomab estanfenatox (ABR217620) T-cell stimulant Renal 
Reniale® Renal (adjuvant)    
Talimogene laherparepvec Melanoma (OncoVEX-GM-CSF) PGG glucan (Imprime PGG®) Immunostimulant CRC 
GV1001 Pancreatic    
TG4010 NSCLC Velimogene aliplasmid (Allovectin®) Immunostimulant Melanoma 
Vitespen (approved) (Oncophage®) Melanoma/renal    
Vaccines
 
Other
 
Name Indication Name MOA Indication 
Algenpantucel-L (HyperAcute®) Pancreatic cancer Girentuximab (adjuvant) (Rencarex®) ADCC Renal 
Astuprotimut-R (ASCI) Melanoma/NSCLC    
Biovest (BiovacID®) Follicular lymphoma Leukocyte interleukin (Multikine®) Combination ITx H&N 
Belagenpumatucel-L (Lucanix®) NSCLC    
CaPVAX (DCVax®-Prostate) Prostate MGN1703 TLR-9 agonist CRC 
Emepepimut-S (Stimuvax®) NSCLC Mycobacterial cell wall–DNA complex (Prostacidin™; Urocidin™) Immunostimulant Bladder/prostate 
IMA901 Renal Naptumomab estanfenatox (ABR217620) T-cell stimulant Renal 
Reniale® Renal (adjuvant)    
Talimogene laherparepvec Melanoma (OncoVEX-GM-CSF) PGG glucan (Imprime PGG®) Immunostimulant CRC 
GV1001 Pancreatic    
TG4010 NSCLC Velimogene aliplasmid (Allovectin®) Immunostimulant Melanoma 
Vitespen (approved) (Oncophage®) Melanoma/renal    

Source: AdisInsight, ClinicalTrials.gov.

ASCI, antigen-specific cancer immunotherapeutics; ADCC, antibody-dependent cell-mediated cytotoxicity; CRC, colorectal cancer; H&N, head and neck; ITx, immunotherapy; GM-CSF, granulocyte-macrophage colony-stimulating factor; MOA, mechanism of action; NSCLC, non-small-cell lung cancer; PGG, poly-[1–6]-d-glucopyranosyl-[1–3]-d-glucopyranose; TLR, toll-like receptor.

CRC is the most common malignancy affecting both men and women in Europe, with an estimated 435 600 cases and 212 100 deaths from the disease in 2008 [27]. Because there is a high risk of recurrence among patients with stage I and II disease, identification of prognostic markers of outcome is an important focus of research. Traditionally, tumour staging using the TNM classification system which summarises data on tumour burden (T), presence of cancer cells in draining and regional lymph nodes (N) and evidence of metastases (M) has been valuable in estimating the outcome in cancer patients. However, the outcomes are known to significantly vary among patients within the same histological tumour stage, possibly because the staging system solely focuses on cancer cells and does not account for factors that can enhance or suppress tumour growth, such as the host's immune system [28].

In a large study of tissue samples from 602 patients with stage I and II CRC, a high density of CD8+ cytotoxic T cells and CD45RO+ memory T cells in the centre and the invasive margin of the tumour significantly correlated with longer disease-free survival (DFS), disease-specific survival (DSS) and OS, respectively, compared with patients whose tumours had low densities (Figure 1) [29]. Using Cox multivariate regression analyses (Table 2), the immune score was found to be significantly and independently associated with DFS, DSS and OS (Hazard ratio: 0.34, 0.35 and 0.54, respectively, all P < 0.0001) and, interestingly, was superior to TNM (tumour–node–metastasis) in predicting tumour recurrence and patient survival [29, 30]. There was also an inverse correlation between the immune cell density and the tumour stage; most in situ or T1 stage tumours had high T-cell infiltration compared with only a small percentage of T4 tumours, suggesting that a strong intratumoural immune response protects against tumour progression. In addition, in patients with recurrence, the number of cytotoxic CD8+ T cells was low regardless of the tumour stage, indicating that even in the case of minimal tumour invasion patients with a low immune score are more likely to relapse. The prognostic power of immune cell infiltration was applicable regardless of whether the tumour tissue was obtained from patients with stage I or IV CRC [28, 29, 31, 32].

Table 2.

Multivariate Cox proportional hazards analysis of patients with stage I/II colorectal cancer (CRC)

Variable PHA testa Hazard ratio 95% CI P 
DFS 
 T stage 0.7817 1.17 0.81 to 1.68 0.4100 
 Perforationb 0.8840 5.51 2.17 to 14.03 0.0003d 
 Immune scorec 0.7243 0.34 0.24 to 0.48 <0.0001d,e 
  0.35f 0.25 to 0.49  
OS 
 T stage 0.4476 1.03 0.81 to 1.33 0.7900 
 Perforationb 0.3728 5.38 2.45 to 11.78 <0.0001d 
 Immune scorec 0.0229g 0.54 0.43 to 0.69 <0.0001d 
DSS 
 T stage 0.8670 1.22 0.79 to 1.88 0.3800 
 Perforationb 0.3559 11.05 4.05 to 30.2 <0.0001d 
 Immune scorec 0.4282 0.35 0.24 to 0.52 <0.0001d 
Variable PHA testa Hazard ratio 95% CI P 
DFS 
 T stage 0.7817 1.17 0.81 to 1.68 0.4100 
 Perforationb 0.8840 5.51 2.17 to 14.03 0.0003d 
 Immune scorec 0.7243 0.34 0.24 to 0.48 <0.0001d,e 
  0.35f 0.25 to 0.49  
OS 
 T stage 0.4476 1.03 0.81 to 1.33 0.7900 
 Perforationb 0.3728 5.38 2.45 to 11.78 <0.0001d 
 Immune scorec 0.0229g 0.54 0.43 to 0.69 <0.0001d 
DSS 
 T stage 0.8670 1.22 0.79 to 1.88 0.3800 
 Perforationb 0.3559 11.05 4.05 to 30.2 <0.0001d 
 Immune scorec 0.4282 0.35 0.24 to 0.52 <0.0001d 

aPHA test (P < 0.05 violates the hazards assumption).

bBowel perforation present (yes, no).

cCD8CT/IMCD45ROCT/IM {stratified into four groups [(4)-Hi, (3)-Hi, (2–1)-Hi and (0)-Hi] according to the number of high densities of CD8 or CD45RO in the centre of the tumour (CT) and the invasive margin (IM)}.

dSignificant.

eMinimum P value cut-off with (4)-Hi, (3)-Hi, (2-1)-Hi or (0)-Hi.

fHazard ratio corrected as suggested by Hollander et al. [30].

gImmune score cannot be considered for OS as it violates the hazards assumption, although it is highly significant.

CI, confidence interval; DFS, disease-free survival; DSS, disease-specific survival; OS, overall survival; T, tumour; PHA, proportional hazards assumption

Figure 1

Kaplan–Meier curves illustrating the duration of disease-free survival (DFS) and overall survival (OS) according to the densities of CD45RO+ memory cells (A and B) and CD8+ cytotoxic T cells (C and D). Survival of patients with stage I/II colorectal cancer (CRC) was assessed for each marker according to whether they had high densities (HiHi), low densities (LoLo) or heterogeneous densities (Het) in the centre and invasive margin of tumours. Duration of DFS and OS of the entire cohort of patients is also represented (all patients). Reprinted with permission from Pages et al. [29]). ©2009 American Society of Clinical Oncology. All rights reserved.

Figure 1

Kaplan–Meier curves illustrating the duration of disease-free survival (DFS) and overall survival (OS) according to the densities of CD45RO+ memory cells (A and B) and CD8+ cytotoxic T cells (C and D). Survival of patients with stage I/II colorectal cancer (CRC) was assessed for each marker according to whether they had high densities (HiHi), low densities (LoLo) or heterogeneous densities (Het) in the centre and invasive margin of tumours. Duration of DFS and OS of the entire cohort of patients is also represented (all patients). Reprinted with permission from Pages et al. [29]). ©2009 American Society of Clinical Oncology. All rights reserved.

An important question is whether this prognostic immune score is specific to CRC or can be more broadly applied to other cancers. Evidence would suggest that the phenomenon is widely applicable; for example, in multivariate analyses, increased infiltration of cytotoxic CD8+ T cells has been shown to correlate with prolonged survival in a variety of epithelial cell cancers, including small-cell lung carcinoma; carcinomas of the endometrium, bile duct, oesophagus and urothelium; pancreatic adenocarcinoma and hepatocellular carcinomas.

These observations represent an important paradigm shift in the field of immuno-oncology; T-cell infiltration will potentially identify those patients, regardless of the tumour type, who will benefit most from immunotherapies and also provides a tool or a target for novel therapeutic approaches [28, 32].

conclusions

Since many treatment approaches target the immune system and not the cancer and do not require identification of specific tumour antigens, there is a reason to believe that future approaches may allow treatment of many, if not all, cancers. Moreover, the identification of T-cell infiltrates in early-stage tumour samples suggests that immunotherapies may have efficacy in patients with early-stage disease and low tumour burdens, enabling the immune system to eradicate primary tumours and micrometastases and protect against recurrence.

Our renewed enthusiasm for this exciting and dynamic treatment approach is driving development forward. Through collaboration with basic and translational researchers we will continue to unravel the complexity of the immune response to cancer, identifying new therapeutic opportunities and ways to optimise established immunotherapies, such as using biomarkers or developing combination regimens. The experience gained during the development of agents like ipilimumab and sipuleucel-T will be invaluable as new agents are developed.

disclosure

AE has served as a consultant for Bristol-Myers Squibb and Merck.

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