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Immunotherapy in Oral Cancer: A Fourth Dimension of Cancer Treatment

  • Marcus A. Couey
  • Rom S. Leidner
  • Simon W. Young
  • R. Bryan BellEmail author
Chapter
  • 318 Downloads

Abstract

The development of immune checkpoint inhibitors and adoptive T cell transfer have transformed the practice of oncology. Initially successful in melanoma, immunotherapy is currently being tested in virtually every solid tumor, including head and neck squamous cell carcinoma (HNSCC). In 2016, the FDA approved two checkpoint inhibitors, nivolumab and pembrolizumab, for the treatment of platinum-refractory recurrent or metastatic HNSCC, after clinical trials showed improved survival where no effective treatment had existed previously. But despite the potential for enduring remissions, checkpoint inhibitors are only effective in a minority of patients. Additional strategies are being developed to harness the immune system by a variety of mechanisms to generate lasting antitumor responses for a greater proportion of cancer patients. These include targeting different pathways in the immune response, combining immunotherapies to produce synergistic effects, and combining immunotherapy with traditional therapies including surgery, chemotherapy, and radiation. Despite its current limitations, immunotherapy is quickly becoming established as the fourth modality for treatment of a wide range of malignancies including oral cancer.

Keywords

Head and neck cancer Oral cancer Immunotherapy Checkpoint inhibitors Costimulatory agonists Cancer vaccines Adoptive cell therapy 

10.1 The Immune System in Head and Neck Cancer

Although many components of the immune system are involved in the antitumor immune response, the most critical immune cell is the T cell. The Cancer Immunity Cycle, as described by Chen and Mellman, explains the steps required for the adaptive immune system to target tumors, including uptake and presentation of antigens by dendritic cells (DC), priming and activation of T cells in the lymph nodes, homing of T cells to the site of the tumor, and T cell recognition and destruction of tumor cells [1] (Fig. 10.1). Cancer cell death then exposes more potential antigens to immune recognition, which can perpetuate the cycle. Each step in this sequence has biochemical stimulators and inhibitors, and appreciation of these steps is critical in developing strategies to overcome immune evasion by tumors.
Fig. 10.1

Therapies that might affect the cancer immunity cycle. (From: Chen DS., Mellman I. “Oncology meets immunology: the cancer immunity cycle.” Immunity 39.1 (2013): 1–10)

The central role of the immune system in both the prevention and evolution of cancer has been described by Schreiber et al. in the concept of immunoediting [2]. Immunoediting starts with the surveillance of the body for abnormal cells by the immune system. In some cases, the immune system is successful in targeting and eliminating a tumor and preventing the occurrence of clinically detectable cancer. However, sometimes the immune system cannot eliminate a subset of the tumor cells, as those cells have acquired phenotypes that subvert immune targeting. After a period of equilibrium, where these resistant tumor cells exist in quiescence, they may begin to proliferate and spread. This is called immune escape and is now recognized as one of the hallmarks of cancer [3].

Advances in whole-exome sequencing have provided great insights into the molecular landscape of head and neck cancer. Remarkable efforts by several groups, including The Cancer Genome Atlas (TCGA), have identified the most commonly altered molecular pathways involved in head and neck squamous cell carcinoma (HNSCC). These data have shown that HNSCCs have a moderate-to-high mutational burden and are heterogeneous tumors. The most common involved pathways are tumor-suppressor genes such as p53, which are either inactivated or mutated. Successful restoration of functional tumor-suppressor pathways in HNSCC through targeted therapy has so far remained elusive. Oncogenic pathways which have been identified in a significant percentage of tumors, such as PI3K, are theoretically more targetable than tumor suppressors. However, results of therapies such as PI3K and mTOR inhibitors have been mostly disappointing [4]. The heterogeneity of cells within a tumor, even those tumors that test positive for targetable mutations, may play an important role in the difficulties encountered with targeted therapies [5].

While the relatively high mutational rate of HNSCC creates difficulty in applying targeted therapies, it may be advantageous for the application of immunotherapy through the presence of more mutations that may be recognized as non-self by the immune system. However, there are numerous escape mechanisms that tumors employ to suppress the natural antitumor capabilities of immune cells. Impaired antitumor responses in HNSCC may be caused by alterations in the generation, processing, and/or presentation of T cell epitopes derived from tumor-associated antigens (TAA) by human leukocyte antigen (HLA) class I and/or class II molecule [6]. Other mechanisms for evading immune targeting by tumors include upregulation of immune-suppressive “checkpoint” ligands (e.g., PD-L1) [7], release of inhibitory cytokines by suppressive immune cells including regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) in the tumor microenvironment [8, 9, 10], or the secretion of immune-suppressive mediators (e.g., TGF-beta) [11]. Knowledge of the specific mechanisms of immune suppression in HNSCC has led to numerous approaches to overcome immune suppression in the tumor microenvironment (Fig. 10.2).
Fig. 10.2

Strategies for immune checkpoint combinations: different classes of therapeutic approaches that have synergistic potential for future combination immunotherapies are depicted. (Modified from: Ai, M, Curran MA. “Immune checkpoint combinations from mouse to man.” Cancer Immunology, Immunotherapy 64.7 (2015): 885–892)

Treatment and prognosis of HNSCC vary depending on anatomical location. For oropharyngeal SCC, carcinogenesis is often driven by infection with high-risk strains of HPV, usually HPV-16. It has been shown that the molecular pathways and immunobiology of HPV-positive tumors are distinct from HPV-negative disease [12]. In addition, HPV-positive HNSCCs respond better to standard therapies and most immunotherapies [13]. The significance of HPV in oral cancer specifically remains uncertain, and there is currently no standard method for identifying HPV as the etiologic agent in oral cavity SCC that is both accepted and available universally [14]. This chapter is meant to focus on cancers arising in the oral cavity and therefore will limit the discussion to HPV-negative HNSCC.

Current therapies and those in development are focused on strategic targeting of the various steps in the Cancer Immunity Cycle. The great promise of immunotherapy lies with the potential for lasting, or durable, responses. This is referred to as the “tail at the end of the survival curve” (Fig. 10.5) and is perhaps the most exciting prospect of immunotherapy.

10.2 A New Standard of Care in Recurrent or Metastatic Head and Neck Cancer

10.2.1 PD-1 Inhibitors

One of the ways that tumors can halt the immune response is through signaling molecules called checkpoints. These inhibitory cell receptors block T cell activity and lead to T cell apoptosis. This is normally a safeguard against autoimmunity. However tumors can upregulate these inhibitory receptors, which promote evasion of immune targeting. Monoclonal antibodies that block the interaction between these receptors and their ligands, known as checkpoint inhibitors (CPI), have shown great promise for many types of solid tumors in recent years (Fig. 10.3).
Fig. 10.3

Timeline of breakthroughs in cancer immunotherapy. (From: Wang, Daniel Y., Gosife Donald Okoye, Thomas G. Neilan, Douglas B. Johnson, and Javid J. Moslehi. “Cardiovascular Toxicities Associated with Cancer Immunotherapies.” Current Cardiology Reports 19:21. 2017)

The most well-studied checkpoint inhibitors in HNSCC are the antiprogrammed cell death protein 1 (anti-PD-1) antibodies nivolumab and pembrolizumab. Through interaction with its ligands programmed death ligand 1 (PD-L1) and 2 (PD-L2), PD-1 acts as an immune rheostat that modulates the immune response within the tumor [1]. The blockade of PD-1 has been shown to prevent the inhibition of T cell activity in the tumor microenvironment, thereby permitting cellular cytotoxicity against tumor cells.

In late 2016, the FDA granted approval of nivolumab, following the results from the randomized phase III trial, CheckMate141 [15]. This study evaluated nivolumab versus investigator’s choice (IC) chemotherapy in patients with recurrent or metastatic (R/M) HNSCC that had progressed within 6 months of platinum-based chemotherapy. This was the first randomized, controlled data showing a survival benefit in R/M HNSCC since the EXTREME regimen, consisting of the combination of platinum, 5-fluorouracil and cetuximab [16]. The study was ended early after meeting its primary endpoint of overall survival (OS), and patients from the control arm were then allowed to crossover to receive nivolumab. A recent update reported 2-year OS of 16.9% in nivolumab-treated patients, which was more than double the rate for patients that received standard therapy (6.0%) [17]. Significant OS benefit was seen regardless of HPV or PD-L1 status.

In mid-2016, the FDA granted accelerated approval of pembrolizumab for platinum-refractory R/M HNSCC based on results from the phase Ib KEYNOTE-012 trial [18]. This trial studied pembrolizumab in patients with R/M disease whose tumors had progressed within 6 months of platinum-based cytotoxic chemotherapy. The objective response rate (ORR) for pembrolizumab was 18%, with 71% of responses lasting 12 months or more. The KEYNOTE-055 trial studied pembrolizumab in R/M HNSCC who had progressed on platinum and the anti-epidermal growth factor receptor (EGFR) antibody, cetuximab. ORR was 16% with a median duration of response of 8 months [19]. A survival benefit with pembrolizumab in platinum-refractory R/M disease was later confirmed in KEYNOTE-040. In this randomized, controlled phase III trial, patients receiving pembrolizumab had a median OS of 8.4 months, vs 6.9 months for IC chemotherapy. Patients with >50% of tumor cells expressing PD-L1 experienced increased benefit with pembrolizumab (median OS 11.6 months) [20].

Recently, results were announced from the first phase III trial of anti-PD-1 therapy in first-line R/M HNSCC. KEYNOTE-048 randomized patients to one of three arms: pembrolizumab monotherapy, pembrolizumab plus platinum and 5-FU, or cetuximab plus platinum and 5-FU (EXTREME regimen). This trial showed that in PD-L1-expressing patients (~85% of patients in this population), pembrolizumab monotherapy was superior to the EXTREME regimen, with 2-year OS of 30.2% vs 18.6%. Further, when looking at the total population (regardless of PD-L1 status), patients who received pembrolizumab with cisplatin and 5-FU had 29% 2-year survival compared with 18.7% with the EXTREME regimen. In June 2019, the FDA approved the use of pembrolizumab with or without cisplatin/5-FU (determined by PD-L1 status) based on data from this trial [21].

Importantly, the anti-PD-1 agents are much better tolerated than cytotoxic chemotherapy, with grade 3–5 drug-related adverse events occurring in 13–14% of patients receiving anti-PD-1 versus 36% with standard of care in phase III, randomized trials. The most common adverse events associated with these agents are fatigue, nausea, rash, decreased appetite, and pruritus. Hypothyroidism occurs in 7.7–13% of patients, vs. about 1% with standard treatment. Pneumonitis is the most severe adverse event associated with anti-PD-1 and can be life-threatening if not recognized early and treated. Numerous physical and social quality of life (QOL) measures were assessed in CheckMate141 which showed advantages of PD-1 inhibitors across the board compared with standard of care chemotherapy. While pembrolizumab and nivolumab have been the most highly studied anti-PD-1 therapies, there are other anti-PD-1 agents currently in development. Spartalizumab (PDR001) and cemiplimab (REGN2810) are being tested alone and in combination with other immunotherapies in multiple solid tumor types including HNSCC.

10.3 Additional Checkpoint Inhibitors

10.3.1 PD-L1

Blockade of checkpoints can be achieved through targeting either the receptor (e.g., PD-1), or the ligand. Of the two ligands for PD-1, PD-L1 is generally thought to play a more prominent role in immunosuppression than PD-L2 [22]. In addition, PD-L1’s binding is not exclusive to the PD-1 receptor; it can also block the immune-stimulating ligand B7–1, causing immune suppression by a separate mechanism (Fig. 10.4) [23]. Furthermore, targeting PD-L1 specifically may reduce the risk of pneumonitis compared with anti-PD-1 therapy, as pneumonitis is thought to be at least partially mediated by PD-L2 [24]. Therefore, the blockade of PD-L1 is expected to confer a different treatment response and adverse-effect profile than anti-PD-1 therapy. Several anti-PD-L1 antibodies are currently being studied in HNSCC, including durvalumab, avelumab, and atezolizumab.
Fig. 10.4

Human cancer immunotherapy with anti-PD-1 and anti-PD-L1/L2 antibodies. (From: Ohaegbulam, KC., et al. “Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway.” Trends in molecular medicine 21.1 (2015): 24–33)

Recently, the results were announced from the phase II HAWK trial of durvalumab in platinum-refractory R/M HNSCC with high PD-L1 expression, defined as greater than 25% tumor cell expression (NCT02207530). ORR was 16%, and 55% of responses were ongoing at data cutoff. Overall survival at 1 year was 33.6%. There was a striking difference in response rate based on HPV status, with an ORR of 29.4% in HPV-positive disease and 10.8% in HPV-negative disease. The incidence of grade 3 or higher adverse events was relatively low at 8%. One patient discontinued therapy because of a treatment-related adverse event, and there were no treatment-related deaths [25]. There are a large number of clinical trials studying durvalumab in combination with other immune-modulating agents, as well as chemotherapy and radiation, which will be discussed later in the chapter.

10.3.2 CTLA-4

In addition to PD-1/PD-L1, there are numerous other immune receptors that act as checkpoints through inhibition of immune cells (Fig. 10.5). The first immune checkpoint to be identified and targeted for cancer immunotherapy was Cytotoxic T-lymphocyte-Associated Protein 4 (CTLA-4). CTLA-4 is a receptor expressed on the surface of T cells that binds with B7 ligands on antigen-presenting cells (APC), causing T cell anergy and apoptosis. While PD-1 inhibits effector cells within the tumor microenvironment (TME), CTLA-4 inhibits T cell activation within the periphery, largely in the lymph nodes [26]. Blockade of CTLA-4 prevents immune-suppressive signaling, while also freeing the B7 ligands to bind the costimulatory receptor CD28. Additionally, antibodies targeting CTLA-4 cause Treg depletion through antibody-dependent cell-mediated cytotoxicity (ADCC), thereby reducing immunosuppressive influences in the TME [27].
Fig. 10.5

T cell costimulatory and coinhibitory receptors. Shown are the families of T cell costimulatory and immune checkpoint receptors as well as those which affect dendritic cells responsible for T cell activation. (From: Ai, M, Curran MA. “Immune checkpoint combinations from mouse to man.” Cancer Immunology, Immunotherapy 64.7 (2015): 885–892)

Ipilimumab, a fully humanized IgG1 anti-CTLA-4 antibody, was the first checkpoint inhibitor to demonstrate improved survival in melanoma and subsequently became the first drug in this class to gain FDA approval [28]. Ipilimumab has since shown activity in numerous solid tumor types; however, immune-related adverse events are more common and more severe than with the anti-PD-1 agents. Tremelimumab is fully humanized IgG2 anti-CTLA-4 antibody, which is being studied in many clinical trials across numerous cancer types including HNSCC, mostly in combination with durvalumab (anti-PD-L1) (Table 10.1).
Table 10.1

Clinical trials: other checkpoint inhibitors

 

Phase

Tumor type

Combination

Comparison

Trial

Expected completion date

CTLA-4

Ipilimumab

III

R/M HNSCC

Nivolumab

Ipi placebo

NCT02823574

08/2020

III

R/M HNSCC

Nrvolumab

Plat/5FU/Cetux

NCT02741570

08/2020

Tremelimumab

II

R/M HNSCC

Durvalumab

Mono vs combo

NCT02319044

09/2018

III

R/M HNSCC

Durvalumab

SOC chemo

NCT02369874

11/2018

III

R/M HNSCC

Durvalumab

SOC chemo

NCT02551159

12/2018

TIM-3

TSR-022

I

Advanced solid tumors

Anti-PDl

NCT02817633

06/2020

LY3321367

I

Advanced

LY3300054

NCT03099109

06/2020

MBG453

I/II

Advanced malignancies

PDR001

NCT02608268

03/2019

LAG-3

Relatlimab

I

Advanced solid tumors

Nivolumab

NCT02966548

07/2020

I/IIa

Advanced solid tumors

Nivolumab

NCT01968109

12/2020

TSR-033

I

Advanced solid tumors

Anti-PDl

NCT03250832

05/2021

REGN3767

I

Advanced malignancies

REGN2810

NCT03005782

03/2022

LAG525

Ι/II

Advanced malignancies

PDR001

NCT02460224

08/2019

TIGIT

BMS-986207

I/IIa

Advanced solid tumors

Nivolumab

NCT02913313

12/2022

OMP-313M32

I

LA/M solid tumors

Nivolumab

NCT03119428

10/2019

MTIG7192A

I

LA/M tumors

Atezolizumab

NCT02794571

09/2019

LA locally advanced, R recurrent, M metastatic, Ipi ipilimumab, plat platinum, cetux cetuximab, mono monotherapy, SOC standard of care

10.3.3 TIM-3

T cell Immunoglobulin and Mucin Domain 3 (TIM-3) is another immune checkpoint expressed on the surface of T cells. High TIM-3 is a marker of T cell exhaustion, similar to PD-1, and has been shown in preclinical and clinical studies to be upregulated in cases of progressive disease after anti-PD-1 therapy [29]. Preclinical models have also shown increased cytokine production and activity of cytotoxic T cells with blockade of TIM-3 and PD-1 pathways in combination compared with PD-1 pathway blockade alone [30]. Therefore, there is sound rationale for studying TIM-3 in combination with therapies targeting the PD-1/PD-L1 pathway. Additionally, blockade of TIM-3 has been shown in preclinical models to promote immune responses and reduce suppressive forces via multiple targets aside from CD8+ T cells, including CD4+ T cells, natural killer (NK) cells, Tregs, MDSCs, and DCs. At least three monoclonal antibodies are currently in phase I-II trials for advanced solid malignancies (Table 10.1).

10.3.4 LAG-3

The immune checkpoint Lymphocyte Activation Gene-3 (LAG-3) has been shown to suppress responses of CD8+ cytotoxic T cells and NK cells and to promote the suppressive influence of Tregs. LAG-3 is co-expressed with PD-1 on dysfunctional or exhausted T cells, and anti-LAG-3 in preclinical studies has demonstrated synergy with anti-PD-1/PD-L1 to improve antitumor immune responses [31]. There are at least four monoclonal antibodies being evaluated in phase I–II clinical trials for advanced solid tumors including HNSCC (Table 10.1).

10.3.5 TIGIT

T cell Immunoglobulin and ITIM Doman (TIGIT) is another immune checkpoint that dampens the immune response through interactions with multiple cell types, including effector T and NK cells, DC cells, and suppressive Tregs. The combined blockade of TIGIT and PD-L1 synergistically promotes CD8+ T cell effector function within tumors [32]. There are at least three anti-TIGIT antibodies currently being evaluated in phase I–II clinical trials for advanced solid tumors (Table 10.1).

10.4 Combinations of Checkpoint Inhibitors

There is abundant preclinical evidence supporting a combinatorial approach to cancer immunotherapy. For example, CTLA-4 acts relatively early in the cancer immunity cycle during T cell priming and activation, while PD-1 comes into play later in the cycle by modulating immune effector cell function within tumors. Additionally, blockade of one immune checkpoint can lead to the increased expression of other checkpoints by tumor cells leading to immune escape [29]. Therefore, it has been hypothesized that adding one or more additional CPI to PD-1/PD-L1 therapy may improve response rates, particularly in PD-L1-negative patients, and prevent resistance to single-agent therapy (Fig. 10.6).
Fig. 10.6

Strategies for immune checkpoint combinations: Shown is the current goal of the field of immunotherapy to increase the percentage of patients experiencing durable, complete responses through combination therapy approaches. (Modified from: Ai, M, Curran MA. “Immune checkpoint combinations from mouse to man.” Cancer Immunology, Immunotherapy 64.7 (2015): 885–892)

Two large studies are currently testing nivolumab (anti-PD-1) alone or in combination with ipilimumab (anti-CTLA-4) in R/M HNSCC. CheckMate714 is a double-blinded, randomized, phase II study in both the platinum-refractory and first-line settings, and CheckMate651 is an open-label, randomized phase III study of the same combination as first-line therapy compared to chemotherapy (NCT02823574, NCT02741570). This combination has been approved for the treatment of patients with advanced melanoma and advanced renal cell carcinoma. Combination nivolumab + ipilimumab has also shown significant promise in the treatment of patients with advanced non-small-cell lung cancer [33]. Data from these trials are not yet mature and will be presented at future meetings.

Tremelimumab (anti-CTLA-4) is now being tested in numerous clinical trials for HNSCC in combination with durvalumab (anti-PD-L1). The CONDOR trial was a phase II, randomized trial of durvalumab and tremelimumab alone and in combination in patients with platinum-refractory R/M HNSCC who had low PD-L1 levels. Median overall survival was 7.6 months in the combination arm, 6.0 months for durvalumab alone, and 5.5 months for tremelimumab alone [34]. EAGLE (NCT02369874) and KESTREL (NCT02551159) are randomized phase III trials studying this combination in platinum-refractory disease and as first-line treatment of R/M HNSCC, respectively.

There is a large body of preclinical evidence for the antitumor activity of other combinations of C. In fact, many of the newer CPI are being developed as combinations from the start, most commonly in combination with PD-1/PD-L1 pathway antagonists. For example, all the current anti-TIM-3, anti-TIGIT, and anti-LAG-3 trials evaluating tolerability and efficacy in advanced solid tumors are testing these agents in combination with anti-PD-1 or anti-PD-L1 antibodies. While clinical trials for these other combinations are still in early phases for the most part, there are early reports of success such as the phase I/IIa trial of relatlimab (anti-LAG-3) with nivolumab (anti-PD-1) in advanced solid tumors. In an expansion cohort of melanoma patients who were refractory to PD-1 therapy alone, 11.5% had objective responses and 37.7% had stable disease with the combination. Patients with ≥1% LAG-3 expression had an ORR of 18%, and patients who also had prior exposure to CTLA-4 had an ORR of 24% [35]. This trial includes head and neck patients as well, and study completion is expected in late 2019.

10.5 Costimulatory Agonists

In addition to T cell receptor (TCR) recognition of MHC-presented antigens, the activation of T cells requires specific costimulatory signals (Fig. 10.5). TCR ligation without the second costimulation signal leads to T cell anergy and immune tolerance [36]. The development of agonist antibodies that activate costimulatory receptors has added a new dimension to cancer immunotherapy. While the activity of checkpoint inhibitors has been described as “releasing the breaks” on the immune system, costimulatory agonists have been described as “stepping on the gas.” Preclinical studies have shown that costimulatory agonists have synergistic activity with CPI, and there are currently many such agents being tested in clinical trials alone and in combination with other immunotherapies.

10.5.1 CD28 Superfamily

Inducible T cell costimulator (ICOS) is a member of the CD28 superfamily that promotes CD4+ T cell growth, differentiation and effector function, as well as survival and memory of both CD4+ and CD8+ T cells [37]. ICOS is only expressed at low levels on naïve T cells but is rapidly upregulated upon TCR ligation [38]. It is also highly expressed on Tregs, and ICOS signaling can therefore contribute to immune suppression, contrary to its action on effector T cells. Preclinical studies have shown effector T cell -mediated antitumor immune responses and Treg depletion with antibodies from subclasses capable of ADCC, as well as synergy with both CTLA-4 and PD-1 blocking agents. There are currently two antibodies in clinical trials in advanced solid tumors (Table 10.2). JTX-2011, a humanized IgG1 monoclonal ICOS agonist antibody, is the furthest along in development. It was found to be well tolerated in phase I trials and is currently undergoing phase II testing in several tumor types including HNSCC [39].
Table 10.2

Clinical trials: costimulatory agonists

 

Phase

Tumor type

Combination

Trial

Expected completion date

ICOS

GSK3359609

I

Advanced solid tumors

Pembrolizumab

NCT02723955

05/2020

JTX-2011

Ι/II

Advanced malignancies

Ipilimumab or nivolumab or pembrolizumab

NCT02904226

12/2022

OX40

MEDI0562

I

Advanced solid tumors

None

NCT02318394

Completed, pending publication

 

I

Advanced solid tumors

Durvalumab or tremelimumab

NCT02705482

12/2019

 

Ib

HNSCC or melanoma (neoadjuvant)

None

NCT03336606

12/2024

PF-4518600

I

LA/M cancers

Utomilumab

NCT02315066

01/2021

 

Ib/II

Advanced solid tumors

Avelumab +/− utomilumab

NCT02554812

05/2020

MOXR0916

Ib

LA/M solid tumors

Atezolizumab

NCT02410512

08/2018

GSK3174998

I

Advanced solid tumors

Pembrolizumab

NCT02528357

01/2020

BMS-986178

I/IIa

Advanced solid tumors

Nivolumab and/or ipilimumab

NCT02737475

10/2021

INCAGN1949

I

A/M solid tumors

None

NCT02923349

02/2019

4-1BB

Urelumab

III

A/M solid tumors/NHL

Nivolumab

NCT02253992

09/2019

 

I

Malignant tumors

Nivolumab

NCT02534506

06/2019

 

I

Metastases in advanced solid tumors

Nivolumab + SBRT

NCT03431948

02 2020

Utomilumab

I

LA/M cancers

PF-4518600

NCT02315066

01/2021

 

Ib/II

Advanced solid tumors

Avelumab +/− PF-4518600

NCT02554812

05 2020

GITR

TRX518

I

Melanoma and other solid tumors

None

NCT01239134

12/2018

 

I

Advanced solid tumors

Pembrolizumab or nivolumab or gemcitabine

NCT02628574

09/2020

GWN323

I

Advanced solid tumors

PDR001

NCT02740270

12/2019

MK-4166

I

Advanced solid tumors

Pembrolizumab

NCT02132754

10/2019

MK-1248

I

Advanced solid tumors

Pembrolizumab

NCT02553499

10/2018

MEDI1873

I

Advanced solid tumors

None

NCT02583165

01/2021

INCAGN01876

I/II

Advanced malignancies

None

NCT02697591

08/2018

BMS-986156

I/IIa

Advanced solid tumors

Nivolumab

NCT02598960

05/2020

CD27

Varlilumab

Ι/Π

Advanced refractory solid tumors

Nivolumab

NCT02335918

01/2020

CD40

SEA-CD40

I

Advanced malignancies

Pembrolizumab

NCT02376699

09/2022

CDX-1140

I

Advanced solid tumors

None

NCT03329950

12/2020

Selicrelumab

Ib

LA/M solid tumors

Atezolizumab

NCT02304393

10/2019

 

Ib

Advanced solid tumors

Emactuzumab

NCT02760797

Completed, pending publication

APX005M

I

Solid tumors

None

NCT02482168

12/2018

ABBV-927

I

Advanced solid tumors

ABBV-181

NCT02988960

11/2019

10.5.2 Tumor Necrosis Factor (TNF) Receptor Superfamily

The TNF superfamily of receptors (TNFRs) are involved in immune cell activation, proliferation, and survival. There are several members of this group that are being targeted with agonist pharmaceuticals in cancer immunotherapy clinical trials, including OX40, 4-1BB, CD27, glucocorticoid-induced TNFR-related protein (GITR), and CD40.

OX40 is transiently expressed on CD4+ and CD8+ T cells and Tregs following TCR ligation. OX40 is also expressed on NK cells, NKT cells, and neutrophils, and its ligand OX40L is transiently expressed on APCs and some T cells. OX40 appears to be important for T cell survival and expansion, and for differentiation of T cells, skewing toward an effector phenotype [40]. OX40 has shown synergistic activity with checkpoint blockade in preclinical studies [41]. Furthermore, OX40 is highly expressed in tumor-infiltrating lymphocytes (TILs) in HNSCC, particularly CD4+ T cells, providing strong rationale for testing in clinical trials in this disease [42, 43]. There are six OX40-targeting antibodies in pharmaceutical pipelines that are currently in clinical trials for advanced solid tumors, including HNSCC (Table 10.2). Interestingly, one such agent was recently tested in a phase Ib neoadjuvant trial prior to surgery: MEDI6469 was administered intravenously at various time intervals prior to definitive surgical resection in 17 patients with stage II–IVA HNSCC [44]. Fifty percent of the patients treated experienced an increase in the percentage of tumor-reactive CD8+ T cells in the tumor after anti-OX40 treatment. Early-phase clinical trials are underway with the goal of understanding how best to incorporate OX40 into combination trials with CPI and conventional therapies.

4-1BB is can be found on many cell types, including cells of hematopoietic and neuronal origins. Like OX40, 4-1BB is transiently expressed on CD4+ and CD8+ T cells following activation. Binding to 4-1BB ligand induces cell proliferation and survival, promotes effector functions, and stimulates memory cell differentiation. Preclinical studies have shown potent antitumor responses predominantly mediated by cytotoxic CD8+ T cells. 4-1BB agonists have also demonstrated enhancement of NK-mediated ADCC [45], making these agents attractive for combinations with targeted therapies and immunotherapies capable of tumor killing or Treg depletion through ADCC. Two 4-1BB agonists are currently in clinical trials in solid tumors (Table 10.2).

GITR, similarly to OX40 and 41-BB, is transiently expressed on CD4+ and CD8+ T cells following TCR ligation. Like these other TNFRs, GITR appears to be less important for T cell priming, and more involved with promoting effector cell functions. GITR is also expressed on DCs, monocytes, granulocytes, and NK cells and is constitutively expressed on Tregs. Preclinical studies have shown that GITR ligation can overcome Treg-mediated immunosuppression, and agonists have shown impressive antitumor efficacy in several cancer models [46]. There are currently seven GITR agonist monoclonal antibodies in phase I–II clinical trials for patients with advanced solid tumors (Table 10.2).

CD27 is a costimulatory receptor that is constitutively expressed on lymphoid cells, including T cell s, B-cells, and NK cells and is upregulated on CD4+ and CD8+ after activation. Binding of CD27 with its ligand CD70 on activated APCs promotes clonal expansion of T cells, in addition to effector and memory T cell differentiation and survival. Contrary to the above TNFRs, CD27 also stimulates T cell priming. Preclinical studies of CD27 agonists have shown efficacy in several tumor models [47]. Varlilumab, a humanized IgG1 monoclonal antibody agonist to CD27, is currently being tested in clinical trials for a variety of cancers, including one study with a phase II cohort in combination with nivolumab in HNSCC (Table 10.2).

CD40 is a member of the TNF-receptor superfamily expressed on multiple cell types including dendritic cells, B cells, monocytes, and some tumor types including HNSCC [48]. Rather than directly activating T cells, CD40 agonists have been shown to activate dendritic cells to induce T cell responses. These agents can also activate macrophages to mount a T cell independent antitumor response and can induce ADCC and complement-dependent cytotoxicity (CDC) through interaction with NK cells [49]. Phase I studies have shown favorable toxicity profiles and therapeutic promise in targeting CD40 [50]. There is a strong rationale for combining CD40 agonists with other immunotherapies, including CPI. Currently, there are at least five of these agents in active clinical trials, alone and in combination with other immunotherapies (Table 10.2).

10.6 Cytokines

Cytokine therapy with IFN-α or IL-2 has been utilized in the treatment of cancer for over 30 years. IFN-α use has greatly diminished due to marginal effectiveness and concerns for acute toxicities [51]. High-dose IL-2 (HD-IL2) is also associated with severe, although generally reversible, acute toxicities including hypotension, renal failure, and thrombocytopenia. However, HD-IL2 is capable of producing durable responses in a minority of patients with metastatic melanoma and renal cell carcinoma (RCC). Patients must be selected for good functional status and organ function, and the therapy must be administered in specialized centers with hospitalization required for the duration of treatment [52]. The antitumor activity of intravenous HD-IL2, however, has not been demonstrated in cancers outside of melanoma and RCC.

The well-established immune-stimulating effects of various cytokines have sustained interest in researching clinical applications for cancers outside of melanoma and RCC, including HNSCC. In 2002, results were published from a randomized phase III trial of perioperatively administered perilymphatic IL-2 in Stage II-IVb oral or oropharyngeal SCC. This therapy appeared to be safe and efficacious, significantly improving disease-free survival and OS. The 5-year survival rate in the perilymphatic IL-2 group was 73%, compared with 55% in the control group, and disease-free survival (DFS) rates were 64% and 51%, respectively [53]. Despite the impressive improvement in outcomes from this randomized, phase III study, perilymphatic IL-2 has not received much attention in the field. One possible reason for this includes the intensive dosing regimen used in the study, including daily injections into the neck for 10 days prior to surgery, and injections five times a month for up to a year after surgery.

Building on this work, another group is investigating in HNSCC, a blend of cytokines termed IRX-2, which primarily consists of IL-2, IL-1β, IFN-γ, and TNF-α. The formulation is administered perilymphatically and is combined with systemic low-dose cyclophosphamide for Treg depletion, along with indomethacin and zinc to inhibit immunosuppressive elements within the systemic circulation and TME. In 2011, nonrandomized phase II data were presented from 27 patients with Stage II-IVa HNSCC receiving perilymphatic IRX-2. The regimen was found to be well-tolerated, with no grade 4 or higher toxicities. 3-year OS and DFS rates were 69% and 62%, respectively; median DFS and OS were not reached after follow-up of at least 3 years [54]. A larger, phase II trial in HNSCC is currently underway (NCT02609386) and a phase Ib trial in combination with durvalumab (anti-PD-1L) and tremelimumab (anti-CTLA-4) is planned to commence in October 2018 (NCT03381183).

Another cytokine mixture-dubbed Multikine has been tested in HNSCC. This formulation contains 14 interleukins, interferons (IFN), chemokines, and colony-stimulating factors. In 2005, published data from a phase II clinical trial in T2-3, N0-2, M0 HNSCC showed an ORR of 41% in 17 patients treated with neoadjuvant perilymphatic Multikine injections [55]. A large phase III trial of Multikine in HNSCC completed enrollment in late 2016, and results are pending (NCT01265849).

IL-15 is cytokine of particular interest currently in cancer immunotherapy. IL-15 shares the immunostimulatory characteristics of IL-2; however, IL-15 does not promote Treg expansion or activation-induced cell death (AICD) of effector T cells, which are characteristics of IL-2 [56]. Two variants of IL-15, modified to improve the pharmacokinetic and pharmacodynamic properties when administered intravenously, are currently in clinical development. Recombinant human IL-15 (rhIL-15) was found to be well-tolerated and produced substantial increases in circulating NK and CD8+ T cells [57]. Additional phase I trials are combining CPI with rhIL-15 or hetIL-15, another modified IL-15, for metastatic or refractory cancer (NCT03388632, NCT02452268).

10.7 Targeting the Innate Immune System

Traditionally, the immune system has been divided into “innate” and “adaptive” components. The term “innate” refers to sensors that do not require rearrangement of genes. Receptors present on innate immune cells, such as dendritic cells and macrophages, are highly conserved between individuals and species. “Adaptive” immune components require rearrangement of genes, leading to great diversity in receptors but are therefore specific to individuals. Adaptive immune components include T cell receptors, B-cell receptors, and antibodies.

The innate and adaptive immune systems are not separate systems but are in fact intimately related. Innate immune cells are involved in the activation of the adaptive immune system through cytokine signaling and antigen presentation [58]. Therefore, the innate immune system is capable of targeting threats directly through “innate” pathways and also of “priming” adaptive immune cells including T cells. Appreciation of this relationship has made targeting the innate immune system attractive for cancer immunotherapy, as well as autoimmune diseases.

10.7.1 TLR Agonists

Toll-like receptors (TLR) are components of innate immunity that recognize foreign molecules (pathogen-associated molecular patterns [PAMPs], e.g., lipopolysaccharide [LPS]) or products of damaged tissues (danger-associated molecular patterns [DAMPs], e.g., HMGB1) [59]. After recognition of a foreign or danger-associated molecule, receptor signaling leads to release cytokines and interferons, which initiate an immune response. Each TLR subtype recognizes a specific type of PAMP or DAMP, for example, LPS for TLR 4 or double-stranded viral RNA for TLR3. While the subtypes TLR can be expressed on a variety of cell types, they are all expressed on dendritic cells [60]. Currently, compounds of clinical interest are agonists of TLR3, 7, 8, or 9, which are present on endosomes, and TLR4, which is present on the cell surface.

TLR7 and 8 are closely related structurally and functionally, recognizing single-stranded RNA from viruses or bacteria. Activation of these TLRs induces production of cytokines and type I interferons [61]. Imiquimod, a topical TLR7 agonist, was FDA-approved in 1997 for the treatment of genital warts after clinical trials showed efficacy against this virus-induced pathology. Imiquimod later demonstrated activity against actinic keratosis, a premalignancy, as well as basal cell carcinoma, and now has FDA approval for both of these conditions [51]. Intratumoral injection of TLR7 and TLR7/8 agonists are undergoing early clinical investigation in multiple tumor types including HNSCC (Table 10.3).
Table 10.3

Clinical trials: innate immune activators

Target

Drug

Phase

Tumor type

Combination

Trial

Completion date

TLR7

LHC165

I

Advanced malignancies

PDR001

NCT03301896

08/2019

TLR7/8

MEDI9197

I

Solid tumors

Durvalumab and/or palliative RT

NCT02556463

08/2020

 

NKTR-262

I

Advanced or metastatic solid tumors

NKTR-214 (modified IL-2)

NCT03435640

12/2019

TLR8

Motolimod

I

R/M/persistent;progressive solid tumors

Cyclophosphamide

NCT02050635

05/2021

  

Ib

Resectable HNSCC (neoadjuvant)

Cetuximab and nivolumab

NCT02124850

Unknown

TLR9

SD-101

I/II

R/M HNSCC

Pembrolizumab

NCT02521870

02/2020

 

IMO-2125

I

Solid tumors

None

NCT03052205

04/2020

 

MGN1703

I

Advanced solid malignancies

Ipilimumab

NCT02668770

05/2020

STING

ADU-S100

I

Advanced or metastatic solid tumors

Ipilimumab

NCT02675439

12/2020

  

I

Advanced or metastatic solid tumors

PDR001

NCT03172936

05/2019

 

MK-1454

I

Advanced or metastatic solid tumors

Pembrolizumab

NCT03010176

10/2021

R recurrent, M metastatic

The phase II Active8 trial randomized patients with R/M HNSCC to receive SOC platinum/5FU/cetuximab with or without the TLR8 agonist, motolimod. Although motolimod failed to improve PFS or OS in the intent-to-treat population, HPV+ patients and those with injection site reactions experienced significant benefit [62]. These results suggest that motolimod may benefit certain subgroups of HNSCC patients, based on HPV status or other biomarkers. A phase Ib trial of motolimod combined with cetuximab in the neoadjuvant setting showed evidence of immune response in the peripheral blood and resected tumor specimens [63]. The study protocol was amended in 2016 to add nivolumab to the combination of cetuximab and motolimod, and those results are pending [64].

TLR9 is a subset of TLR that recognizes CpG-rich DNA, a PAMP. Activation of TLR9 leads to TNF and type I IFN production, which in turn can activate T cells. Preliminary data are available from a phase I/II study of the TLR9 agonist, SD-101, with pembrolizumab in R/M HNSCC. Out of 16 PD-1-naïve patients currently enrolled, ORR in 10 evaluable patients is 40% (four PR, one SD, five PD). Final results of the study after data maturation are anticipated, but these early results are promising [65]. Other TLR9 agonists in phase I studies in solid tumors include IMO-2125 and MGN1703 (Table 10.3). IMO-2125 is also in phase III development in combination with CPI in melanoma.

10.7.2 STING Agonists

The STING (stimulator of interferon genes) pathway has recently been recognized as a critical component of the antitumor response. STING is an endoplasmic reticulum protein which binds to cytosolic (tumor) DNA, causing activation dendritic cells. Experimental studies in STING −/− mice show a markedly defective CD8+ T cell priming [66]. Preclinical studies have also shown that activation of the STING pathway can increase effector T cell tumor infiltration [67]. ADU-S100 is a cyclic dinucleotide (CDN) that was discovered to activate all known human STING alleles and is currently undergoing phase I clinical evaluation in advanced solid tumors in combination with ipilimumab or PDR001 (anti-PD-1). Another CDN STING agonist, known as MK-1454, is also in phase I trials in advanced/metastatic solid tumors, alone or in combination with pembrolizumab (Table 10.3).

STING agonists are local therapy—they are injected into the tumor and have no systemic effect. One group is developing a novel intervention using a biomaterial containing CDN ligands that is called STINGblade, which is implanted locally into the resection site at the time of surgery and is extremely effective at preventing local recurrence following total or subtotal surgical resection [68]. Using several different models of HNSCC, they showed that antitumor activity was host-STING and CD8-dependent, indicating that adaptive immune responses are required for control of disease and improved survival. Subsequent work demonstrated that a novel approach to analyzing cytokine response using tumor explants treated ex vivo identified tumors with variable immune responses to STING ligands, which could enable personalization of the immunotherapy-containing biomaterial to induce tumor cure.

10.8 Vaccines

Just as vaccines can train the immune system to recognize and destroy pathogens, thereby preventing infection, vaccination can also initiate antitumor immune responses [69]. To induce an effective immune response and avoid targeting of self-antigens, vaccination would ideally utilize antigens that are expressed only on tumor cells and not on normal cells, i.e., tumor-specific antigens (TSA) including viral proteins and tumor-specific mutated antigens or “neoantigens.” Alternative targets include tumor-associated antigens (TAA) including tissue differentiation antigens, antigens that are overexpressed on tumors compared with normal tissue (e.g., EGFR), and cancer germline antigens that are not normally expressed on somatic cells but are aberrantly expressed in tumor cells [70]. Each type of target antigen caries potential advantages and disadvantages for vaccination, outlined in Table 10.4.
Table 10.4

Targeting of tumor-associated antigens

Class

Advantages

Concerns

Examples

Tissue differentiation antigens

• Shared antigens

• “Off the shelf” treatments can be developed

• Expression on normal tissues• Potential for on-target, off-tumor toxicity

MART-1

gp100

CEA

CD19

Tumor germline (“tumor-testis”) antigens

• Shared antigens

• “Off the shelf” treatments can be developed

• Potentially tumor-specific

• Potential for on-target off-tumor toxicity

• May be expressed in a low frequency of cancers

ΝY-ESOl

MAGE-A3

Normal proteins overexpressed by cancer cells

• Shared antigens

• “Off the shelf” treatments can be developed

• On-target, off-tumor toxicity

hTERT

EGFR

mesothelin

Viral proteins

• Shared antigens

• “Off the shelf” treatments can be developed

• Tumor-specific, thus minimal risk of on-target off-tumor toxicity

• Low frequency of virus-associated cancers

HPV

EBV

MCC

Tumor-specific mutated antigens

• Tumor specific, thus minimal risk of on-target off-tumor toxicity

• Shared driver hot-spot mutations can potentially be targeted

• Currently requires surgical resection for next-generation sequencing

• Most immunogenic mutations identified so far are patient-specific

• Extended time to develop personalized treatment targeting mutations

Mum-1

B-catenin

CDK4

ERBB2IP

Modified from: Ilyas S, Yang JC. Landscape of Tumor Antigens in T cell Immunotherapy. Journal of immunology (Baltimore, Md: 1950). 2015;195(11):5117–5122. doi: https://doi.org/10.4049/jimmunol.1501657)

Numerous types of cancer vaccines have been tested in preclinical models and in clinical trials. These include peptide vaccines, tumor lysates, DNA or RNA vaccines, and cellular vaccines including dendritic cells that have been exposed to antigen and danger signals. Sipuleucel-T (Provenge), an autogenous cellular vaccine targeting prostatic acid phosphatase, was approved by the FDA for the treatment of metastatic prostate cancer in 2010. While Sipuleucel-T was shown to increase OS in a randomized phase III trial, there was no increase in PFS [71]. Sipuleucel-T remains the only FDA-approved therapeutic vaccine for the treatment of cancer.

The ability to identify neoantigens through next-generation sequencing (NGS) techniques is appealing, in that neoantigens would theoretically avoid self-reactivity seen with tissue differentiation antigens or overexpressed antigens. However, this approach is based on patient-specific antigens and relies on complex mathematical modeling to predict binding to the patient’s MHC types. Short-lived peptides are another potential source of tumor-associated antigens that have not been tolerized, due to the usual rapid degradation in autophagosomes. By “freezing” these vesicles in vitro, preventing fusion with lysosomes and subsequent destruction of the antigens, a source of tumor-associated antigens can be obtained which otherwise would have been “thrown away” by normal cell metabolism. This technique has been used to create a vaccine known as DRibbles, which has been shown to contain shared antigens capable of cross-recognition between different tumors and is currently in phase I clinical trials in multiple tumor types, with plans to expand to oral cancer [72].

Therapeutic vaccines have been tested clinically in HNSCC, mostly showing modest efficacy [73, 74, 75, 76]. While vaccination can facilitate antigen presentation, it does not address deficiencies in T cell activation or suppressive forces within tumors. Furthermore, targeting specific antigens may lead to immune editing and shedding of that antigen, unless the mutant target is a true “driver” of oncogenesis. Therefore, vaccination as a monotherapy is unlikely to be successful in most settings and should be approached as an additional tool in the immunotherapy arsenal rather than a standalone therapy. Future directions for cancer vaccines will undoubtedly involve other therapies such as costimulatory agonists or checkpoint blockade to capitalize on antigen presentation or reduce immune-suppressive influences that may prevent immune response despite recognition of a tumor [77]. Ongoing trials in HNSCC are listed in Table 10.5.
Table 10.5

Clinical trials: therapeutic vaccines in HNSCC (including HPV-negative)

Category

Target

Product

Phase

Combination

Trial

Estimated completion date

Tissue differentiation antigen

CEA

CEA(6D)/TRICOM

I

None

NCT02999646

Completed, results pending

Tissue differentiation antigen

CEA

GI-6207

I

None

NCT00924092

Completed, results pending

Tissue differentiation antigen

MUC-l

-

I/II

Tadalafil

NCT02544880

04/2021

Cancer germline antigen

MAGE-A3

Biropepimut-S

II

cyc, GM-CSF, poly ICLC

NCT02873819

12/2020

Tumor lysate

Tumor- derived antigens

Allovax

II

None

NCT02624999

12/2018

Tumor lysate (irradiated)

Tumor- derived antigens

MVX-ONCO-1

II

None

NCT02999646

06/2020

Tumor-associated antigens

CEA, MUC-l, Ras, Brachyury

NANT vaccine

I/II

chemo, RT, CPI, cytokines

NCT03109764

01/2019

Neoantigen—vaccine/antibody hybrid

Patient-specific neoantigens

Vaccibody VB10.NEO

I/IIa

None

NCT03548467

03/2023

cyc cyclophosphamide, CPI checkpoint inhibitors

10.9 Adoptive Cell Therapy

Adoptive cell therapy (ACT) is an immunotherapeutic approach that involves the extraction of T cells from a patient, expansion of a T cell population ex vivo, and infusion of the T cells back into the patient, usually after chemotherapeutic lymphocyte depletion and followed by administration of cytokines such as IL-2 [78]. Several methods of ACT are in development, including extracting tumor-infiltrating lymphocytes (TIL), which are expected to include some T cells that have specificity for TAA. Alternatively, T cells may be extracted from the peripheral blood and either (1) selected for tumor reactivity ex vivo, (2) exposed to dendritic cells loaded with specific TAA, (3) transduced with specific T cell receptors (TCR) with affinity for known TAAs, or (4) transduced with a chimeric antigen receptor (CAR) that has the antigen-recognizing domain of an antibody and the signaling domain of a TCR [60]. These approaches essentially skip the majority of the cancer immunity cycle, including antigen recognition, T cell activation and proliferation, by directly introducing cancer-fighting T cells into the patient. ACT is therefore termed “passive immunity,” as it circumvents reliance on the patient’s immune response.

ACT has proven to be a potent strategy in melanoma, capable of inducing complete responses, and investigation of this method has broadened to include cancers of epithelial origin [79]. There are currently three ACT clinical trials that include patients with HPV-negative HNSCC (Table 10.6). Early results from the LN-145 TIL trial showed an ORR of 38% in eight patients evaluable [80, 81]. Additionally, preliminary data from a phase I dose-escalation study of intratumorally injected pan-ErbB CAR T cell s showed a disease control rate (DCR = CR + PR + SD) of 69%, despite rapidly progressing tumors at trial enrollment [82].
Table 10.6

Clinical trials: adoptive cell therapy in HNSCC (including HPV-negative)

Method

Product

Phase

Combination

Trial

Estimated completion date

TIL

LN-145

II

Lymphodepletion/IL-2

NCT03083873

10/2018

TCR-engineered

IMA201

I

Lymphodepletion/IL-2

NCT03247309

12/2019

CAR-T

T4

I

None

NCT01818323

6/2019

10.10 Oncolytic Viruses

It has been shown that certain viruses can preferentially replicate within malignant cells while preserving normal cells. Some viruses naturally possess this capability (myxoma virus, Newcastle disease virus (NDV), reovirus), while other types of viruses (herpes simplex, vaccinia, adenovirus) can be genetically modified to specifically infect malignant cells [83]. In addition to direct tumor cell killing, oncolytic viruses can induce immunogenic cell death (ICD), essentially acting as a cancer vaccine [84]. As with many new cancer therapies in development, oncolytic viruses will likely find the most utility when combined with immunotherapies such as CPI, and this is reflected by the design of many current clinical trials (Table 10.7).
Table 10.7

Clinical trials: oncolytic viruses in HNSCC and solid tumors

Virus

Product

Phase

Tumor type

Combination

Trial

Estimated completion date

Herpes virus

T-VEC

Ib/III

R/M HNSCC

Pembrolizumab

NCT02626000

08/2020

Measles

MV-NIS

I

R/M HNSCC

None

NCT01846091

12/2018

Vaccinia

Pexa-Vec

I

A/M solid tumors

Ipilimumab

NCT02977156

11/2019

Vaccinia

p53MVA

I

Refractory solid tumors

Pembolizumab

NCT02432963

02/2019

Adenovirus

Enadenotucirev

I

A/M epithelial tumors

Nivolumab

NCT02636036

03/2019

A advanced, R recurrent, M metastatic

In 2015, the first FDA approval of an oncolytic virus was granted to a genetically engineered, GM-CSF-transduced Herpes Simplex Virus (HSV-1), Talimogene Laherparepvec or T-VEC, for use in locally advanced or nonresectable melanoma. In HNSCC, T-VEC was tested in a small phase I/II study in combination with chemoradiotherapy in advanced HNSCC, showing an OS of 70.5% at median follow-up of 29 months. Patients all received post-therapy neck dissection, which was not standard of care for many of these patients; however, a pathologic CR rate of 94% in neck dissection specimens was a promising finding [85]. T-VEC is being tested in many other types of cancers and is currently in a phase Ib/III study in HNSCC in combination with pembrolizumab [86]. HF10, a spontaneously occurring mutant HSV-1 virus, was shown to be well-tolerated in a phase I trial in HNSCC [87], and in a phase II trial in advanced melanoma, HF10 combined with nivolumab showed an ORR of 41% with a 16% rate of CR [88].

Another example is Cavatak™, a coxsackievirus developed by Viralytics, which seeks out and attaches itself to a protein that is highly expressed on the surface of many cancer cells, intercellular adhesion molecule-1 (ICAM-1). Since ICAM-1 is expressed in HNSCC [89], a phase 1 clinical trial studying Cavatak with pembrolizumab has been designed and is currently in its final stages of preparation before opening for recruitment. GL-ONC1, an attenuated vaccinia virus, was well-tolerated with concurrent chemoradiotherapy in HNSCC [90] and is in phase II development in recurrent ovarian cancer (NCT02759588). Oncorine (H101), an E1B-deleted adenovirus, was approved in China in 2005 for use in HNSCC after a phase III study showed an ORR of 78% when combined with cisplatin and 5-FU [91, 92]. The use of H101 so far remains limited to China.

A trial called REO 018 trial was initially designed as a randomized phase III study of Reolysin, a reovirus, in combination with carboplatin and paclitaxel in platinum-refractory HNSCC. The study was reformatted after interim analysis found differential responses in patients with locoregional disease versus patients with metastatic disease alone. The company claimed a statistically significant increase in PFS and OS in patients with locoregional disease, but stated that there were too few patients to power a statistical analysis for patients with distal metastases alone [93]. From review of the company’s webpage, it appears that further development is currently focused on myeloma, breast, and pancreatic cancer [94].

10.11 The Role of Conventional Therapies in Activating the Immune System

While the efficacy of traditional cancer treatments, including chemotherapy, radiation, and targeted therapies, has historically been ascribed to direct cytotoxicity or inhibition of cellular activities, there is increasing appreciation for the immune-stimulating effects of these treatments. As described above, the Cancer Immunity Cycle begins with the release of cancer cell antigens. This is achieved by a process known as Immunogenic Cell Death (ICD), in which the killing of tumor cells can elicit an antitumor immune response. In addition to promoting recognition of tumor antigens through ICD, many chemotherapeutic agents have been shown to modulate immunosuppressive influences, e.g., through depletion of Tregs or MDSCs [95].

Many chemotherapeutics have been assessed for the various components of ICD. While cisplatin has previously been thought to be incapable of inducing bona fide ICD on its own, recent work on HNSCC models indicate that cisplatin can effectively induce ICD [96]. This strengthens the rationale for combining SOC platinum agents with immunotherapy. KEYNOTE-048 was the first randomized phase III trial of anti-PD-1 therapy plus chemotherapy in HNSCC. As mentioned previously in section 10.2, the positive results from this trial led to approval of pembrolizumab alone or in combination with platinum chemotherapy in first line R/M disease. Additional trials of cytotoxic chemotherapy combined with immunotherapy in HNSCC are listed in Table 10.8.
Table 10.8

Immunotherapy with chemotherapy in HNSCC

Chemo agent

Phase

Settiug

Immunotherapy

Timing of immunotherapy

Trial

Docetaxel + cisplatin + 5FU

I

PULA

Durvalumab

Induction (before chemo/rad)

NCT02997332

Evofosfamide

I

LA or M

Ipilimumab

Concurrent (second line)

NCT03098160

Docetaxel

Ι/II

R/M

Pembrolizumab

Concurrent (second line)

NCT02718820

Platinum + 5FU

III

R/M

Pembrolizumab

Concurrent (first line)

NCT02358031

Radiation may also play a synergistic role in combination with immunotherapy. In addition to induction of ICD, radiation therapy has been shown to recruit T cells to the irradiated tumor and increase susceptibility of tumor cells to cytotoxic effector cells [98]. Radiation also upregulates PD-L1 expression on tumor cells, which may limit the immunogenicity of radiation alone, but offers a therapeutic opportunity for combination with PD-1 inhibitors [99]. In HNSCC, immunotherapy appears to increase the antitumor response from radiation, rather than facilitate distant abscopal responses through an autovaccination effect of radiation [100]. Nonetheless, there is abundant evidence for the synergistic effect of radiation and immunotherapy [101]. There are numerous studies combining immunotherapy and radiation in HNSCC (Table 10.9), including a phase I study of neoadjuvant nivolumab combined with hypofractionated stereotactic body radiotherapy (SBRT) prior to surgical resection in the definitive setting (NCT03247712).
Table 10.9

Immunotherapy with radiation in HNSCC

Type of radiation

Phase

Setting

Immunotherapy

Timing in relation to RT

Trial

With surgery

Neoadjuvant SBRT

I/II

Curative

Nivolumab

Neoadjuvant + adjuvant

NCT03247712

IMRT

II

LA

Pembrolizumab

Neoadjuvant + adjuvant

NCT02296684

Without surgery

IMRT

II

LA

Pembrolizumab

Concurrent

NCT02707588

"High dose"

II

M

Pembrolizumab

Concurrent

NCT03085719

Re-irradiation

II

R

Pembrolizumab

During and after

NCT02289209

Re-irradiation

I/II

R

Nivolumab

Before, during and after

NCT03317327

SBRT

II

M

Nivolumab

During and after

NCT02684253

Proton SBRT

Observational

R/M

Nivolumab

Before, during and after

NCT03539198

Additionally, there are mechanistic rationales for combining targeted therapies with immunotherapy. The antitumor activity of cetuximab in HNSCC is now appreciated to be primarily ADCC, as opposed to direct cytotoxicity. By combining cetuximab with CPI or other immunotherapies, immune-suppressive forces within the TME could potentially be counteracted leading to increased efficacy over either agent alone [102]. An interim safety analysis of a phase II trial of pembrolizumab and cetuximab in R/M HNSCC showed good tolerability with no DLTs [103]. There are several other efficacy studies underway which combine cetuximab with CPI with or without chemotherapy and radiation.

Lenvatinib is a multiple kinase inhibitor approved for differentiated thyroid cancer and advanced renal cell carcinoma. In addition to its effects on tumor angiogenesis and proliferation, lenvatinib has been shown to decrease suppressive TAM populations within tumors and to increase numbers of effector CD8+ cells [104]. Interim analysis of a phase Ib/II clinical trial of lenvatinib with pembrolizumab in metastatic HNSCC showed an ORR of 41%, although the rate of grade 3–4 adverse events was 73% [105]. Interim analysis of a phase I/II trial of pembrolizumab in combination with vorinostat, a histone deacetylase inhibitor, showed an ORR of 36% with DCR of 56%. Another study of Acalabrutinib, a Bruton’s tyrosine kinase inhibitor, in combination with pembrolizumab in advanced HNSCC, is underway. Trials of targeted therapies with immunotherapy in HNSCC are listed in Table 10.10.
Table 10.10

Immunotherapy with targeted therapy in HNSCC

Targeted therapy

Phase

Setting

Immunotherapy

Timing of immunotherapy

Trial

Acalabrutinib

II

LAa or R/M

Pembrolizumab

Concurrent

NCT02454179

Vorinostat

Ι/II

LAa or M

Pembrolizumab

Concurrent

NCT02538510

Cetuximab

I/II

R/M

Nivolumab

Concurrent

NCT03370276

 

II

R/M

Pembrolizumab

Concurrent

NCT03082534

Lenvatinib

I/II

M

Pembrolizumab

Concurrent

NCT02501096

aNot amenable to surgery

There are a number of “preoperative window,” neoadjuvant immunotherapy studies underway in HNSCC (Table 10.11). In addition to testing immunotherapies in earlier stages of disease with curative intent, studies such as these provide great potential for understanding the effects of immunotherapy in human cancer. Results from a phase II study of neoadjuvant nivolumab in resectable HNSCC showed good tolerability and tumor reductions within 1 month in nearly half of evaluable patients [106]. Many other neoadjuvant immunotherapy trials in HNSCC are underway, with a focus on analysis of immune effects within the surgical specimens. The histological and clinical comparison of tumors before and after immunotherapy may provide much insight into the effects in vivo, including the potential to identify biomarkers for response and further therapeutic targets.
Table 10.11

Preoperative “window of opportunity” immunotherapy trials

Imtnuaotherapy

Phase

Endpoint

Trial

Expected completion date

Nivolumab

II

Response; indicators of immune response in tissue/blood

NCT03021993

03/2020

Nivolumab +/− ipilimumab

II

Response, recurrence

NCT02919683

04/2024

Nivolumab +/− ipilimumab or relatlimab or daratumumab

I/II

Response, recurrence

NCT02488759

12/2019

Cemiplimab (RENG2810)

II

Response, recurrence

NCT03565783

01/2020

Durvalumab

II

Indicators of immune response in tissue/blood

NCT02827838

01/2019

Ipilimumab (intratumoral)

I

Indicators of immune response in tissue/blood

NCT02812524

07/2019

MEDI0562 (anti-OX40)

Ib

Indicators of immune response in tissue/blood

NCT03336606

12/2024

Due to the large number of clinical trials combining chemotherapy, radiation, and/or targeted therapies with immunotherapy in HNSCC in a variety of settings (neoadjuvant, adjuvant, recurrent/metastatic), much will be learned about the safety and efficacy of combinations. Studies not already listed in previous sections are presented in Table 10.12. Moving forward, a major focus of preclinical research and clinical trials moving will be to determine the optimal doses and timing of standard therapies to promote responses to different types of immunotherapy.
Table 10.12

Immunotherapy with chemotherapy/targeted therapy and radiation in HNSCC

Type of chemotherapy

Phase

Setting

Immunotherapy

Timing of immunotherapy

Trial

With surgery

Carboplatin + nab-paclitaxel

II

LA

Durvalumab

Neoadjuvant and adjuvant

NCT03174275

Cisplatin

II

LA

Pembrolizumab

Neoadjuvant and adjuvant

NCT02641093

Without surgery

Cisplatin or cetuximab

I

LAa

Nivolumab

Before, during, after CRT

NCT02764593

 

I

LAa

Durvalumab

During radiation

NCT03509012

Cetuximab

III

PULA

Avelumab

Before, during, after CRT

NCT02999087

 

Ib

LAa

Ipilimumab

During and after CRT

NCT01860430

Cisplatin

III

LAa

Pembrolizumab

Before, during, after CRT

NCT03040999

LA locally advanced, PULA previously untreated locally advanced, R recurrent, M metastatic

aNot amenable to surgery

10.12 Conclusions

Immunotherapy is rapidly changing the standard of care in oncology. The appearance of a tail at the end of the survival curve with checkpoint inhibition in advanced cancers provides a graphic representation of the durable responses that can be achieved with this new group of therapies. This is the great promise of cancer immunotherapy, that is, the possibility of achieving lasting responses or even cures.

As evidence of the enthusiasm around immunotherapy, the number of new products in development and early-phase clinical trials has skyrocketed in the last decade. In 2017, it was estimated that there were 800–1000 cancer immunotherapy trials in the US involving over 100,000 patients [107, 108]. The same year, a report from the Pharmaceutical Research and Manufacturers of America found that there were 248 immuno-oncology agents in clinical trials, which only included “the most recognized classes of immunotherapy” [109]. In addition to the therapies described in this chapter, there are many other immunotherapies and immune adjuncts in development, including but not limited to agents that target tumor metabolism (e.g., IDO-1 and the adenosine pathway) [110, 111, 112], therapies to deplete or inhibit Tregs, MDSC, or TAM (e.g., anti-CCR4, PDE-5 inhibitors, anti-CSF1R) [113, 114, 115], and checkpoint inhibitors that target NK cells (e.g., anti-KIR, anti-NKG2A) [116, 117].

Moving forward in this new era of cancer immunotherapy will require continuing integration between the clinic and laboratory. Not only will preclinical science remain critical in developing new approaches in patient care, but laboratory evaluation of pathologic tumor responses, immune cell infiltrates, and circulating immune components will allow full-circle analysis and understanding of the physiologic effects of experimental treatments. The increasing number of neoadjuvant trials will facilitate this route of scientific discovery by providing postimmunotherapy tissue samples for comparison with pretreatment biopsies. Cutting-edge technologies for specimen analysis, such as NGS allowing whole-exome, RNA and T cell receptor sequencing, as well as advanced imaging techniques for multiplex immunohistochemistry, will allow for greater understanding of the in vivo effects of various immunotherapies on tumor biology. This work, along with clinical outcome correlations, will be critical in identifying predictive biomarkers and prognostic indicators and will provide evidence for future directions in cancer research.

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Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Marcus A. Couey
    • 1
  • Rom S. Leidner
    • 1
  • Simon W. Young
    • 2
  • R. Bryan Bell
    • 1
    Email author
  1. 1.Earle A. Chiles Research Institute in the Robert W. Franz Cancer CenterProvidence Cancer InstitutePortlandUSA
  2. 2.Department of Oral and Maxillofacial SurgeryUniversity of Texas Health Science Center at HoustonHoustonUSA

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