Abscopal Effect in Non-injected Tumors Achieved with Cytokine-Armed Oncolytic Adenovirus

Abstract

Cancer treatment with local administration of armed oncolytic viruses could potentially induce systemic antitumor effects, or the abscopal effect, as they self-amplify in tumors, induce danger signaling, and promote tumor-associated antigen presentation. In this study, oncolytic adenovirus coding for human tumor necrosis factor alpha (TNF-α) and interleukin-2 (IL-2) Ad5/3-E2F-d24-hTNF-α-IRES-hIL-2 (also known as [a.k.a.] TILT-123) provoked antitumor efficacy in tumors that were injected with Ad5/3-E2F-d24-hTNF-α-IRES-hIL-2 and those that were left non-injected in the same animal. Importantly, the virus was able to travel to distant tumors. To dissect the effects of oncolysis and cytokines, we studied replication-incompetent viruses in mice. Systemic antitumor effects were similar in both models, highlighting the importance of the arming device. The cytokines induced positive changes in immune cell infiltrates and induced the expression of several immune-reaction-related genes in tumors. In addition, Ad5/3-E2F-d24-hTNF-α-IRES-hIL-2 was able to increase homing of adoptively transferred tumor-infiltrating lymphocytes into both injected and non-injected tumors, possibly mediated through chemokine expression. In summary, local treatment with Ad5/3-E2F-d24-hTNF-α-IRES-hIL-2 resulted in systemic antitumor efficacy by inducing immune cell infiltration and trafficking into both treated and untreated tumors. Moreover, the oncolytic adenovirus platform had superior systemic effects over replication-deficient vector through spreading into distant tumors.

Immune Modulation in Lung Cancer: Current Concepts and Future Strategies

“…A comparable effect can be achieved by locally applied oncolytic therapies, either viruses devoid of virulence factors [354], or synthetic amino acid oligomers that mimic host-defense peptides and disrupt cellular membranes to cause immunogenic lysis of tumor cells [355]. Like radiotherapy, oncolytics convert the tumor to an in situ vaccine [356] and can also elicit abscopal effects [357, 358]. On the other hand, several immunomodulatory strategies are being developed according to the principles of precision medicine and target specific pathways and/or cells of the TME.…”

Safety, biodistribution and viral shedding of oncolytic vaccinia virus TG6002 administered intravenously in healthy beagle dogs

“…However, this route has one major shortcoming in that it focuses on treatment of non-metastatic accessible tumors. Even if an abscopal effect has been reported in murine models, only limited data of distant effects are available in human medicine 35 – 40 . To overcome the drawback of the intratumoral route, the intravenous route has been considered 41 , 42 .…”

Breaking Therapy Resistance: An Update on Oncolytic Newcastle Disease Virus for Improvements of Cancer Therapy

“…Data obtained from two syngeneic mouse tumor models revealed that adenovirus coding for CD40L mediated multiple antitumor effects including oncolysis, apoptosis, induction of T-cell responses, and upregulation of Th1 cytokines [123]. Another vector, Ad5/3-E2F-d24-hTNF-a-IRES-hIL-2, induced abscopal effects in non-injected tumors thus revealing systemic antitumor efficacy [124]. Type I IFN signaling was required for the induction of antigen-specific CD8+ T cell responses in the gut mucosa following intra-muscular adenovirus vector vaccination [125].…”