|Year : 2018 | Volume
| Issue : 1 | Page : 2-11
Evolving role of immunotherapy in head-and-neck cancers: A systemic review
Raajit Chanana, Vanita Noronha, Amit Joshi, Vijay Patil, Kumar Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||29-Jun-2018|
Dr. Raajit Chanana
91, Pocket B Sukhdev Vihar, New Delhi - 110 025
Source of Support: None, Conflict of Interest: None
Head-and-neck squamous cell cancers (HNSCCs) are one of the most common cancers worldwide and account for more than half million new cases and 380,000 deaths per year. A large number of patients are diagnosed with locally advanced disease and require multimodal treatment approaches. Despite advances in radiation and surgical techniques and the use of chemotherapy and monoclonal antibodies in advanced disease, more than half of all patients recur. Tumor cells from various solid malignancies, including HNSCC, over-express PD-LI to habituate the immune checkpoint pathways to evade immune surveillance. In this review, we summarize the current literature on immunotherapeutic options that are available for HNSCC patients.
Keywords: Head-and-neck cancers, immunology, immunotherapy, nivolumab, pembrolizumab
|How to cite this article:|
Chanana R, Noronha V, Joshi A, Patil V, Prabhash K. Evolving role of immunotherapy in head-and-neck cancers: A systemic review. J Head Neck Physicians Surg 2018;6:2-11
|How to cite this URL:|
Chanana R, Noronha V, Joshi A, Patil V, Prabhash K. Evolving role of immunotherapy in head-and-neck cancers: A systemic review. J Head Neck Physicians Surg [serial online] 2018 [cited 2019 Aug 24];6:2-11. Available from: http://www.jhnps.org/text.asp?2018/6/1/2/235621
| Introduction|| |
Head-and-neck squamous cell cancers (HNSCCs) are one of the most common cancers worldwide and account for more than half million new cases and 380,000 deaths per year. Major etiological risk factor includes tobacco use, betel-quid and areca-nut chewing, alcohol consumption, human papillomavirus (HPV) infection (oropharyngeal cancer), and Epstein–Barr virus infection (nasopharyngeal cancer). A large number of patients are diagnosed with locally advanced disease and require multimodal treatment approaches. Despite advances in radiation and surgical techniques and the use of chemotherapy and monoclonal antibodies in advanced disease, more than half of all patients recur locoregionally or distantly.
There has been extensive research on the complex and dynamic interaction between tumor cells and host immune cells which has led to the development of various approaches to attack tumor cells through heightened immune response. Tumor cells from various solid malignancies, including HNSCC, over-express PD-LI to habituate the immune checkpoint pathways to evade immune surveillance. Pembrolizumab and nivolumab are PD-1 antibodies that interrupt the immunosuppressive pathway of inhibitory checkpoints, which are used by tumor cells to prevent immune reaction. In this review, we summarize the current literature on immunology and immunotherapeutic options that are available for HNSCC patients at this time.
| Immunology in Head-And-Neck Cancers|| |
HNSCC highly immunosuppressive malignancy with a high mutational burden. Most common mechanisms responsible for carcinogenesis in HNSCC include local immune evasion, induction of immune tolerance, and disruption of T cell signaling.
Avoiding immune destruction is one of the hallmarks of cancer. Tumors evade immune response through multiple immunologic resistance mechanisms: development of T-cell tolerance, modulation of inflammatory and angiogenic cytokines, downregulation of antigen processing machinery (APM), and the expression of immune checkpoint ligand end receptors. Tumor cells also develop an immune suppressive microenvironment by promoting the secretion of immunosuppressive cytokines such as transforming growth factor-beta (TGFβ) and interleukin 10 (IL-10) which suppress T-cell proliferation and cytotoxic function and downregulate expression of co-stimulatory molecules and MHC. These cytokines inhibit dendritic cell maturation, macrophage activation, cytolysis by natural killer (NK) cells, and Cytotoxic T lymphocytes (CTLs). There are three types of immunosuppressive hematopoietic cells that are recruited in the tumor microenvironment and play an important role in immune escape: myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and regulatory T-cells (Tregs). Infiltrating MDSCs produce arginase-I to metabolize L-arginine (which is an essential amino acid that is crucial for the function of T-cells) to dampen T-cell response.,, TAMs play an important role in tumor immunosuppression, migration, and metastasis. TAMs in tumor microenvironment are associated with poor clinical outcome. The tumor-infiltrating Tregs suppress immune response through production of IL-10 and TGFβ.,,
HPV cancer is a key model for understanding tumor immune evasion. Although HPV infection is common, HPV-associated cancer is very rare. Various studies have shown that HPV-infected cells actively promote stromal inflammation and interact with local microenvironment to promote oncogenesis. In HPV-associated cancer, there is a weak T-cell response to HPV early antigens in blood along with high levels of TILs that lack cytotoxicity and increased numbers of IL-10 producing Tregs. HPV+ HNSCC also has high levels of T-infiltrated lymphocytes with high PD-1 expression, and high levels of PD-L1 expression on tumor cells, and TAMs. These results signify that an intrinsic immunologic response is generated against HPV HNSCC which induce PD-1/ PD-L1 axis and may limit the capacity of TILs to culminate an immunologic attack.
Immune tolerance is defined as failure to mount an immune response to antigen. Tumor cells are heterogeneous with nonuniform expression of tumor-associated antigens (TAAs) and tumor-specific antigens (TSAs). HNSCC cells with high levels of TAAs or TSAs are more likely to be detected by the immune system and eliminated as compared to HNSCC cells with no or low levels of TSAs or TAAs which exhibit low immunogenicity and escape from immune surveillance., The interplay between tumor antigen (TA) and TA-specific CTLs is necessary for CTL recognition and tumor cell destruction. APM components work in tandem to generate antigenic peptides, translocate into endoplasmic reticulum, load MHC Class I H chain with peptides, and finally transport MHC Class I molecules to the cell surface to present the peptide to T-lymphocytes. Tumor cells have the potential to reduce T cell-mediated recognition by downregulating or mutating HLA I molecules and/or APM components to attenuate antigen presentation. The downregulation of HLA Class I antigen and most APM components has been observed in a clinical trial of 63 primary laryngeal squamous cell carcinomas.
Deregulation of T-cell signaling
T-cell receptors (TCRs) interact with co-stimulating ligands and co-stimulatory receptors to provide T-cell signal recognition. Cancer cells inhibit T-cell-mediated recognition and activation by downregulating MHC I antigen presentation to endogenous TCR and also through the inhibitory co-stimulatory receptor pathways. Two of the most commonly involved checkpoint inhibitory mechanisms are CTLA-4 and PD-1/ PD-L1, which act at earlier and later stages of immune response to tumors. CTLA-4 competes with CD28 receptor, an activating co-stimulatory receptor, for binding to B7 ligand (CD80 and CD86) found on APCs, resulting in T-cell inactivation. In normal cells, PD-1 binds to its ligands PD-L1/PD-L2 to reduce T-cell effector activity and terminate immune response. However, PD-L1 is overexpressed in the majority of HNSCC tumors, and this immune brake signal is adopted by HNSCC cells to evade immune elimination. Two of the most commonly involved checkpoint inhibitory mechanisms are CTLA-4 and PD-1/ PD-L1, which act at earlier and later stages of immune response to tumors. T-cell immunoglobulin mucin-3 (Tim-3), lymphocyte activation gene 3, and T-cell tyrosine-based inhibitory motif domain are other inhibitory co-stimulatory receptors, which are also reported to be upregulated in exhausted T-cells isolated from solid malignancies.,,
| Immunotherapy With Radiotherapy|| |
The combination of radiation therapy (RT) with cetuximab was shown to offer superior locoregional control and overall survival (OS) compared to radiation alone for locoregionally advanced HNSCC, in the landmark Phase III trial. Subgroup analysis at 5 years suggested that oropharyngeal primary site, AJCC Stage T1-3, Stage N1-3, and age >65 were associated with increased benefit from the addition of cetuximab. Cetuximab induces not only TA-specific CTL responses but also immunosuppressive regulatory T-cells that express CTLA-4, thus limiting the efficacy of cytotoxic T-lymphocytes. Based on this speculation that blockade of CTLA-4 could prevent activation of this inhibitory pathway and potentially enhance the efficacy of cetuximab, Phase I dose-escalation study PULA-HNSCC integrated ipilimumab, an anti-CTLA-4 monoclonal antibody, into a standard regimen of cetuximab plus RT in patients with previously untreated, locally advanced HNSCC. Eligible patients had Stage III-IVB SCC of the larynx or pharynx. Three of six patients in Cohort 1 experienced Grade 3 dermatologic adverse events and 1 patient had Grade 4 colitis. Four patients recurred, three of whom died. The probability of 2-year progression-free survival (PFS) and OS was 77% and 71%, respectively. The authors concluded that ipilimumab plus C-IMRT is tolerable and yields acceptable survival, and the recommended dose of ipilimumab for Phase II study is 1 mg/kg.
Radiotherapy is associated with the abscopal effect or radiation-induced bystander effect, in which local treatment leads to a response in distant lesions. In experimental mouse models, irradiation induces increased PD-L1 expression on both tumor and MDSCs, which may promote disease relapse. The concomitant administration of anti-PD-L1 synergistically controlled tumor growth and even mediated abscopal regression of distant lesions. In the 2017 ASCO annual meeting, date regarding the safety of the combination of pembrolizumab with definitive chemoradiation was presented in patients with locally advanced oropharyngeal, hypopharyngeal, and laryngeal cancers. Patients received weekly cisplatin at a dose of 40 mg/m 2, 200 mg Pembrolizumab every 3 weeks, and radiation at 2 Gy daily for 35 planned fractions. Interim analysis of 27 patients showed 21 (78%) received all planned doses of Pembrolizumab and the study was discontinued on three patients due to immune-related adverse events and on three more due to protocol reasons. At day 150 after the start of chemoradiation with pembrolizumab, 21 patients (78%) had a complete response.
A number of ongoing trials are evaluating the addition of immunotherapy to radiotherapy in locally advanced head-and-neck cancers [Table 1]. Phase III trial (NCT02952586) to evaluate cisplatin-based CRT ± avelumab as first line in newly diagnosed, locally advanced HNSCC. The primary endpoint in this study is PFS and the secondary endpoint is OS. A Phase II trial (NCT02289209) is evaluating re-irradiation with pembrolizumab in HNSCC patients with locoregional inoperable recurrence or second primary tumor. Another trial is evaluating RT+ pembrolizumab (NCT02318771) in recurrent/metastatic or inoperable across solid tumors including HNSCC. KEYNOTE-412 is a Phase 3, randomized, placebo-controlled, double-blind trial enrolling subjects with newly diagnosed, treatment-naive, oropharyngeal p16-positive, oropharyngeal p16–negative, and larynx/hypopharynx/oral cavity SCC. Approximately 780 subjects will be randomly assigned (1:1) to receive pembrolizumab plus cisplatin-based CRT or placebo plus cisplatin-based CRT. Another ongoing Phase III trial (NCT02764593; RTOG3504) is evaluating cisplatin-based chemoradiation ± nivolumab in newly diagnosed, immediate-high risk, locally advanced HNSCC patients.
| Immunotherapy in Locally Advanced and Recurrent/metastatic Head-And-Neck Cancers|| |
Nivolumab has gained Food and Drug Administration (FDA) and European Medicines Agency approval for the treatment of HNSCC in patients' progressing during or following platinum-based therapy based on the results of Phase III CheckMate-141 study. Three hundred and sixty-one patients who progressed on or within 6 months of platinum-based therapy were randomized to receive either nivolumab 3 mg/kg every 2 weeks or a treatment according to the investigator's choice (IC) (docetaxel, methotrexate, or cetuximab). A 30% reduction in the risk of death was observed with nivolumab; the median OS was 7.5 months versus 5.1 months and hazard ratio (HR) = 0.70. Patients with PD-L1 ≤1% expression (57.3% were ≤1%), the median OS for nivolumab was 8.8 months versus 4.6 months; HR = 0.55. There was no significant difference in OS when PD-L1 expression was <1%. The response rate was 13.3% in the nivolumab group versus 5.8% in the standard group. Treatment was well tolerated, with only 13.1% of Grade 3–4 events. The most common toxicities of any grade were fatigue (14%), nausea (8.5%), diarrhea (6.8%), skin reactions (15.7%), and endocrine effects (7.6%). In an analysis based on EORTC QLQ-C30 score and pain and sensory problems on the EORTC QLQ-HandN35 questionnaires, nivolumab was associated with an improved quality of life in comparison with chemotherapy. Nivolumab delayed time to deterioration of patient-reported quality-of-life outcomes and stabilized symptoms and functioning for up to 4 months from the start of treatment. Patients benefited from nivolumab regardless of PD-L1 expression. Updated clinical outcomes of data presented in ESMO 2017 concluded that nivolumab treatment beyond first progression in some patient of R/M SCCHN with certain immune profile was tolerable and associated with tumor size reductions.
Pembrolizumab is a humanized monoclonal IgG4 anti-PD-1 that blocks the interaction between PD-1 and its ligands. FDA granted accelerated approval to Pembrolizumab in August 2016 based on the results of Phase Ib keynote-12. Sixty patients (38% HPV positive) with recurrent or metastatic (R/M) HNSCC with at least 1% of PD-L1 expression were treated with pembrolizumab 10 mg/kg every 2 weeks. Both treatment-naive patients and pretreated patients with no limitations for the number of previous treatments were included. Nearly 70% of population were treated with ≤2 lines of chemotherapy for R/M disease. PFS and OS were 2 and 13 months, respectively. PD-L1 expression levels were associated with overall response and PFS. An expansion cohort of the Keynote-012 trial, enrolled 132 patients unrestricted for PD-L1 positivity with a fixed dose of 200 mg of pembrolizumab every 3 weeks, confirmed the results with a response rate of 18%, PFS and OS of 2 and 8 months, respectively. In the subsequent nonrandomized Phase II keynote-55 study, 171 patients with R/M HNSCC resistant to both platinum and cetuximab (progression within 6 months of the last dose of each therapy) were treated with pembrolizumab. Response rate was 16% with a median PFS was 2.1 months and OS was 8 months, with no influence of HPV on clinical activity [Table 2]. However, the recently published Phase III Keynote-040 study, which randomized patients with R/M HNSCC after a platinum-based chemotherapy to receive either pembrolizumab (n = 247) or IC treatment (methotrexate, docetaxel, or cetuximab), did not achieve significant OS (8.4 vs. 7.1 months; HR = 0.81). There was no difference in PFS. Among patients with combined positive score (CPS) of at least 1%, median OS was 8.7 months with pembrolizumab versus 7.1 months with standard treatments (HR = 0.75; P = 0.0078). Based on the above data, pembrolizumab may be used in patients who have progressed after platinum and cetuximab based treatment and have a PD-L1 ≤1%.
Epacadostat is an oral inhibitor of IDO1, an intracellular enzyme that leads to immunosuppression. In a Phase I/II study of combination of epacadostat plus pembrolizumab in patients with metastatic SCCHN, overall response rate and disease control rate were 34% and 39%, respectively. Responses were seen independent of PD-1 and HPV status. Grade 3 or 4 adverse events were reported in 18% of the patients including one pneumonitis. Based on these results, Phase III study is ongoing.
In a Phase II trial of patients with Stage III or IV locally advanced, HPV-negative SCCHN single dose of 200 mg pembrolizumab before tumor resection was given. Pathological treatment response was achieved in 42% of patients. Those patients with extracapsular extension or positive margins on pathologic examination were treated with chemoradiation with cisplatin followed by pembrolizumab. None of the 14 patients with a survival follow-up of at least 12-month experienced locoregional recurrence or disease-specific death. Future studies are evaluating the role of neoadjuvant immunotherapy in head-and-neck cancers.
Durvalumab is a fully human monoclonal antibody against PD-L1, which blocks PD-L1 binding to its receptors (PD-1 and CD80), resulting in enhanced T-cell responses. Durvalumab had demonstrated promising antitumor activity with an acceptable safety profile in PD-L1 high patients with R/M HNSCC. The single-arm, Phase 2 HAWK study evaluated durvalumab as monotherapy in PD-L1 high patients with R/M HNSCC who have failed platinum-based chemotherapy. Patients with confirmed PD-L1 expression (>25%), who had progression or recurrence during/after 1 platinum-based regimen for R/M HNSCC received durvalumab 10 mg/kg IV every 2 weeks up to 12 months or until progression or unacceptable toxicity. Among evaluable patients (n = 111), ORR was 13.5% and 31.5% had stable disease. The incidence of Grade 3 treatment-related adverse events was 9.8% and no treatment-related AEs led to death.
Atezolizumab is a fully humanized monoclonal antibody IgG1 isotype, which inhibits binding of PD-L1 to its ligands. The safety and clinical activity of atezolizumab in advanced HNSCC was demonstrated in a Phase I study. Patients with HNC received atezolizumab IV q3w (15 or 20 mg/kg or 1200 mg). Twenty-one out of 32 patients (66%) had a treatment-related AE. Three patients (9%) had Grade 3 treatment-related AEs (tumor lysis syndrome, hyponatremia, pruritus, and colitis). One patient (3%) had Grade 4 treatment-related cardiac tamponade. Out of 32 patients, confirmed ORR was 22% and median PFS and OS were 2.6 months and 6.0 months, respectively.
A large number of trials are underway which are evaluating the role of immunotherapy in managing R/M HNSCC [Table 2]. Anti-CTLA-4 antibodies, ipilimumab and tremelimumab, are beginning to be evaluated in HNSCC. Phase II randomized study CheckMate 714 is comparing ipilimumab + nivolumab to nivolumab alone in first-line recurrent/metastatic HNSCC. A randomized Phase III trial (CheckMate 651) is comparing ipilimumab + nivolumab to standard of care (EXTREME regimen) in R/M HNSCC patients with overall and PFS as the primary end points. Phase III trial (NCT; KESTREL) is comparing the activity of durvalumab or durvalumab + tremelimumab to the standard of care as first-line therapy for recurrent/metastatic HNSCC. Another Phase III trial (NCT02369874; EAGLE) is designed to investigate the durvalumab, durvalumab + tremelimumab, and standard of care to PD-L1 positive and PD-L1 negative, platinum-refractory R/M HNSCC. The primary end points of these two Phase III studies are PFS and OS in the durvalumab + tremelimumab versus standard of care treatment arms. In KEYNOTE-048, which is another Phase III randomized study, pembrolizumab alone or pembrolizumab + platinum/5-FU is being compared to the standard of care regimen of cetuximab + platinum/5-FU for first-line treatment of R/M HNSCC. The primary end points are PFS and OS.
Pseudoprogression and hyperprogression
Pseudoprogression is a distinct phenomenon which is seen in about 10% of patients treated with immunotherapy. It usually occurs soon after starting treatment. It resembles true neoplastic growth, but actually it is due to transient infiltration of immune cells. This phenomenon is rare in SCCHN. The possibility of its occurrence should be weighed against the risk of complications of continued immunotherapy beyond tumor progression and of missed opportunities for switching treatments. Both clinical and radiological aspects must be taken into account, when assessing response to treatment. This holds especially important, where deterioration of general status accompanying ambiguous radiological findings indicates disease progression. In patients who have clinical benefit, with imaging studies revealing tumor size increment should not always undergo a change in management. To correctly interpret such atypical radiographic response patterns, immune-related response criteria (irRC) have been introduced based on data obtained from Phase II trials evaluating ipilimumab in advanced melanoma. irRC requires the confirmation of response by repeat assessment at least 4 weeks after the first suspicious finding, and identification of new lesions does not exclude an objective response. Another important and potentially severe phenomenon is “hyperprogression” or “hyperprogressive disease” which occurs in a unique subset of patients whose disease paradoxically accelerate and “flare-up” on immunotherapy. In a retrospective analysis of HNSCC patients treated with anti-PD1/ PDL1 agents in four French cancer centers, hyperprogression was observed in 29% of patients and was associated with a significant increase in local recurrence and a shorter PFS according to RECIST (P = 0.003) and irRECIST (P = 0.02). The possible mechanisms include major immune reaction which may promote tumor progression, mutations, or polymorphisms in genes that encode immune modifiers, induction of DNA damage by the generation of free radicals or other mechanisms such as angiogenesis and tissue remodeling promotion by the production of growth factors and matrix metalloproteinases induced by inflammation and also by promoting regulatory T-cells that suppress antitumor T-cell response.
| Cytokine Therapy|| |
As described previously, there is an imbalance in the cytokine profile in the tumor microenvironment tumor favoring immune suppressive cytokines over immune-stimulating cytokines to promote immune escape of HNSCC tumor cells. IL-2 therapy has been extensively studied in HNSCC. In unresectable HNSCC patients, peritumoral delivery of IL-2 has shown to increase peripheral NK cells and increased T-cell cytotoxicity within the tumor. A randomized Phase III trial was conducted to evaluate the clinical benefit of adding perilymphatic IL-2 to surgery and radiation in resectable advanced HNSCC. Injection of IL-2 at the cervical lymph nodes was well tolerated and multivariate analysis showed that the addition of IL-2 therapy significantly increased disease-free survival and OS. Subsequent studies also showed that local delivery, peritumoral or perilymphatic, of IL-2 has activity to heighten the immune response.
IRX-2 is composed of IL-2, IL-6, IL-8, IL-1 β, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), interferon γ (IFNγ), and TNFα, purified from peripheral blood mononuclear cells. It has been studied in a Phase II clinical trial, in combination with immune adjuvants cyclophosphamide and indomethacin in untreated, resectable, locally advanced HNSCC patients. About 16% of patients had tumor responses and 74% of patients had decreased/stable tumor size before definitive surgery. This study showed that IRX-2 treatment resulted in a substantial increase in lymphocyte infiltration (LI) at the tumor and regional lymphatic sites. Increased LI was associated with changes in fibrosis and necrosis in resected tumors, 65% event-free survival (EFS) at 2 years, and 65% OS at 5 years, better than rates for historical matched controls. IRX-2 (citoplurikin) is being tested in a randomized phase II trial of neoadjuvant and adjuvant therapy in patients with newly diagnosed curative resectable oral cavity cancer (NCT02609386. INSPIRE).
| Cancer Vaccines|| |
Cancer vaccines activate the adaptive immune system through the presentation of TAs by APCs. Vaccines targeting TSA are preferred as autoimmune reaction to normal cells can be avoided. A cadre of cancer vaccine strategies has been tried including protein or peptide vaccines, DNA-based vaccines, recombinant vector-based vaccines containing TA-encoding DNA in viral or bacterial vector, delivery of whole killed tumor cells, or delivery of protein or peptide-activated dendritic cells. Several cancer vaccine trials have been investigated in HNSCC patients. A Phase Ib trial using DCs combined with wild-type p53 peptide was conducted in HNSCC. The treatment was well-tolerated, and p53-specific T-cell frequencies were increased in about 69% (11/16) of the patients and 2-year disease-free survival was 88%. A pilot study using Trojan peptide vaccine against MAGE-A3 or HPV16 peptide showed acceptable toxicity and stimulated systemic T-cell responses in 80% (4/5) of the patients. A peptide vaccine against LY6K, CDCA1, and IMP3 was studied in a Phase II trial for locally advanced HNSCC and showed a median OS was 4.9 months for the vaccinated arm as compared to 3.5 months for the unvaccinated group. A current Phase I trial is examining modified vaccinia virus Ankara vaccine expressing p53 in combination with pembrolizumab (NCT02432963) in the R/M setting. Talimogene laherparepvec is an oncolytic herpes simplex virus 1 vaccine encoding GM-CSF that has shown some promise in HNSCC. In a Phase I/II study, combination of this vaccine with standard cisplatin/radiation for the first-line treatment of advanced Stage III/IV HNSCC showed an OS of 70.5% at a median follow-up of 29 months. It is currently in a Phase I/IIIb trial in combination with pembrolizumab in R/M HNSCC patients (NCT02626000) in the MASTERKEY232/KEYNOTE-137 trial. INO-3112 is a DNA vaccine which combines two previously developed DNA vaccines (plasmids encoding HPV16 and HPV18 E6/E7) that results in an HPV-specific CD8+ T cell response. The Hespecta vaccine family (the acronym is derived from HPV E Six Peptide Conjugated to Amplivant) includes ISA101 and ISA201, which are peptide vaccines derived from HPV16 E6 and E7 proteins. A Phase II trial (NCT02426892) is evaluating ISA101 as monotherapy and in combination with nivolumab for HPV16+ tumors. ISA201 is a second-generation vaccine in which 2 HPV16 E6 peptides are conjugated to a TLR2 agonist. A Phase I trial (NCT02821494) of ISA201 is ongoing for HPV+ tumors that were definitively treated. These preliminary studies are encouraging, but it still remains unclear, without additional clinical trial data, how cancer vaccines will be incorporated in the management of HNSCC patients.
| Biomarkers or Immunotherapy|| |
High expression of PD-L1 is an independent prognostic factor of patient's outcome, even when verified together with recognized prognostic factors such as tumor size, lymph node involvement, distant metastases, surgical margin status, lymphatic invasion, vascular invasion, grading, and extracapsular expansion. Strong PD-L1 expression has been associated with the occurrence of distant metastases in some studies. However, no definitive conclusions can be drawn on the role of PD-L1 in identifying patients responding to immunotherapy, given that similar studies lead to contrasting results as published studies report different definitions of PD-L1 positivity and different data on relation with clinical outcome. In the randomized Checkmate 141 trial, PD-L1 expression was assessed on tumor cells of 72% of the patients. The magnitude of survival benefit was greater in PD-L1 ≤1% population, HR for death 0.55 (0.36–0.86) versus 0.89 (0.54–1.85), whereas no advantage was demonstrated for increasing PD-L1 expression. The expanded cohort of the Keynote-012 trial used two different methods to define PD-L1 positivity: the CPS which is defined as ≤1% of expression in both tumor and mononuclear inflammatory cells and the tumor proportion score which is defined as ≤1% of expression only in tumor cells. A relation between PD-L1 positivity and response rate only with the CPS (22 vs. 4%; P = 0.021) was identified. Similarly, statistically significant difference for PFS and OS were observed for PD-L1 positive patients using CPS. However, in the Keynote-055 study, using the same CPS score, PD-L1 positivity was not predictive of response, the response rate being 12% even in PD-L1-negative patients compared with 18% in positive patients. The response rates were higher in patients with ≤50% of PD-L1 expression (27 vs. 13%). PFS and survival were similar for PD-L1-positive or negative patients. This study demonstrated that patients with negative PD-L1 could also benefit from treatment with PD-1 inhibitor. A prospective profile of the tumor immune microenvironment in 34 immunotherapy-naive R/M HNSCC patients, described a cohort of inflamed tumors characterized by a robust CD8+ T-cell infiltrate with high checkpoint co-expression (PD-1/ TIM3), that exhibited longer survival compared with noninflamed group (9.5 vs. 2 months), independent of HPV and smoking status. The noninflamed group had a lower immune checkpoint co-expressing CD8+ T-cell infiltrate and higher Treg abundance. These findings could indicate that the inflamed tumor patients are the best candidates for PD-1 blockade.
An 18-gene T-cell inflamed gene expression profile in the tumor microenvironment which was analyzed in a recent study has shown to predict response to pembrolizumab across multiple solid tumors, independently of PD-L1 expression. The three main biomarkers capable of predicting response are PD-L1 expression and/or amplification, high-tumor mutational burden, and mismatch repair gene defects. A National Cancer Institute working group recommended five groups of correlative biomarkers for cancer immunotherapy: tumor-related (e.g., IFNγ gene signature, PD-1/PD-L1, and CTLA-4 expression), peripheral blood mononuclear cell-related (e.g., circulating MDSCs and regulatory T-lymphocytes, virus peptide pools in HPV positive and shared tumor antigen peptide pools in HPV-negative cases), serum-related (e.g., cytokines, growth factors, antibodies), imaging-related (positron emission tomography/computed tomography), and biomarkers from stool samples and oral swabs for future microbiome studies. However, at present, none of these biomarkers have been prospectively validated, so their use is limited to clinical research.
| Conclusion|| |
The immune system is a vital component in HNSCC development and progression. Extensive research on the complex interaction between tumor cells and host immune cells has revealed targets for molecularly-targeted immunotherapeutic drug development, in particular immune checkpoint inhibitors. Recent data have shown that immune checkpoint inhibitors are highly active and superior to the standard of care in the recurrent/metastatic HNSCC setting and various studies are ongoing to evaluate immunotherapies, as single agents or in combinational regimens, for treatment naive and recurrent/metastatic HNSCC. One of the main problems with immunotherapy is the lack of robust predictive markers of efficacy, especially when the costs of these treatments are considered. Role of immunotherapy in brain metastasis is also not defined. Data from the upcoming trials will pave the way for newer treatment regimens and the results should be meticulously applied to determine how, when, and which immunotherapies should be considered as treatment options for HNSCC patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, et al.
Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: A systematic analysis for the global burden of disease study. JAMA Oncol 2017;3:524-48.
Sankaranarayanan R, Masuyer E, Swaminathan R, Ferlay J, Whelan S. Head and neck cancer: A global perspective on epidemiology and prognosis. Anticancer Res 1998;18:4779-86.
Sankaranarayanan R, Ramadas K, Thomas G, Muwonge R, Thara S, Mathew B, et al.
Effect of screening on oral cancer mortality in Kerala, India: A cluster-randomised controlled trial. Lancet 2005;365:1927-33.
He J, Hu Y, Hu M, Li B. Development of PD-1/PD-L1 pathway in tumor immune microenvironment and treatment for non-small cell lung cancer. Sci Rep 2015;5:13110.
Alsaab HO, Sau S, Alzhrani R, Tatiparti K, Bhise K, Kashaw SK, et al.
PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: Mechanism, combinations, and clinical outcome. Front Pharmacol 2017;8:561.
Fuereder T. Immunotherapy for head and neck squamous cell carcinoma. Memo 2016;9:66-9.
Xie X, O'Neill W, Pan Q. Immunotherapy for head and neck cancer: The future of treatment? Expert Opin Biol Ther 2017;17:701-8.
Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 2011;144:646-74.
Pitt JM, Vétizou M, Daillère R, Roberti MP, Yamazaki T, Routy B, et al.
Resistance mechanisms to immune-checkpoint blockade in cancer: Tumor-intrinsic and -extrinsic factors. Immunity 2016;44:1255-69.
Nagaraj S, Schrum AG, Cho HI, Celis E, Gabrilovich DI. Mechanism of T cell tolerance induced by myeloid-derived suppressor cells. J Immunol 2010;184:3106-16.
Vasquez-Dunddel D, Pan F, Zeng Q, Gorbounov M, Albesiano E, Fu J, et al.
STAT3 regulates arginase-I in myeloid-derived suppressor cells from cancer patients. J Clin Invest 2013;123:1580-9.
Califano JA, Khan Z, Noonan KA, Rudraraju L, Zhang Z, Wang H, et al.
Tadalafil augments tumor specific immunity in patients with head and neck squamous cell carcinoma. Clin Cancer Res 2015;21:30-8.
Young MR, Wright MA, Lozano Y, Prechel MM, Benefield J, Leonetti JP, et al.
Increased recurrence and metastasis in patients whose primary head and neck squamous cell carcinomas secreted granulocyte-macrophage colony-stimulating factor and contained CD34+ natural suppressor cells. Int J Cancer 1997;74:69-74.
De Palma M, Lewis CE. Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell 2013;23:277-86.
Balermpas P, Rödel F, Liberz R, Oppermann J, Wagenblast J, Ghanaati S, et al.
Head and neck cancer relapse after chemoradiotherapy correlates with CD163+ macrophages in primary tumour and CD11b+ myeloid cells in recurrences. Br J Cancer 2014;111:1509-18.
Fujii N, Shomori K, Shiomi T, Nakabayashi M, Takeda C, Ryoke K, et al.
Cancer-associated fibroblasts and CD163-positive macrophages in oral squamous cell carcinoma: Their clinicopathological and prognostic significance. J Oral Pathol Med 2012;41:444-51.
Westrich JA, Warren CJ, Pyeon D. Evasion of host immune defenses by human papillomavirus. Virus Res 2017;231:21-33.
Bansal A, Singh MP, Rai B. Human papillomavirus-associated cancers: A growing global problem. Int J Appl Basic Med Res 2016;6:84-9.
Woodby B, Scott M, Bodily J. The interaction between human papillomaviruses and the stromal microenvironment. Prog Mol Biol Transl Sci 2016;144:169-238.
Smola S, Trimble C, Stern PL. Human papillomavirus-driven immune deviation: Challenge and novel opportunity for immunotherapy. Ther Adv Vaccines 2017;5:69-82.
Ono T, Azuma K, Kawahara A, Sasada T, Hattori S, Sato F, et al.
Association between PD-L1 expression combined with tumor-infiltrating lymphocytes and the prognosis of patients with advanced hypopharyngeal squamous cell carcinoma. Oncotarget 2017;8:92699-714.
Mroz EA, Tward AD, Hammon RJ, Ren Y, Rocco JW. Intra-tumor genetic heterogeneity and mortality in head and neck cancer: Analysis of data from the cancer genome atlas. PLoS Med 2015;12:e1001786.
Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: From immunosurveillance to tumor escape. Nat Immunol 2002;3:991-8.
Khong HT, Restifo NP. Natural selection of tumor variants in the generation of “tumor escape” phenotypes. Nat Immunol 2002;3:999-1005.
Ferris RL, Whiteside TL, Ferrone S. Immune escape associated with functional defects in antigen-processing machinery in head and neck cancer. Clin Cancer Res 2006;12:3890-5.
Ogino T, Shigyo H, Ishii H, Katayama A, Miyokawa N, Harabuchi Y, et al.
HLA class I antigen down-regulation in primary laryngeal squamous cell carcinoma lesions as a poor prognostic marker. Cancer Res 2006;66:9281-9.
López-Albaitero A, Nayak JV, Ogino T, Machandia A, Gooding W, DeLeo AB, et al.
Role of antigen-processing machinery in the in vitro
resistance of squamous cell carcinoma of the head and neck cells to recognition by CTL. J Immunol 2006;176:3402-9.
Woo SR, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ, et al.
Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res 2012;72:917-27.
Johnston RJ, Comps-Agrar L, Hackney J, Yu X, Huseni M, Yang Y, et al.
The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell 2014;26:923-37.
Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C, et al.
Upregulation of tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med 2010;207:2175-86.
Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, et al.
Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010;11:21-8.
Bauman JE, William E. Gooding WE, Clump DA, Kim S, Brian J, Karlovits BJ, et al
. Phase I trial of cetuximab, intensity modulated radiotherapy (IMRT), and ipilimumab in previously untreated, locally advanced head and neck squamous cell carcinoma (PULA HNSCC). Ann Oncol 2017;28:5.
Marín A, Martín M, Liñán O, Alvarenga F, López M, Fernández L, et al.
Bystander effects and radiotherapy. Rep Pract Oncol Radiother 2015;20:12-21.
Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, et al.
Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 2014;124:687-95.
Powell SF, Gitau MM, Sumey CJ, Reynolds JT, Lohr M, McGraw S. Safety of pembrolizumab with chemoradiation (CRT) in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN); 2017.
Ferris RL, Blumenschein G Jr., Fayette J, Guigay J, Colevas AD, Licitra L, et al.
Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016;375:1856-67.
Harrington KJ, Ferris RL, Blumenschein G Jr., Colevas AD, Fayette J, Licitra L, et al.
Nivolumab versus standard, single-agent therapy of investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): Health-related quality-of-life results from a randomised, phase 3 trial. Lancet Oncol 2017;18:1104-15.
Haddad R, Blumenschein G Jr., Fayette J, Guigay J, Colevas AD, Licitra L, et al
. Treatment beyond progression with nivolumab in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the headand neck (SCCHN) in the phase 3 checkmate 141 study: A biomarker analysis and updated clinical outcomes. ESMO; 2017.
Seiwert TY, Burtness B, Mehra R, Weiss J, Berger R, Eder JP, et al.
Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): An open-label, multicentre, phase 1b trial. Lancet Oncol 2016;17:956-65.
Chow LQ, Haddad R, Gupta S, Mahipal A, Mehra R, Tahara M, et al.
Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: Results from the phase Ib KEYNOTE-012 expansion cohort. J Clin Oncol 2016;34:3838-45.
Bauml J, Seiwert TY, Pfister DG, Worden F, Liu SV, Gilbert J, et al.
Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: Results from a single-arm, phase II study. J Clin Oncol 2017;35:1542-9.
Cohen EE, Harrington KJ, Le Tourneau C, Dinis J, Licitra L, Ahn.M-J, et al
. Pembrolizumab (pembro) vs. standard of care (SOC) for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC): Phase 3 KEYNOTE-040 trial. ESMO; 2017.
Hamid O, Bauer TM, Spira AI, Olszanski AJ, Patel SP, Wasser JS, et al
. Epacadostat Plus Pembrolizumab in Patients with SCCHN: Preliminary Phase 1/2 Results from ECHO-202/Keynote-037, ASCO; 2017.
Uppaluri R, Zolkind P, Lin T, Nussenbaum B, Jackson R, Rich J, et al
. Neoadjuvant Pembrolizumab in Surgically Resectable, HPV Negative, Locally Advanced Head and Neck Squamous Cell Carcinoma (HNSCC), ASCO; 2017.
Zandberg D, Algazi A, Jimeno A, Good JS, Fayette J, Bouganim N, et al
. Durvalumab for Recurrent/Metastatic (R/M) Head and Neck Squamous Cell Carcinoma (HNSCC): Preliminary Results from a Single-Arm, Phase 2 Study. ESMO; 2017.
Bahleda R, Braiteh FS, Balmanoukian AS, Brana I, Hodi FS, Garbo L, et al
. Long-Term Safety and Clinical Outcomes of Atezolizumab in Head and Neck Cancer: Phase Ia Trial Results. ESMO; 2017.
Chiou VL, Burotto M. Pseudoprogression and immune-related response in solid tumors. J Clin Oncol 2015;33:3541-3.
Baxi SS, Dunn LA, Burtness BA. Amidst the excitement: A cautionary tale of immunotherapy, pseudoprogression and head and neck squamous cell carcinoma. Oral Oncol 2016;62:147-8.
Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al.
IRECIST: Guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 2017;18:e143-52.
Saâda-Bouzid E, Defaucheux C, Karabajakian A, Coloma VP, Servois V, Paoletti X, et al.
Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Ann Oncol 2017;28:1605-11.
Hoesli RC, Moyer JS. Immunotherapy for head and neck squamous cell carcinoma. Curr Oral Health Rep 2016;3:74-81.
De Stefani A, Forni G, Ragona R, Cavallo G, Bussi M, Usai A, et al.
Improved survival with perilymphatic interleukin 2 in patients with resectable squamous cell carcinoma of the oral cavity and oropharynx. Cancer 2002;95:90-7.
Czystowska M, Han J, Szczepanski MJ, Szajnik M, Quadrini K, Brandwein H, et al.
IRX-2, a novel immunotherapeutic, protects human T cells from tumor-induced cell death. Cell Death Differ 2009;16:708-18.
Wolf GT, Fee WE Jr., Dolan RW, Moyer JS, Kaplan MJ, Spring PM, et al.
Novel neoadjuvant immunotherapy regimen safety and survival in head and neck squamous cell cancer. Head Neck 2011;33:1666-74.
Schuler PJ, Harasymczuk M, Visus C, Deleo A, Trivedi S, Lei Y, et al.
Phase I dendritic cell p53 peptide vaccine for head and neck cancer. Clin Cancer Res 2014;20:2433-44.
Voskens CJ, Sewell D, Hertzano R, DeSanto J, Rollins S, Lee M, et al.
Induction of MAGE-A3 and HPV-16 immunity by TROJAN vaccines in patients with head and neck carcinoma. Head Neck 2012;34:1734-46.
Yoshitake Y, Fukuma D, Yuno A, Hirayama M, Nakayama H, Tanaka T, et al.
Phase II clinical trial of multiple peptide vaccination for advanced head and neck cancer patients revealed induction of immune responses and improved OS. Clin Cancer Res 2015;21:312-21.
Coffin R. Interview with Robert coffin, inventor of T-VEC: The first oncolytic immunotherapy approved for the treatment of cancer. Immunotherapy 2016;8:103-6.
Harrington KJ, Hingorani M, Tanay MA, Hickey J, Bhide SA, Clarke PM, et al.
Phase I/II study of oncolytic HSV GM-CSF in combination with radiotherapy and cisplatin in untreated stage III/IV squamous cell cancer of the head and neck. Clin Cancer Res 2010;16:4005-15.
Aggarwal C, Cohen RB, Morrow MP, Kraynyak K, Bauml J, Gregory S, et al
. Immunogenicity Results Using Human Papillomavirus (HPV) Specifi c DNA Vaccine, INO-3112 (HPV16/HPV18 plasmids+IL-12) in HPV+ Head and Neck Squamous Cell Carcinoma. ASCO; 2017.
Hanna GJ, Liu H, Jones RE, Bacay AF, Lizotte PH, Ivanova EV, et al.
Defining an inflamed tumor immunophenotype in recurrent, metastatic squamous cell carcinoma of the head and neck. Oral Oncol 2017;67:61-9.
Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, et al.
IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest 2017;127:2930-40.
Bauman JE, Cohen E, Ferris RL, Adelstein DJ, Brizel DM, Ridge JA, et al.
Immunotherapy of head and neck cancer: Emerging clinical trials from a national cancer institute head and neck cancer steering committee planning meeting. Cancer 2017;123:1259-71.
[Table 1], [Table 2]