title: Possible improved survival of patients with stage IV AJCC melanoma receiving SRL 172 immunotherapy: correlation with induction of increased levels of intracellular interleukin-2 in peripheral blood lymphocytes.
abstract: OBJECTIVE
  This phase I-II study was designed to assess safety and clinical efficacy of SRL 172 vaccine in patients with advanced stage IV (AJCC) malignant melanoma. Induction of intracellular cytokines (IL-2 and INF-gamma) in peripheral blood lymphocytes (PBLCs) from these patients was assayed and correlated to clinical outcome.
  
  
  METHODS
  SRL 172 was administered intradermally to 24 patients with stage IV malignant melanoma, initially at 15-day intervals for three vaccinations and then at monthly intervals. Lymphocyte activation for cytokines in PBLCs was assayed prior to each vaccine administration using a FACS-based intracellular cytokine assay. Survival was compared to historical controls.
  
  
  RESULTS
  The vaccination schedule resulted in sustained intracellular IL-2 induction in PBLCs in 9 of 23 patients (39%) who received at least three doses. Cytokine induction became apparent within the first three administrations of vaccine and was maximal at 8-12 weeks. Induction of intracellular IL-2 production (group 1) was associated with improved survival (P < 0.036). The median survival of the nine patients demonstrating IL-2 induction was 59 (95% confidence interval (95% CI): 47-71) weeks compared to 31 (95% CI: 18-44) weeks for the non-inducers. Induction of INF-gamma (group 2) was found in 10 patients and 6 patients had IL-2 and INF-gamma induction (group 3). There was no survival advantage for these patient groups. Although no objective responses were documented the group as a whole had a median survival of 44 (95% CI: 31-59) weeks which is better than that of historical controls. SRL 172 was safe and well tolerated.
  
  
  CONCLUSIONS
  SRL 172 is effective in inducing intracellular IL-2 responses in PBLCs of a significant number of patients with stage IV (AJCC) melanoma. This is correlated with improved survival. The survival analysis is sufficiently encouraging to suggest that further prospective trials are justified. The methodology we present in this study may help in developing surrogate markers that will allow rational immunotherapeutic strategies to be designed for cancer patients.
authors.affiliation: Division of Medical Oncology, St. George's Medical School, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Maraveyas
authors.forename: B
authors.initials: B
authors.lastname: Baban
authors.forename: D
authors.initials: D
authors.lastname: Kennard
authors.forename: G A
authors.initials: GA
authors.lastname: Rook
authors.forename: M
authors.initials: M
authors.lastname: Westby
authors.forename: J M
authors.initials: JM
authors.lastname: Grange
authors.forename: P
authors.initials: P
authors.lastname: Lydyard
authors.forename: J L
authors.initials: JL
authors.lastname: Stanford
authors.forename: M
authors.initials: M
authors.lastname: Jones
authors.forename: P
authors.initials: P
authors.lastname: Selby
authors.forename: A G
authors.initials: AG
authors.lastname: Dalgleish
mesh_terms: D019496:Cancer Vaccines / Q000009:adverse effects; D005260:Female; D006801:Humans; D016233:Immunotherapy, Active / Q000009:adverse effects; D007371:Interferon-gamma / Q000096:biosynthesis / Q000097:blood; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000097:blood*; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008545:Melanoma / Q000097:blood / Q000401:mortality* / Q000473:pathology / Q000628:therapy*; D009161:Mycobacterium / Q000276:immunology; D009367:Neoplasm Staging; D011379:Prognosis; D016019:Survival Analysis; D016896:Treatment Outcome; D015164:Vaccines, Inactivated / Q000009:adverse effects
chemical_list: D019496:Cancer Vaccines; D007376:Interleukin-2; D015164:Vaccines, Inactivated; D007371:Interferon-gamma