Table 3 Clinical trials using GM-CSF transduced tumor cells as vaccines Authors Tumor type Slingluff et al 2003 . Melanoma Randomized comparison of multipeptide vac- cine either in emulsion with GM-CSF or pulsed on monocytoid DCs Nelson et al 2000 Renal cell carcinoma Simons et al 1999; Simons and Sacks 2006 Prostate cancer Kusumoto et al 2001 Soiffer et al 1998; Soiffer et al 2003 Salgia et al 2003 Jaffee et al 2001 Melanoma Melanoma Non-small cell lung Cancer Pancreatic cancer Clinical uses of GM-CSF Clinical results – Overall immune responses, including T-cell responses were superior in the GM-CSF arm, compared to the DC arm – Helper T-cell responses were detected and correlated with T-cell reactivity to the mela- noma peptides – 2 PR in the GM-CSF arm, 1 in the DC arm. -2 SD in the GM-CSF arm and 1 in the DC arm – mOS:14.8 months for patients in the GM- CSF arm and 6.2 months for the DC arm. – Increase in DTH response against autologous tumor cells – 1 PR – Increase in DTH response – Induction of tumor speciﬁc T-cell and B-cell responses – Increase in DTH response – Increase in melanoma speciﬁc CTLs in most patients – Increase in DTH response – Eosinophilia – TILs highly cytotoxic – 1 CR, 1PR, 1MR, 3 minor responses – Increase in DTH response – T-cell and plasma cell inﬁltration of metastatic sites – 5 SD, 1 mixed response – Increase in DTH response – Increased systemic GM-CSF levels – 2/5 patients receiving highest cell dose 25 months in CR Abbreviations: DTH, delayed type hypersensitivity; PR, partial response; CTLs, cytotoxic T lymphocytes;TILs, tumor inﬁltrating lymphocytes; MR, minor response; SD, stable disease; mOS, median overall survival; CR, complete response. results and continue to be tested in the treatment of solid and hematological malignancies. Results from phase 1 and 2 clinical trials indicate that tumor-peptide loaded DC can induce clinically signiﬁcant immune responses in patients with lymphoma and melanoma (Hsu et al 1996; Hersey et al 2004). Antigen-loaded DC as cancer vaccines have been limited by uncertainty regarding the best DC subtype to use, the optimal maturation status of the DC, the best site of admin- istration (sub-cutaneous, intra-venous, or intra-nodal) and the optimal schedule of administration. More research is needed in order to answer these questions and deﬁne the optimal use of GM-CSF as an adjuvant in cell-mediated vaccines. Future directions Pre-clinical and clinical data support the role of GM-CSF as an immune adjuvant in the treatment of malignant solid and liquid Biologics:Targets & Therapy 2008:2(1) tumors, but the challenge remains to devise combinations of cytotoxic and cytokine therapy which are synergistic in break- ing immune tolerance, enhancing antigen presentation and up-regulating anti-tumor T-cell responses. Local production of GM-CSF by tumors in the setting of tumor-speciﬁc vaccina- tion has shown promise in the induction of anti-tumor immune responses. However, the laboratory correlates of response; such as, the lymphocytic and inﬂammatory inﬁltrates that develop at the site of vaccination and cytokine injection, do not reproducibly correlate with improved clinical outcomes, and well designed translational studies are needed to better deﬁne the anti-tumor activity of GM-CSF and other cytokines. Vac- cines and cytokine therapies are attractive for use in patients who cannot tolerate further cytotoxic chemotherapy, owing to their relatively low toxicity, and in patients whose tumors are in a minimal residual disease state. 23