Immunomodulation of responses to active immunization with a polyvalent immunotherapeutic: cyclophosphamide, H2 blockade, IL-2/IFNα and GM-CSF

Abstract

2564 Background: Strong humoral and cellular immune responses in patients with melanoma receiving a specific active immunotherapeutic (Canvaxin; CancerVax Corp, Carlsbad, CA) have been correlated with improved survival. We examined the impact of several immunomodulators on the strength of immune response. Methods: Analysis of sequential phase II clinical trials using Canvaxin alone (n=446) or in combination with cyclophosphamide (n=92), cimetidine (n= 357), indomethacin (n=54) or IL-2/INFα (n=71) was performed with regard to maximal immune response within 16 weeks of treatment. A randomized clinical trial (n= 97) of Canvaxin with or without the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) was also analyzed. Delayed-type hypersensitivity (DTH) to vaccine was measured in all trials. IgM and IgG responses to the TA90 tumor-associated antigen were measured prospectively in the GM-CSF trial. Results: DTH responses were greater in patients with stage IV melanoma with concurrent cyclophosphamide (mean induration 20.6 mm with cyclophosphamide vs. 14.2 without, p=0.011). This was not seen in patients with stage III disease or in any stage with cimetidine, indomethacin or IL-2/IFNα treatment. The randomized GM-CSF trial did not show a significant difference (by logistic regression) in maximal DTH response (15.9± 9.7 mm with GM-CSF vs. 16.7 ± 9.9 mm without). There was a significant increase in maximal anti-TA90 IgM titers in the GM-CSF arm (797 ± 622 vs. 541 ± 533; p=0.0123), but no difference in anti-TA90 IgG (680 ± 557 with GM-CSF vs. 612 ± 510 without GM-CSF.) Maximal absolute lymphocyte counts during treatment were also elevated in the GM-CSF arm. Adverse event profiles were not markedly different, but GM-CSF patients reported more grade 1–2 fatigue. Conclusions: These data suggest that the addition of cyclophosphamide to adjuvant active specific immunotherapy in stage IV melanoma impacts DTH responses, and GM-CSF increases IgM response. Since this represents an impact on both the cellular (DTH) and humoral (IgM) arms of immunity, further study of modulator combinations is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration CancerVax CancerVax