title: Combination immunotherapy of squamous cell carcinoma of the head and neck: a phase 2 trial.
abstract: OBJECTIVE
  To test the efficacy of a natural cytokine mixture (IRX-2), cyclophosphamide, indomethacin, and zinc to induce immune regression of squamous cell carcinoma (SCC) of the head and neck (H&N) prior to conventional therapy and to characterize the responses.
  
  
  METHODS
  A phase 2 trial was performed in 15 adults with recently diagnosed, biopsy-confirmed H&N SCC (3 with stage II disease, 6 with stage III disease, and 6 with stage IV disease). The patients were treated with 20 days of perilymphatic injections of IRX-2 (administered subcutaneously at the base of the skull) in combination with contrasuppression consisting of a low-dose infusion of cyclophosphamide (300 mg/m2), and daily oral indomethacin and zinc (StressTabs) in a 21-day cycle before surgery and/or radiotherapy. Tumor dimensions, toxic effects, and disease-free survival were monitored. The tumor sections were histologically examined after surgery, and tumor reduction, fragmentation, and lymphoid infiltration were assessed.
  
  
  RESULTS
  All 15 patients responded clinically to the 21-day IRX-2 protocol: 1 with a complete response, 7 with a partial response, and 7 with a minor response. All 15 patients responded pathologically with tumor reduction (mean, 42%) and fragmentation (mean, 50%) in the histological section and increased lymphoid infiltration. The adverse effects of the IRX-2 protocol were negligible except for an allergic skin rash (n = 1) and parotiditis (n = 1). Indomethacin caused gastritis in 1 patient. Reduction of pain and ulceration and bleeding were observed in 8 and 4 patients, respectively. Four of 5 patients with lymphopenia showed increased CD3, CD4, and CD8 cell counts. After surgery (n = 13) and/or radiotherapy (n = 10) and with a mean follow-up of 17 months, 3 patients have had recurrences, 1 patient has died of disease, 1 patient has been re-treated with immunotherapy and has no evidence of disease, and 1 patient is alive with disease. Two patients died of other causes with no evidence of disease.
  
  
  CONCLUSIONS
  The IRX-2 immunotherapy induced lymphocyte mobilization and infiltration in H&N SCC associated with clinical and histological tumor responses indicative of immune regression in all 15 patients. Minimal toxic effects were observed, and overall survival may have been improved. A phase 3 trial seems warranted.
authors.affiliation: Department of Surgery, National Institute of Cancerology, Mexico City, Mexico.
authors.forename: J L
authors.initials: JL
authors.lastname: Barrera
authors.forename: E
authors.initials: E
authors.lastname: Verastegui
authors.forename: A
authors.initials: A
authors.lastname: Meneses
authors.forename: J
authors.initials: J
authors.lastname: Zinser
authors.forename: J
authors.initials: J
authors.lastname: de la Garza
authors.forename: J W
authors.initials: JW
authors.lastname: Hadden
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000009:adverse effects / Q000627:therapeutic use; D016207:Cytokines / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004338:Drug Combinations; D005260:Female; D006258:Head and Neck Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007213:Indomethacin / Q000009:adverse effects / Q000627:therapeutic use; D008207:Lymphatic Metastasis; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D015032:Zinc / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D016207:Cytokines; D004338:Drug Combinations; C114857:IRX 2; D003520:Cyclophosphamide; D015032:Zinc; D007213:Indomethacin