Basic Overview of Current Immunotherapy Approaches in Cancer
Publication: American Society of Clinical Oncology Educational Book
Over the past decade, the role of the immune system in controlling tumorigenesis and tumor progression has been well established. Although the role of the adaptive (e.g., lymphocyte-mediated) immune responses has been extensively addressed, the function of the innate immune responses is less well understood. Accumulating evidence shows a correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various malignancies. In particular, the presence of CD8+ cytotoxic T cells and the ratio of CD8+ effector T cells/CD4+/forkhead box P3+ regulatory T cells (Tregs) seems to correlate with improved prognosis and long-term survival in many solid tumors.1-9 T-cell antigen receptors (TCR) on T lymphocytes engage with antigenic peptides presented on the cell surface in the context of the major histocompatibility complex (MHC). The TCR is a disulfide-linked membrane-anchored heterodimeric protein complex composed of highly variable alpha and beta chains and the invariable CD3 chain molecules.10 To respond to the myriad of possible foreign antigens, the adaptive immune system maintains a highly diverse repertoire of TCR configurations through a process known as somatic V(D)J recombination. Under normal circumstances, T cells with a diverse TCR repertoire circulate in the body patrolling for evidence of foreign peptides presented in the surface of cells because of infection or cancer.10 When a T cell encounters a tumor antigen, this results in activation, clonal proliferation/expansion, and a cytolytic response. The innate and adaptive immune systems interact to mediate the anticancer immune surveillance and immune editing.11 Dysfunctional tumor immune interactions leading to immune evasion are key events in tumorigenesis and metastasis.12 Tumors achieve this through diverse mechanisms leading to impaired antigen recognition or by creating a highly immunosuppressive tumor microenvironment. Reduced tumor epitope recognition can occur through epigenetic and post-transcriptional silencing or by alterations in the antigen-presenting/peptide-processing machinery. The presence of an immune-suppressive tumor microenvironment can be a consequence of diverse factors (alone or in combination), including the enrichment in regulatory cells (e.g., Tregs, immune inhibitory B cells, and myeloid-derived suppressor cells [MDSCs]), upregulation of co-inhibitory lymphocyte signals (e.g., membrane checkpoint ligands/receptors), elevated tolerogenic enzymes (e.g., indoleamine 2,3-dioxygenase-1, arginase-1), reduced immunoglobulin (Ig)-mediated opsonization, and the presence of a metabolically unfavorable milieu for immune cells (Fig. 1).13
Figure 1. Summary of Tumor Immune-Evasion Mechanisms Acting Through Antigenic Silencing and Immune-Suppressive Microenvironment
Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography © 2016 All Rights Reserved.
Novel anticancer immunostimulatory therapies harnessing pre-existing (ineffective) immune responses by targeting the immune checkpoint pathways have shown remarkable clinical activity across several tumor types. However, a majority of patients do not benefit from these agents, and this is likely because of the complexity/multiplicity of mechanisms in play, the heterogeneity in the immune contexture across tumors, and varying (and perhaps dynamic) tumor immunogenicity. Thus, drugs targeting various mechanisms of immune tolerance and combinations thereof are being actively investigated. Most immunotherapeutic agents currently in development could broadly be categorized into: (1) drugs targeting the tumor immune evasion via blockade of negative regulatory signals (e.g., co-inhibitory checkpoints and tolerogenic enzymes) and (2) agents that directly stimulate immunogenic pathways (e.g., agonists of costimulatory receptors). Additional immunostimulatory strategies include enhancers of antigen presentation (e.g., vaccines), the use of exogenous recombinant cytokines, oncolytic viruses, and cell therapies using native or modified antigen-competent immune cells. In this study, we will summarize the current state of these therapies and discuss their most salient biologic features and clinical perspectives.
Targeting Immune Tolerance Via Co-inhibitory Checkpoints
After TCR engagement with an antigen (e.g., signal 1), the activation and mounting of a T-cell response is context dependent and finely modulated by diverse coregulatory signals (e.g., signal 2) ultimately deciding the response fate. This process comprises a complex mechanism of simultaneous and overlapping co-inhibitory and costimulatory pathways resulting in elimination of self-reactive T cells and amplification of the antigen-specific immune responses (Fig. 1). Several drugs targeting these pathways are currently in clinical development, and some have received regulatory approval by the U.S. Food and Drug Administration (FDA) for use in various solid tumors (Table 1).
Co-inhibitory Checkpoint Pathways
CTLA-4.
CTLA-4 is expressed mainly on T cells, with some expression in other immune cells including B lymphocytes and fibroblasts.14,15 In the priming phase of antigen presentation and following TCR-peptide complex engagement, surface CTLA-4 acts as a negative regulatory receptor of T cells.15 In naive T lymphocytes, CTLA-4 is expressed at a very low level and is rapidly upregulated upon TCR engagement.15,16 The level of CTLA-4 is variable across T-cell subtypes and is regulated by the calcium/calcineurin-induced transcription factor NFATc1 (nuclear factor of activated T cells 1).17,18 Both CD4 helper and CD8 effector T cells express CTLA-4 when activated; however, the level of expression is prominently higher in CD4 T cells. Transport and cell-surface targeting (exocytosis and endocytosis) of CTLA-4 is tightly regulated by complex mechanisms not completely understood, some of them independent of T-cell activation.19 CTLA-4 is a homolog of CD28, which is a key costimulatory receptor on T cells, and hence it competes for the binding of the same ligands, CD80 and CD86. However, CTLA-4 has a higher affinity than CD28 for both ligands, resulting in interference with the immune synapse and T-cell inactivation.20 Therapeutic anti–CTLA-4 monoclonal antibodies have shown remarkable clinical activity in advanced melanoma, and the precise mechanism of action is not completely understood. In addition to the expected mechanism of disrupting the CD28 activation on T cells, anti–CTLA-4 antibodies promote depletion of Tregs in the tumor microenvironment. This effect is seem to be mediated by innate cells in the tumor expressing high levels of FcγRIV.21
PD-1/PD-L1 axis.
PD-1 is a co-inhibitory receptor expressed on several immune cells. PD-1 is highly expressed on activated T cells, B lymphocytes, natural killer (NK) cells, and MDSCs.22,23 In the effector phase of the immune response, PD-1 expression is induced by TCR-antigen engagement and by common γ-chain cytokines like interleukin (IL)-2, IL-7, IL-15, and IL-21. PD-1 has two known ligands, PD-L1 and PD-L2, both of which are expressed at relatively low levels in healthy tissues. Peripheral PD-L1 and PD-L2 expression is believed to mediate the natural immune tolerance to avoid tissue autoimmune responses and damage after a sustained inflammatory response.24,25 PD-L2 has higher affinity for the PD-1 receptor than PD-L1; when expressed in equal levels, it outcompetes PD-L1 for PD-1 engagement.25,26 PD-L2 is expressed in low levels compared with PD-L1; however, in the presence of Th2 signals, PD-L2 expression is upregulated.25 The precise role of PD-L2 in cancer immunity, tolerance, and PD-1 receptor blockade is yet unclear. PD-1 engagement with its ligands leads to effector T-cell exhaustion and apoptosis.27-29 In addition, PD-1 engagement with PD-L1 on tumors may render the tumor cells resistant to lysis by cytotoxic T-lymphocytes (CTLs) and Fas-induced apoptosis.30,31 PD-L1 expression/upregulation has been documented in various tumors, including melanoma, non–small cell lung cancer (NSCLC), breast cancer, and squamous cell head and neck cancer.1,8,9,32-34 Notably, diverse studies show that tumor PD-L1 expression is associated with increased benefit to PD-1 axis blockers, particularly in melanoma and nonsquamous NSCLC. The activation of key oncogenic pathways, including phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK), can increase PD-L1 expression in model systems.35-37 Activating mutations in tyrosine kinases such as EGFR and BRAF and loss of phosphatase and tensin homolog is also associated with PD-L1 expression via increased MAPK signaling.36-38 In addition, PD-L1 is potently induced by Th1 signals, and the majority of tumors upregulate PD-L1 in response to a proinflammatory milieu or the presence of antitumor immune pressure. This is mediated by proinflammatory cytokines including interferon gamma (IFN-γ) and IL-4 through STAT1 and IFN regulatory factor-1.
T-cell Ig and ITIM domain.
T-cell immunoglobulin and ITIM domain (TIGIT) is a T-cell co-inhibitory receptor of the immunoglobulin (Ig) superfamily member. TIGIT is expressed by subsets of CD4+ T cells (memory and regulatory), CD8+ T cells, and NK cells. The ligands for TIGIT are Ig-like transmembrane cell adhesion molecules called nectins, CD155 (poliovirus receptor [PVR]), CD112 (PVRL2), and (lower-affinity) CD113 (PVRL3, NECTIN-3).39 The PVR also binds to CD226, which is a costimulatory receptor on T cells playing an important role in antiviral and antitumoral responses.40,41 Upon activation by its cognate ligands, TIGIT suppresses NK cell killing and CD4+ T-cell activation and induces tolerance by increasing dendritic cell production of anti-inflammatory cytokines such as IL-10.42 TIGIT is highly expressed in tumor-infiltrating CD8+ T cells and is often coexpressed with other co-inhibitory receptors, particularly PD-1.43 In preclinical models, combined blockade of PD-L1 and TIGIT resulted in restoring antitumor immunity better than blockade of PD-L1 alone.43
Lymphocyte activation gene 3.
Lymphocyte activation gene 3 (LAG-3) is a T-cell co-inhibitory transmembrane receptor belonging to the Ig superfamily. LAG-3 is expressed by activated T cells (CD4+ and CD8+) and NK cells.44,45 This receptor binds with the MHC class II (MHC-II) molecule and also interacts with TCR/CD3 complexes on T cells, inhibiting the calcium response to CD3 stimulation. Blockade of LAG-3 promotes T-cell activation, proliferation, and effector function.46 Regulatory T-cell activity is highly dependent on LAG-3 expression, and, thus, LAG-3 plays a crucial role in lymphocyte homoeostasis and function.47 In addition, certain tumor types express MHC-II, and interaction of these tumor cells with LAG-3 activates antiapoptotic lymphocyte signals.48
V-domain Ig-containing suppressor of T-cell activation.
V-domain Ig-containing suppressor of T-cell activation (VISTA) is another transmembrane Ig superfamily member.49 It is expressed on T cells and CD11b+ antigen-presenting cell (APC)/myeloid cells, but not in B lymphocytes.50,51 The interactions and binding partners of VISTA on APCs are not clearly understood. VISTA on APCs and soluble VISTA-Ig fusion protein are considered as inhibitory ligands.49,52 VISTA is not known to be expressed on tumor cells; however, it is found in MDSCs, tumor-associated macrophages, and dendritic cells. Blocking VISTA in murine models enhances the CD4+ and CD8+ T cell proliferation and proinflammatory cytokine production.
T-cell Ig and mucin domain-3.
The T-cell Ig and mucin domain-3 (TIM) family of co-inhibitory receptors are transmembrane proteins containing a single IgV domain followed by a variable-length mucin domain and a cytoplasmic tail with a tyrosine-based signaling motif.53 There are three members of the TIM family (TIM-1, -3, and -4) identified in humans, but the role of TIM-1 and -4 remain unclear. TIM-3 is expressed on IFN-γ–secreting T helper 1 CD4+ and CD8+ T cells and on T helper 17 cells.54 TIM-3 expression is upregulated by antigenic stimulation and in response to proinflammatory cytokines. Galectin-9 is the proposed ligand for TIM-3, and interaction with TIM-3 induces tolerance and T-cell exhaustion.55-57 Coexpression of both TIM-3 and PD-1 can be seen in antigen-specific T cells and promotes T-cell exhaustion that may not readily be reversed by PD-1 inhibitors alone. In murine models, combined treatment with anti–Tim-3 and anti–PD-L1 resulted in considerable antitumor immune responses and reduction in tumor size compared with either treatment alone.58
Enhancing Endogenous Antitumor Immune Responses
Immune surveillance plays a major role in tumor elimination. Tumors overcome the prolonged dormancy/latency phase through a process of immune editing, resulting in selective pressure eradicating or diminishing the most immunogenic clones. By the time of clinical manifestation, many tumors are proficient in immune evasion and hence do not mount a strong antitumor immune response.13 The presence of a pre-existing endogenous antitumor immune response is indispensable for maintaining tumor dormancy and a key factor in inducing immune reinvigoration using the immune checkpoint blockers CTLA-4 and PD-1/PD-L1. This could explain why these drugs are effective only in a fraction of patients with advanced malignancies, and a majority of the patients do not benefit to these agents. Several genetic and epigenetic mechanisms are involved in antigen loss/silencing, rendering tumors less visible to the immune system.13 These changes impact the degree of effector T-cell infiltration and favor an imbalance toward accumulation of Tregs. Understanding the mechanisms of epitope loss or suppression of an endogenous immune response could uncover novel therapeutic options. Reciprocal to the blockade of co-inhibitory receptors, diverse strategies are used to directly stimulate the antitumor rejection, including vaccines, agonistic antibodies for costimulatory receptors, immunostimulatory cytokines, oncolytic viruses, and cell therapies (Fig. 1). Although many of these strategies are being clinically developed, there is often limited information about fundamental biologic aspects of such interventions.
Therapeutic Cancer Vaccine
Antigen presentation is the first step in generating an immune response. Cancer vaccines generate and augment the adaptive antitumor response largely by increased tumor antigen presentation. Cancer vaccines are broadly of two types: either active whole-cell vaccines or specific peptide antigen preparations. There are two types of tumor antigens that are considered targets for immunotherapy: tumor-specific antigens (TSAs) and tumor-associated antigens (TAAs). TSAs are highly tumor specific and expressed only in tumor cells, whereas TAAs are more widely expressed in both tumor and nontumor cells. Use of TSAs can avoid off-target autoimmune adverse events, but tumor responses are limited by the presence of the target antigen. TAAs are expressed in higher levels in tumors relative to nontumor cells, but they generate weaker immune response and higher off-target autoimmune events. APCs, like dendritic cells or macrophages, display these vaccine antigens to activate B and T cells, resulting in increased antitumor responses.59 In general, cancer vaccines are administered with an adjuvant nonspecific immune stimulant to increase immune reactivity. Cancer cells present TAAs and TSAs via HLA molecules on the cell surface. Identification and re-introduction of these peptides may amplify antitumor cytotoxic responses. Targets for TAA or TSA peptide vaccination are identified by cloning complementary DNAs that encode TAAs and TSAs that are recognized by CD8 T cells. Diverse RNA expression platforms are used to identify genes that are differentially expressed between tumor cells and normal counterparts. Several TAAs/TSAs are potential candidates for vaccines and are in clinical development in various tumor types. Most of the vaccine peptide targets are restricted to specific HLA haplotypes, and hence efficacy may be limited selected patients. Also, the elicited antitumor responses are restricted to the peptide target and hence may not be sufficient for a clinically meaningful tumor response. Solid tumors like melanoma and lung cancer have high rates of somatic mutations and could result in multiple mutant neoantigens. Personalized vaccine approaches targeting specific mutant neoepitopes detected in a particular tumor and matched with the patient HLA type are under investigation. Using a whole tumor cell vaccine may allow dendritic cells to process and present multiple antigens and elicit a stronger polyclonal cytotoxic T-cell response. Heat shock proteins such as HSP-3 gp96, localized in the endoplasmic reticulum, are thought to serve as a chaperon for peptides on their way to MHC-I and -II molecules. Allogeneic tumor cells transfected with complementary DNA for gp96-Ig have been used as vaccines.60 These cells continually secrete heat shock protein gp96 along with its chaperoned antigens, thereby augmenting antigen presentation and efficiency of tumor-rejecting CD8 T cells.61 Several therapeutic cancer vaccines are currently in clinical trials alone or in combination with other immunotherapeutic approaches. Sipuleucel-T is the only therapeutic cancer vaccine that is FDA approved. It is a fusion protein consisting of recombinant prostate acid phosphatase, which needs to be incubated with the patient’s isolated APCs ex vivo. However, the company producing this vaccine filed bankruptcy, likely because of the difficulties and cost of continuously developing clinical-grade preparations. Granulocyte macrophage colony-stimulating factor (GM-CSF) is used as an immune stimulant to activate the dendritic cells ex vivo.62
Costimulatory Checkpoint Pathways on Cancer
Glucocorticoid-induced tumor necrosis factor receptor.
Glucocorticoid-induced tumor necrosis factor receptor (GITR) is a member of the tumor necrosis factor receptor superfamily. It is expressed on the surface of multiple types of immune cells, including Tregs, effector T cells, B lymphocytes, NK cells, and activated dendritic cells.63 GITR activation increases the function of T cells, NK cells, APCs, and B lymphocytes. Signaling through GITR enhances CD4+ and CD8+ T cell proliferation in conjunction with TCR stimulation and reduces Treg-mediated suppression. GITR signaling may thereby enhance host immune responses against tumor and aid in tumor rejection.64 GITR agonistic antibodies in combination with PD-1 blockade were demonstrated to be synergistic in murine models.65
OX40.
OX40 is a member of the TNFRSF. OX40 is expressed by both CD4+ and CD8+ T cells during the antigen-priming phase,66 in response to TCR/CD3 cross-linking and in the presence of proinflammatory cytokines in the tumor microenvironment.67 OX40 is not expressed in resting or nonactivated T cells.68 A substantial proportion of TILs, both CD4 and CD8, express OX40, possibly following antigen engagement with TCR.69,70 Binding of OX40 receptor to its ligand OX40L induces proliferation and activation of the effector T-cell response.71 Agonistic antibodies to OX40 promote effector T-cell response and induce tumor regression experimental models.71
4-1BB.
Similar to the other costimulatory receptors, 4-1BB (CD137) is also a member of the TNFRSF. 4-1BB is expressed on diverse immune cell types and transiently upregulated upon activation in CD8 and CD4 T cells.72 In addition, 4-1BB has been detected in dendritic cells and NK T cells.73,74 Recent results suggest that 4-1BB agonists could reprogram Tregs into cytotoxic CD4 T cells with antitumor activity.75 4-1BB agonists have been demonstrated to induce tumor regression in several murine models, and these effects were more pronounced when combined with other immunotherapy strategies such has negative checkpoint antagonists, oncolytic viruses, and T-cell therapy.76,77
CD40.
CD40 is a type I transmembrane glycoprotein belonging to the TNFRSF. CD40 is expressed on APCs such has dendritic cells, activated monocytes, and macrophages. In addition, CD40 is present on endothelial and vascular smooth muscle cells.78 CD40 binds to the CD40 ligand (CD40L, CD154), which is primarily expressed on activated CD4 T cells. This interaction of CD40/CD40L increases expression of other costimulatory molecules and MHC peptides and stimulates production of proinflammatory cytokines. The CD40/CD40L pathway has also been proposed as a critical step in the initiation of an adaptive immune response.79 CD40 agonists demonstrate antitumor immune responses in murine models, and clinical activity in humans has been noted in early clinical trials.80-82
Cytokines
Cytokines are a group of relatively small proteins (approximately 5–20 kDa) that play a critical role in cell signaling, allowing immune cells to communicate and respond in a synchronous/organized manner. They allow the communication between physically distant cells/tissues and modulate the intensity and duration of the immune response against target antigens. Cytokines are produced by nearly all immune and most nonimmune stromal cells, including lymphocytes, myeloid cells, APCs, fibroblasts, and endothelial cells. In addition, diverse cytokines can be produced by tumor cells.83 Proinflammatory cytokines can promote effector T-cell proliferation and activation. Therapeutic manipulation of the cytokine environment is a promising approach to cancer immunotherapy. In addition, the modulation of cytokines can directly affect tumor cells, leading to apoptosis and inhibition of proliferation.84,85 Among clinically used cytokines, high-dose IL-2 has been approved for treatment of metastatic renal cell carcinoma and melanoma. Several additional cytokines are currently in clinical development.
1.
IFNs: IFNs are cytokines expressed by nearly all normal cells and have a critical role in modulating cellular interactions with the stroma. There are three categories of IFNs (e.g., types I–III). Type I IFNs include IFN-α and IFN-β and are the most used in anticancer immunotherapy. Type I IFNs induce the expression of MHC-I on tumor cells and promote maturation of dendritic cells.86,87 Type I IFNs also activate effector T cells, NK cells, and macrophages, induce direct tumor cell apoptosis, and alter the tumor neovasculature.85 IFNs can also stimulate the secretion of IL-4, resulting in activation of B cells. IFN-α was extensively investigated in clinical trials in various settings, and pegylated recombinant IFN-α-2b is FDA approved for adjuvant treatment in melanoma. Clinical activity of IFN as a single agent is modest; however, it may be a useful component in combinatorial strategies with other immunotherapies.
2.
IL-2: IL-2 and other members of the IL-2 family are considered as T-cell growth factors. IL-2 acts via the IL-2 receptor, a trimeric complex composed of α (CD25), β (CD122), and γ (CD132) chains.88,89 The β and γ chain are involved in intracellular signaling, whereas the ligand-specific α chain is only involved in cytokine binding.88 The affinity of the IL-2 interaction with T cells depends on the chains present in the cell surface. The α chain is inducible and is found only in T cells. The β and γ chains are expressed on T cells, B cells, and NK cells. However, B cells and NK cells only have an intermediate affinity IL-2 receptor. Stimulation with IL-2 induces proliferation and enhanced cytotoxicity of NK cells and promote differentiation of B cells.90 IL-2 preferentially activates the high-affinity IL-2R, driving the expansion of high-affinity IL-2R–expressing cells including immunosuppressive CD4+ Tregs, which limits anticancer activity of recombinant human IL-2 (rhIL-2; aldesleukin). The high-affinity IL-2R is also expressed on vascular and pulmonary endothelial cells, which could contribute to rhIL-2–mediated toxicity via capillary leak syndrome.91 IL-2 induces tumor regression and T- and NK-cell proliferation in patients with melanoma and renal cell carcinoma. Moreover, objective responses are seen in nearly 20% of patients, but they are associated with notable grade 3 to 4 toxicities, mainly relating to capillary leak syndrome.92 Although the use of IL-2 was FDA approved for use in renal cell carcinoma and melanoma nearly 2 decades ago, its use is limited by its safety profile. A novel fusion protein comprising of a circularly permuted IL-2 and IL-2Rα (ALKS 4230) designed to selectively activate the intermediate-affinity IL-2R is currently in clinical development.
3.
IL-15: IL-15 has structural similarity with IL-2, and both bind the shared IL-2Rβγ receptor and activate intracellular signaling by JAK/STAT, MAPK, and PI3K pathways in T and NK cells. Unlike IL-2, IL-15 does not engage the high-affinity IL-2Rα constitutively upregulated on Tregs.93 Therefore, IL-15 does not induce the expansion of these immunosuppressive cells. The other key difference of IL-15 as compared with IL-2 is that IL-15 promotes early T-cell stimulation and activation without causing activation-induced cell death (AICD) of T cells.94 Studies using IL-15 bound to the soluble IL-15Rα demonstrate a stronger biologic and antitumor activity compared with unbound IL-15.95,96 Novel fusion peptides of IL-15/IL-15Rα are in clinical development as monotherapy and in combination with other immunotherapies, including immune checkpoint inhibitors.
4.
IL-21: IL-21 has high homology with IL-2 and shares the γc receptor and a cytokine-specific α-receptor. IL-21 is primarily produced by activated CD4 T cells and induces T-cell proliferation and enhancement of CD8+ T cell– and NK cell–mediated cytotoxicity without promoting AICD.97,98 IL-21 agonists enhance the in vivo CD8 T-cell proliferation and induce durable tumor responses in murine models.99 In early clinical trials, IL-21 agonists appear to be well tolerated and have signs of activity.100
5.
IL-7: IL-7 is a cytokine of the IL-2 family of T-cell growth factors and signals through the γc receptor subunit promoting survival and proliferation signals in effector T cells.101 IL-7 is a homeostatic cytokine, induces memory T cells, and enhances the T-cell repertoire diversity. The receptor IL-7R is expressed on immature B-cell progenitors, and IL-7 appears to be critical in B-cell development. Unlike IL-2, IL-7 selectively expands CD8 T cells over Tregs.102 IL-7 agonists are currently in clinical development and appear to be well tolerated and promote antitumor immune responses.103
Oncolytic virus therapy.
Oncolytic viruses (OVs) are a relatively new class of cancer therapeutics with a distinct mechanism of action. OV consist of either native or engineered viruses capable of preferentially replicating in cancer cells. OV infection induces direct oncolytic activity and also augments the endogenous antitumor immune response. They can also induce immunogenic cell death by release of danger-associated molecular pattern signals such as calreticulin, high-mobility group protein B1, and TAAs.104 OVs present potent danger signals to dendritic cells and efficiently cross present TAAs to induce adaptive antitumor immune response.105 The administration route of OVs seems to be a key factor in determining the initial host immune response. Intravenous and intra-arterial delivery results in rapid elimination of the OV by circulating antibodies of the humoral defense. Intratumoral injection can also result in limited OV replications because of intracellular and microenvironmental antiviral defense responses in infected tumor cells. OV replication and tumoricidal activity can be improved with pharmacologic agents, such as histone deacetylase inhibitors, immune-modulating drugs, or by altering the expression of genes that block antiviral defense mechanisms.106,107 Several types of viruses are currently being investigated as potential OVs, including herpesvirus, poxvirus, picornavirus, adenovirus, paramyxovirus, parvovirus, reovirus, Newcastle disease virus, and rhabdovirus.108 To date, the only FDA-approved OV is an oncolytic herpes simplex virus 1–expressing GM-CSF (talimogene laherparepvec, or T-Vec). T-Vec is approved for use as an intratumor injection in metastatic melanoma. Several other OVs are currently in clinical development.
Adoptive T-cell therapy.
TCR interaction with immunogenic tumor cell-surface MHC-peptide complexes triggers a cascade of tumor-specific immune responses resulting in tumor cell recognition/elimination. The amount, affinity, and functionality of the T-cell clones expanded to attack the tumor are proportional to the effectiveness in tumor elimination. The rationale for adoptive T-cell therapy (ACT) is to artificially enrich the amount of T cells that are able to recognize TSAs and kill tumor cells. To this end, T cells with tumor antigen specificity are enriched or genetically manipulated to develop predetermined antigenic specificity and potency ex vivo. The earliest attempts of ACT harvested TILs from surgical specimens. After isolation and selection, the TILs were expanded in vitro using T-cell growth factors such as recombinant IL-2.109 These autologous T-cell preparations are administered back to the patient after chemotherapy-induced lymphodepletion aimed to eliminate Tregs and competing mechanisms of the immune system.110 The adoptively transferred T cells maintain specificity to tumor antigens and recognize the antigens presented on the tumor cell surface by the MHC-I complex.111 In early phase trials in melanoma, ACT with TILs achieved objective responses of 50%–70%, including a few complete responses.112,113 However, TILs are difficult to collect/expand, and the usual low frequency of TAA-specific cells limits their use in many patients. Circulating tumor-specific T cells (CTLs) can be collected, enriched, and expanded ex vivo and used for ACTs.114,115 However, CTLs with TCR specificity for TAAs are mostly of low affinity due to close resemblance to self-antigens and natural negative selection of high-affinity clones. Using novel molecular-engineering approaches, transgenic TCRs with high-antigen specificity for TAAs and optimized affinity can be produced. This approach can augment the ability of transferred T cells to induce clinical responses while maintaining high specificity for tumor antigens.116,117 However, TAA recognition by T cells is MHC restricted. This MHC restriction is a major limitation because solid tumors evade immune recognition by downregulating MHC expression and TAA processing and presentation.13 In addition, allelic and haplotypic diversity of HLA peptides among individuals is a challenge for systematic off-the-shelf production of transgenic TCR T cells for clinical use. For effective response of transgenic T cells, it is required to individualize production of these TCRs or create a vast library of cells that can recognize TAAs within the MHC context of multiple HLA types.
To overcome such limitations imposed by MHC restriction, chimeric antigen receptors (CARs) were designed.118 CARs are recombinant proteins comprising of the TCR exodomain, which recognizes antigen and the cytoplasmic domain of the TCR zeta (ζ) chain that mediates T-cell signaling. In addition, CARs could be designed to include costimulatory signals and T-cell activation moieties. These CARs can be transfected into immune effector cells using a variety of technologies enabling rapid ex vivo production of TAA-specific T cells.118 Unlike conventional TCRs, CARs can recognize antigens that are unprocessed and independent of the MHC complex and proteasomal processing. In addition, CARs can also recognize carbohydrate, ganglioside, proteoglycan, and heavily glycosylated protein.118 Early results, particularly among patients with CD19-positive hematologic malignancies, are encouraging, with responses over 50% in heavily pretreated patients.119,120 However, clinical studies in solid tumors have been largely disappointing, except one trial including 19 patients with neuroblastoma (three patients with complete response, one patient with partial response, and one with stable disease).120,121 Reasons for the lack of efficacy in solid tumors include the relative absence of unique TAAs, inefficient trafficking of CAR T cells in the tumor microenvironment, and, most importantly, the highly immunosuppressive milieu within the tumor bed.120 CAR gene constructs including costimulatory molecules can enhance the antitumor activity.122,123 Newer approaches use CAR constructs capable of generating CAR T cells redirected for universal cytokine killing (TRUCKs). These TRUCK T cells can release proinflammatory cytokines at the time of target interaction, augmenting T-cell activation and infiltration by innate immune cells to eliminate antigen-negative cancer cells.124 Another recent approach is using bispecific T-cell engager (BiTE) antibody constructs linking onto a single polypeptide chain (e.g., the minimal binding domains of monoclonal antibodies) for tumor-associated surface antigens and the T-cell receptor–associated molecule CD3. Recently, blinatumomab, a BiTE antibody targeting CD19, was approved by the FDA for Philadelphia chromosome-negative, relapsed, or refractory B-cell precursor acute lymphoblastic leukemia. Several BiTe antibodies are currently under clinical investigation.125 Despite their promising clinical activity, these treatments have on- and off-target toxicities in nontumor tissues that express the targeted antigen. It is therefore critical to use highly TSAs for such approaches and to optimize the affinity and specificity of the CAR and the lymphodepleting regimens used prior to ACT. Another major complication with ACT is cytokine release syndrome (CRS). This is a consequence of simultaneous and uncontrolled release of several proinflammatory cytokines, including IL-6, TNF-α, and IFN-γ, secondary to unbalanced T-cell activation. Clinically, CRS manifests with high fever, hypotension, and potential multiorgan failure, but is often self-limited or rapidly reversed with anticytokine-directed therapies like tocilizumab (IL-6R antagonist).126
Conclusion
Recent success of novel anticancer immunotherapies has led to a new era of cancer treatment. Immunotherapies can elicit clinically meaningful and durable responses in multiple tumor types. Unfortunately, the response rates to immunotherapy are still modest, and, clearly, more efforts are required to improve outcomes with these treatments. Development of predictive biomarkers or personalized/precision immunotherapy could help overcome some of these limitations.
A key factor underlying the limited response seen in diverse trials is the complexity in the host-immune tumor interactions and the existence of multiple redundant mechanisms of tumor-mediated immune suppression. Also, clear understanding of the fundamentals of tumor antigen production/maintenance, antigenic evolution, and tumor immune heterogeneity are essential. Increased efforts in basic and translational research should also shed light on the structural and functional regulation of most coregulatory immune pathways and their specific role in diverse human malignancies. Understanding the dynamic interactions between tumor cells and immune system will allow us to personalize immunotherapies and design optimal combinatorial approaches to improve outcomes for patients with advanced malignancies.
Authors' Disclosures of Potential Conflicts of Interest
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc.
Vamsidhar Velcheti
Honoraria: Bristol-Myers Squibb, Foundation Medicine, Genentech/Roche, Merck, Novartis
Consulting or Advisory Role: Amgen, AstraZeneca/MedImmune, Bristol-Myers Squibb, Celgene, Clovis Oncology, Foundation Medicine, Genentech, Genoptix, Merck, Takeda
Research Funding: Alkermes (Inst), Altor BioScience (Inst), Atreca (Inst), Bristol-Myers Squibb (Inst), Eisai (Inst), Genentech (Inst), Genoptix (Inst), Heat Biologics (Inst), Leap Therapeutics (Inst), Merck (Inst), NantOmics (Inst), OncoPlex Diagnostics (Inst), Trovagene (Inst)
Travel, Accommodations, Expenses: AstraZeneca/MedImmune, Eisai, Foundation Medicine, Merck
Kurt Schalper
Honoraria: Takeda
Consulting or Advisory Role: Celgene, Shattuck Labs
Research Funding: Moderna Therapeutics, Navigate BioPharma, Onkaido Therapeutics, Pierre Fabre, Surface Oncology, Takeda, Tesaro, Vasculox
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Basic Overview of Current Immunotherapy Approaches in Cancer. Am Soc Clin Oncol Educ Book 36, 298-308(2016).
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