A. G. Ramirez1, N. A. Wages2, M. E. Smolkin2, C. L. Slingluff1 1University Of Virginia,Surgery,Charlottesville, VA, USA 2University Of Virginia,Public Health Sciences,Charlottesville, VA, USA
Introduction:
Cancer vaccines have promise as monotherapy or in combination immunotherapy regimens. The impact of patient age and gender on immune response and clinical outcome after cancer vaccinations are not known. Decline in immunogenicity with increasing age have led to uncertainty over inclusion of elderly patients in cancer vaccine trials. Gender differences in response to injury and to vaccination for infectious diseases suggest an independent effect of gender on immune response. We hypothesized younger age and female gender may be predictive of higher rates of immune response to a multipeptide cancer vaccine.
Methods:
Patients with resected stage IIB-IV melanoma were enrolled in three clinical trials: Mel43, Mel44, and Mel48, received 6 vaccinations with 12 Class I MHC restricted peptides from melanocytic differentiation antigens and cancer testis antigens. T cell responses were detected by direct IFN-y ELIspot assay. Clinical data, including age and gender, were collected. Cumulative incidence (CI) analyses of immune response measureable by Week 7 were used to compare patients based on age and gender, overall and within study arms. Kaplan-Meier estimates and log-rank tests were used to compare overall survival (OS) and disease-free survival (DFS). Chi-squared tests were performed to compare the percentage of immune responders by age and gender.
Results:
T cell responses were evaluated in 327 patients. Immune responses were detected in 49.5% (111/224) males and 47.6% (49/103) females. There was no difference in immune response by gender (p=0.74 by CI analysis; p=0.73 by Chi-squared test). Younger females responded earlier; however, the difference equilibrated over time. Menopausal status did not appear to be associated with difference in immune response (p=0.63). Interestingly, males experienced improved DFS (p=0.04) and a trend towards better OS (p=0.08). Female patients had a median DFS of 19.9 months versus 53.3 months for males. Immune responses were detected in 53% (130/249) of patients less than 64 yo but in only 38.5% (30/78) of older patients (p=0.02 by CI over time; p=0.03 by Chi-squared test). Sub-analysis of individual study arms showed comparable differences (p=0.02). No difference was detected in OS or DFS by age group (p=0.6 and 0.9, respectively).
Conclusion:
Our study reveals a decline in rates of immune response to peptide vaccines with increasing age; however, a significant percentage of elderly patients do develop immune responses to vaccination. Male patients had improved clinical outcomes, but gender differences were not associated with immune response. Thus, in clinical trials with immunologic endpoints, age should be considered in comparing outcomes between study arms. Older patients can be immunized and should not be excluded on the basis of age. Discordance between these clinical variables for immune response and clinical outcomes suggests complex interactions that may deserve further study with other immune therapies.