Armed oncolytic immunotherapies for overcoming tumor induced immune suppression

Dendritic cells (DCs) are the sentinels of the immune system and are specialized in initiating adaptive immune responses by presenting foreign antigens to T cells. Thus, dendritic cells are critical regulators of immune responses and accordingly have been a focus of cancer immunotherapy research. DC therapy is considered as a promising approach in cancer immunotherapy. However, DC-based vaccines have shown limited efficacy in clinical trials. Oncolytic adenovirus replicates and lyses only cancer cells. Virus-mediated lysis of cancer cells also induces danger signals and exposes tumor epitopes that promote immune system activation against cancer. This study investigated the oncolytic adenovirus 3 coding for CD40 Ligand: Ad3-hTERT-CMV-CD40L (also known as TILT-234) as an enhancer of DC therapy. In the first study, human cancer patient data suggested that intravenous adenovirus administration is able to transduce distant tumors and virally-produced CD40L can activate DCs in situ. Studies with mice suggested that the virus possesses potent antitumor activity. In the second study, treatment with Ad3-hTERT-CMV-CD40L and DCs showed 100% survival of humanized mice and resulted in greater antitumor efficacy than either approach as monotherapy. The third study focused on the treatment of prostate cancer. In this study, treatment with companion therapy (i.e. Ad3-hTERT-CMV-CD40L and DC therapy) was shown to induce greater antitumor immune responses in vivo and in established prostate cancer histocultures. In the fourth study, we focused on the interaction of a chimeric adenovirus Ad5/3 with human lymphocytes and erythrocytes. This study showed that the binding of Ad5/3 with human lymphocytes and erythrocytes occurs in a reversible manner, which enables the virus to transduce different tumors and to retain oncolytic potency both in vitro and in vivo, with or without neutralizing antibodies. In summary, the first three studies demonstrated the ability of Ad3-hTERT-CMV-CD40L to modulate the tumor microenvironment and that local delivery of CD40L is safe and efficient regarding DC therapy. In conclusion, Ad3-hTERT-CMV-CD40L was shown to be a potential enabler of DC therapy. The fourth study revealed the ability of a chimeric Ad5/3 adenovirus to transduce non-injected tumors through blood, even in the presence of neutralizing antibodies.