Head and Neck

Head and Neck Pathophysiology

Most patients with HNSCC present with advanced stage disease (Stage III to IVB).2,3 Furthermore, a significant proportion of patients will develop disease recurrence with up to 60% risk of local failure and up to 30% risk of distant failure despite aggressive, site-specific multimodality therapy.3,4 At this stage, morbidity and mortality are high resulting from patients from recurrent and/or metastatic disease that no longer responds to curative therapy.

Palliative systemic therapy typically consists of doublet, platinum-based chemotherapy, with an understanding that the increase in efficacy compared with single agents is primarily related to improved response rate, not survival. Until recently, the most active regimens consisted of platinum combined with fluorouracil or a taxane; these regimens generally resulted in a 30% response rate, median progression-free survival (PFS) of 3 to 4 months, and median overall survival (OS) of 6 to 8 months.5,6 At present, EGFR-targeted therapy added to cytotoxic chemotherapy results in a median survival time of 10 months,7 underscoring the lack of durable efficacy among the most active regimens for patients with recurrent and/or metastatic SCCHN.

With increasing data suggesting favorable prognostic implications of human papillomavirus (HPV) in the recurrent and/or metastatic setting, survival rates may differ for patients based on HPV status.8,9 Although HPV status is being increasingly used as a stratification factor for therapeutic clinical trials in recurrent and/or metastatic SCCHN, it does not currently impact standard practice patterns for recurrent and/or metastatic disease. For the overwhelming majority of patients with recurrent and/or metastatic SCCHN, survival outcomes remain poor, illustrating the urgent need to develop novel therapeutic options that prolong survival while optimizing quality of life.

The Role of the Immune System

The complex relationship between the immune system and cancer can be described by the hypothesis of cancer immunoediting, which encompasses the dynamics of tumor development over time.10 Cancer immunoediting is comprised of three phases—(1) elimination, (2) equilibrium, and (3) escape. Both innate and adaptive immunity belong to the elimination phase, also referred to as immunosurveillance. If the immune system is unable to completely eradicate the tumor cells, the microenvironment enters the next phase, equilibrium. This may be a prolonged period of time during which tumor cells are maintained in a state of functional dormancy by the immune system. However, a byproduct of this selective pressure is the emergence and promotion of tumor cell variants with decreased immunogenicity, thereby increasing resistance to immunologic attack. Following this phase, tumor cell variants with low immunogenicity can enter the escape phase, during which the immunologically sculpted tumor successfully evades the immune system and grows sufficiently to be clinically detected.10 Overall, this immune dysregulation effects; cytokine levels, the expression of inhibitory receptors, and the number and function of immune cells.

Recent evidence suggests that tumors coopt physiologic mechanisms of tissue protection from inflammatory destruction via upregulation of immune inhibitory ligands; this has provided a new perspective for understanding tumor immune resistance. Antigen-induced activation and proliferation of T cells are regulated by the temporal expression of both costimulatory and coinhibitory receptors and their ligands. Coordinated signaling through these receptors modulates the initiation, amplification, and subsequent resolution of adaptive immune responses. In the absence of coinhibitory signaling, persistent T-cell activation can lead to excessive tissue damage in the setting of infection as well as autoimmunity. In the context of cancer, in which immune responses are directed against antigens specifically or selectively expressed by tumor cells, these immune checkpoints can represent major obstacles to the generation and maintenance of clinically meaningful antitumor immunity.11

Perhaps the most basic evidence of a relationship between SCCHN and the immune system is that immunodeficiency increases SCCHN risk.12 For example, premalignant leukoplakia develops in 13% of renal transplant patients as compared to 0.6% of age- and sex-matched individuals, and about 10% will become SCCHN.13,14 Increased incidence of SCCHN has been observed in bone marrow transplant patients15,16,17 HIV-positive patients.18 While SCCHN is not an AIDS-defining illness, HIV-positive patients develop SCCHN earlier in life with more advanced disease and a poorer prognosis.19 As significant as immunodeficiency may be in SCCHN risk elevation, most patients have normal immune systems when the cancer develops. In the immunocompetent patient, the process to blame is immunoediting.20

Immune Checkpoint Inhibition in HNSCC

The immunotherapeutic landscape for SCCHN encompasses a variety of targets that suppress or stimulate the immune system’s ability to eliminate neoplastic cells.21 Activation of checkpoint receptors, such as programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein (CTLA-4), causes T cell suppression. By contrast, activation of costimulatory receptors, such as CD40, glucocorticoid-induced tumor necrosis factor receptor, and toll-like receptors causes immune system stimulation. In addition to receptor signaling, certain enzymes, such as indoleamine 2,3-dioxygenase, and arginase 1, modify the tumor microenvironment by depleting nutrients essential for T cell proliferation while other enzymes, such as inducible nitric oxide synthase, produce toxins that inhibit T cell proliferation. A functioning immune system with the capacity to eliminate neoplastic cells is dependent on T cell recognition of antigens along with costimulatory and inhibitory signals. Costimulatory signals contribute to the defense against pathogens while inhibitory signals prevent autoimmunity. Cancer cells have been shown to express ligands that lead to inhibitory signaling in order to evade elimination by T cells.22 These ligands bind to receptors, often called checkpoint receptor proteins, on the surface of T cells, resulting in T cell suppression.

One such inhibitory receptor is PD-1, which is expressed on activated T cells.21 PD-1 expression and engagement has been shown to inhibit immune-modulated tissue damage as well as lead to suppression of T cell proliferation during chronic infections.23 The expression of checkpoint ligands such as PD-L1 and PD-L2 by tumors leads to evasion of the antitumor immune response.21 Efforts to prevent this mechanism of immune evasion have led to the development and approval of the two newest therapies for SCCHN. Combinations of immune and antineoplastic therapies are being studied to maximize immunostimulatory effects.

Safety and Efficacy of Immune Checkpoint Inhibitors

Overall, the PD-1, CTLA-4 and PD-L1 inhibitors are well tolerated with manageable toxicities.24 Adverse effects from these agents have been termed immune-related adverse events (irAEs).

Adverse events common to all PD-1-axis agents include fatigue, endocrinopathies (particularly thyroid dysfunction), rash, pneumonitis, colitis, and hepatitis.25 Pneumonitis in particular is an important toxicity to note, as it resulted in several deaths in the early-phase trial of PD-1 inhibition. Since the recognition of the potential severity of this toxicity, early recognition and aggressive treatment has appeared to minimize the mortality due to pneumonitis. In general, the toxicities associated with PD-1 and PD-L1 agents are controllable with immunosuppression. Because irAEs likely arise from general immunologic enhancement, temporary immunosuppression with corticosteroids, tumor necrosis factor antagonists, mycophenolate mofetil, or other agents is often necessary and should follow established algorithms.26

Theoretically, patients with underlying autoimmune conditions may have a higher risk of immune-related toxicity; however, this has not been clearly defined because these patients are typically excluded from clinical trials of immunotherapeutics.24

Elevations in serum levels of hepatic enzymes (AST and ALT) can be seen with both CTLA-4 and PD-1 blockade, and in almost all cases, these are asymptomatic laboratory abnormalities only.27 Immune checkpoint blockade may also result in endocrinopathies affecting the pituitary, adrenal, and thyroid glands. Clinical symptoms may vary but often involve nonspecific symptoms such as fatigue, headache, and nausea. Diagnosis is usually made by characteristic laboratory findings and/or radiographic changes, such as enlargement of the pituitary gland.28 Adverse events associated with immune checkpoint inhibition are unique enough that clinicians should have an understanding of their underlying cause and be familiar with the most common irAEs, their presentation, and appropriate management.

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