IRX-2 natural cytokine biologic for immunotherapy in patients with head and neck cancers

Abstract

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.

Chemokine-Cytokine Networks in the Head and Neck Tumor Microenvironment

“…Another strategy for restoring antitumor immune functions in HNSCC is the use of a primary-cell-derived biologic known as IRX-2. IRX-2 is a natural cytokine biologic derived from peripheral blood mononuclear cells (PBMCs) that contain active components such as IL-2, IL-1β, TNF-α, and IFN-γ [ 226 ]. IRX-2 helps overcome tumor-mediated immunosuppression by acting on multiple immune cells such as DCs, NK, and T cells.…”

Extracellular Vesicles as Biomarkers in Cancer Immunotherapy

“…TDE bearing FASL eliminate antigen-specific effector T cells. Other inhibitory, immunosuppressive proteins—such as FASL, TGFβ1, TRAIL, COX2, CD39/CD73, PDL1, CTLA4, and others—are reported to be associated with TDEs [ 78 ].…”

Immunotherapy for cancer of the oral cavity and oropharynx

“…Також виявлено, що загальна кількість Т-лімфоцитів не змінюється, але середнє число циркулюючих у периферичної крові naive Т-клітин (CD3+ CD45RA+ CCR7+) і Т-клітин центральної пам'яті (CD3+ CD45RA-CCR7+ CD27+) зменшилася, а середня кількість ефекторних Т-клітин пам'яті (CD3+ CD45RA+ CCR7-CD27-) збільшилася помірно. Отже, можна вважати, що IRX-2 бере участь у стимулюванні і диференціації naive Т-клітин у Т-клітини пам'яті [24]. Поліпшення 5-річного виживання корелює з високою загальною інфільтрацією лімфоцитів у зразках пухлини [24].…”

“…Отже, можна вважати, що IRX-2 бере участь у стимулюванні і диференціації naive Т-клітин у Т-клітини пам'яті [24]. Поліпшення 5-річного виживання корелює з високою загальною інфільтрацією лімфоцитів у зразках пухлини [24]. Для підтвердження цих даних проводиться велике міжнародне дослідження (фаза ІІВ), результати яких ще не опубліковані.…”