Alzheimer’s disease (AD) process is understood to involve the accumulation of amyloid plaques and tau tangles in the brain. However, attempts at targeting the main culprits, neurotoxic Aβ peptides, have thus far proven unsuccessful for improving cognitive function. Recent clinical trials with passively administrated anti-Aβ antibodies failed to slow cognitive decline in mild-moderate AD patients, but suggest that an immunotherapeutic approach could be effective in patients with mild AD. In an AD mouse model (Tg2576) we tested the immunogenicity (cellular and humoral immune responses) and efficacy (AD-like pathology) of clinical grade Lu AF20513 vaccine. Lu AF20513 induces robust “non-self” T cell responses and production of anti-Aβ antibodies that reduce AD-like pathology in the brains of Tg2576 mice without inducing microglial activation and enhancing astrocytosis or CAA. Importantly, a single immunization with Lu AF20513 induces strong humoral immunity in mice with pre-existing memory Th cells. In addition, Lu AF20513 induces strong humoral responses in guinea pigs and monkeys. Collectively, these data suggest translation of Lu AF20513 to clinical setting with aims to (i) induce therapeutically potent anti-Aβ antibody responses in patients with mild AD, particularly if they have memory Th cells generated after immunizations with conventional Tetanus Toxoid vaccine; (ii) exclude likely pathological autoreactive T cell responses.

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It is believed that primary tumor resection modulates host-tumor immune interaction, but this has not been characterized in a stringent breast cancer tumor model. This report, using the 4T1 murine mammary tumor model, characterizes for the first time the dynamic longitudinal changes in immunosuppressive and effector components of the immune system after resection of an established orthotopic primary tumor with a defined natural history of developing lung metastases. More specifically, we analyzed changes of absolute numbers and frequencies of MDSC, regulatory T cells (Treg), as well as activated CD4 and CD8 positive T cells in spleens and, in some studies, lungs of 4T1 tumor-bearing mice and mice after primary tumor resection. Importantly, using mathematical analyses we established that primary resection of an orthotopic tumor had created a “window of opportunity” with decreased tumor-associated immune suppression that existed for approximately 10 days. Although tumor resection did slightly prolong survival, it did not affect the ultimate development of metastatic disease since animals with resected tumors or intact primary tumors eventually died by day 47 and 43, respectively. This window of opportunity likely occurs in humans providing a rationale and parameters for integration and testing of immunotherapeutic strategies in this critical “window of opportunity” to combat the development of metastatic disease.

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