The Effects of Checkpoint Blockade and a CD40 Agonist on Tindependent and T-dependent Antibody Responses in Mice: Implications for Optimization of Vaccination Strategies in Patients Receiving Immunotherapies

Abstract

Background: Patients with cancer often do not receive vaccines to preventable infectious diseases such as influenza and pneumococcal pneumonia because of a lack of knowledge about the optimal timing of vaccination relative to their underlying disease or their current cancer treatments. Cancer immunotherapies, which rely on the ability to promote immune responsiveness to tumors, are a promising therapeutic modality, but their impact on vaccination is largely unexplored. Methods:We used a pre-clinical mouse model to evaluate the antibody response to a T-dependent (TD) or a Tindependent (TI) antigen immunization with concomitant administration of either checkpoint inhibitors such as antibodies to CTLA-4 or PD-L1 or an antibody to CD40 that has adjuvant properties. Results:We found that checkpoint blockade with anti-CTLA-4 or anti-PD-L1 antibodies provided reduction in IgM, IgG, and most IgG subclasses when immunized with either TI or TD antigens. On the other hand, a CD40 agonist antibody provoked modest reductions in all immunoglobulins in response to TD antigen but provided marked increases in most immunoglobulins and IgG subclasses in response to TI antigen.Conclusions: These data suggest that the timing of vaccinations relative to immunotherapies might be an important factor in determining the efficacy of vaccination. If these findings are shown to extend to humans, the antibody response to vaccination might be attenuated and patients might be at increased risk for infection. This pilot study provides potential mechanistic insights into an important consideration in patients receiving immunotherapies.