Overcoming age-related tumor progression using the HEPLISAV-B vaccine in combination with immunotherapies 2259634

Abstract Introduction As we age, the adaptive immune system declines due to factors such as reduced thymic cellularity, altered tissue architecture, decreased production of naïve T cells, and a limited repertoire of peripheral T cell receptors. Yet, most preclinical tumor models rely on young mice, overlooking the immunological decline that shapes therapeutic outcomes in older hosts. This gap limits translation of otherwise promising immunotherapies to the aging cancer population. To address this, we examined how age influences antitumor immunity and immune cell trafficking in a triple-negative breast cancer (TNBC) model treated with either intratumoral (i.t.) HEPLISAV-B (HEP B) vaccine or a combinatorial immunotherapy composed of i.t. HEP B vaccine, i.t. complexed IL-15, and intraperitoneal (i.p.) anti—PD-1. We hypothesized that treatment could reverse the effects of aging on tumorigenesis. Methods The TNBC cell line 4T1 expressing luciferase was used to establish tumors in young (6-8 weeks) and aged (24-26 weeks) female BALB/c mice. Mice were treated with i.t. injections of the HEP B vaccine or HEP B in combination with i.t. injections of IL-15 and i.p. injections of anti-PD-1. Tumor progression and survival were monitored. Flow cytometry quantified expression of trafficking receptors (CXCR4, B7). Results The HEP B vaccine and combination therapy induced complete tumor regression in 90% of young mice recipients (n = 10) and 60% of aged mice (n = 9) in a survival study out to 60 days. Aged mice showed faster tumor growth in controls but similar regression rates when treated. Aging altered the expression of key homing molecules on tumor-infiltrating CD8 T cells with decreased CXCR4 and elevated B7, suggesting impaired trafficking and retention. Changes in the CD4:CD8 T cell ratio were observed between groups. Conclusion Treatment with the HEP B vaccine or a combination therapy can overcome age-related hurdles in tumor regression. Funding Source Rush Philanthropy; Roumbas Estate Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)