Background: The therapeutic blockade of the PD1/PD-L1 axis with monoclonal antibodies has led to a breakthrough in cancer treatment, as it plays a key role in the immune evasion of tumors. Nevertheless, treating patients with cancer with vaccines that stimulate a targeted immune response is another attractive approach for which few side effects have been observed in combination immunotherapy clinical trials. In this sense, our group has recently developed a therapeutic cancer vaccine candidate called PKPD-L1^Vac which contains as an antigen the extracellular domain of human PD-L1 fused to a 47 amino-terminal, part of the LpdA gene of N. meningitides, which is produced in E. coli. The investigation of potential toxicities associated with PD-L1 blockade by a new therapy in preclinical studies is critical to optimizing the efficacy and safety of that new therapy. Methods: Here, we describe immunogenicity and preliminary safety studies in mice, rats, rabbits, and non-human primates that make use of a 200 μg dose of PKPD-L1 in combination with VSSPs or alum phosphate to contribute to the assessment of potential adverse events that are relevant to the future clinical development program of this novel candidate. Results: The administration of PKPD-L1^Vac to the four species at the doses studied was immunogenic and did not result in behavioral, clinical, hematological, or serum biochemical changes. Conclusions: Therefore, PKPD-L1^Vac could be considered suitable for further complex toxicological studies and the way for its clinical evaluation in humans has been opened.