Head and neck squamous cell carcinoma (
HNSCC) is an immunosuppressive
malignancy characterized by
tumor-driven immune-system abnormalities that contribute to
disease progression. For patients with surgically resectable
HNSCC, treatment is often curative surgery followed by irradiation or chemoradiation in high-risk settings to reduce the risk of recurrence. Poor survival and considerable morbidity of current treatments suggest the need for new therapeutic modalities that can improve outcomes. Defects in antitumor immunity of
HNSCC patients include suppressed dendritic cell (DC) maturation, deficient antigen-presenting cell function, compromised natural killer (NK)-cell cytotoxicity, increased apoptosis of activated T lymphocytes, and impaired immune-cell migration to
tumor sites. Strategies for relieving immunosuppression and restoring antitumor immune functions could benefit
HNSCC patients.
IRX-2 is a primary cell-derived
biologic consisting of physiologic levels of T-helper type 1
cytokines produced by stimulating peripheral blood mononuclear cells of normal donors with
phytohemagglutinin. The primary active components in
IRX-2 are
IL2, IL1β, IFNγ, and TNFα. In vitro,
IRX-2 acts on multiple immune-system cell types, including DCs, T cells, and NK cells, to overcome
tumor-mediated immunosuppression. In clinical settings,
IRX-2 is administered as part of a 21-day neoadjuvant regimen, which includes additional pharmacologic agents (low-dose
cyclophosphamide,
indomethacin, and
zinc) to promote anticancer immunoresponses. In a Phase IIA trial in 27 patients with surgically resectable, previously untreated
HNSCC, neoadjuvant
IRX-2 increased infiltration of T cells, B cells, and DCs into
tumors and was associated with radiological reductions in
tumor size. Event-free survival was 64% at 2 years, and overall 5-year survival was 65%. Follow-up and data analysis are under way in the multicenter, randomized, Phase IIB INSPIRE trial evaluating the
IRX-2 regimen as a stand-alone
therapy for activating the immune system to recognize and attack
tumors.