Maximizing cancer therapy via complementary mechanisms of immune activation: PD-1 blockade, neoantigen vaccination, and Tregs depletion.

BACKGROUND: A number of different immune pathways are involved in the effective killing of cancer cells, collectively named as the 'Cancer Immunity Cycle'. Anti-PD-1 checkpoint blockade (CPB) therapy is active on one of these pathways and reinvigorates anticancer T cell immunity, leading to long-term responses in a limited fraction of patients with cancer. We have previously shown that neoantigens-based adenovirus vectored vaccine in combination with anti-PD-1 further expands pre-existing anticancer immunity and elicits novel neoantigen-specific T cells thereby increasing efficacy to 50% of tumor clearance in mice. Here we added a third component to the CPB plus vaccine combination, which is able to modify the suppressive tumor microenvironment by reducing the number of tumor-infiltrating regulatory T cells (Tregs), as strategy for improving the therapeutic efficacy and overcoming resistance. METHODS: The antitumor efficacy of anti-PD-1, neoantigen vaccine and Treg modulating agents, either Bempegaldesleukin (BEMPEG: NKTR-214) or an anti-CTLA-4 mAb with Treg-depleting activity, was investigated in murine tumor models. We evaluated tumor growth in treated animals, neoantigen-specific T cells in tumors, tumor-infiltrating lymphocytes (TILs) and intratumoral Tregs. RESULTS: The addition of BEMPEG or anti-CTLA-4 to the combination of vaccine and anti-PD-1 led to complete eradication of large tumors in nearby 100% of treated animals, in association with expansion and activation of cancer neoantigen-specific T cells and reduction of tumor-infiltrating Tregs. CONCLUSION: These data support the notion that the integrated regulation of three steps of the cancer immunity cycle, including expansion of neoantigen-specific T cells, reversal of the exhausted T cell phenotype together with the reduction of intratumoral Tregs may represent a novel rationally designed drug combination approach to achieve higher cure rates.

Chimpanzee adenoviral vectors as vaccines - challenges to move the technology into the fast lane.

INTRODUCTION: In recent years, replication-defective chimpanzee-derived adenoviruses have been extensively evaluated as genetic vaccines. These vectors share desirable properties with human adenoviruses like the broad tissue tropism and the ease of large-scale manufacturing. Additionally, chimpanzee adenoviruses have the advantage to overcome the negative impact of pre-existing anti-human adenovirus immunity. Areas covered: Here the authors review current pre-clinical research and clinical trials that utilize chimpanzee-derived adenoviral vectors as vaccines. A wealth of studies are ongoing to evaluate different vector backbones and administration routes with the aim of improving immune responses. The challenges associated with the identification of an optimal chimpanzee vector and immunization strategies for different immunological outcomes will be discussed. Expert commentary: The demonstration that chimpanzee adenoviruses can be safely used in humans has paved the way to the use of a whole new array of vectors of different serotypes. However, so far no predictive signature of vector immunity in humans has been identified. The high magnitude of T cell responses elicited by chimpanzee adenoviruses has allowed dissecting the qualitative aspects that may be important for protective immunity. Ultimately, only the results from the most clinically advanced products will help establish the efficacy of the vaccine vector platform in the field of disease prevention.