Bi- and Tri-Specific T Cell Engager-Armed Oncolytic Viruses: Next-Generation Cancer Immunotherapy

Abstract

<jats:p>Oncolytic viruses (OVs) are potent anti-cancer biologics with a bright future, having substantial evidence of efficacy in patients with cancer. Bi- and tri-specific antibodies targeting tumor antigens and capable of activating T cell receptor signaling have also shown great promise in cancer immunotherapy. In a cutting-edge strategy, investigators have incorporated the two independent anti-cancer modalities, transforming them into bi- or tri-specific T cell engager (BiTE or TriTE)-armed OVs for targeted immunotherapy. Since 2014, multiple research teams have studied this combinatorial strategy, and it showed substantial efficacy in various tumor models. Here, we first provide a brief overview of the current status of oncolytic virotherapy and the use of multi-specific antibodies for cancer immunotherapy. We then summarize progress on BiTE and TriTE antibodies as a novel class of cancer therapeutics in preclinical and clinical studies, followed by a discussion of BiTE- or TriTE-armed OVs for cancer therapy in translational models. In addition, T cell receptor mimics (TCRm) have been developed into BiTEs and are expected to greatly expand the application of BiTEs and BiTE-armed OVs for the effective targeting of intracellular tumor antigens. Future applications of such innovative combination strategies are emerging as precision cancer immunotherapies.</jats:p>

Redirecting the Immune Microenvironment in Acute Myeloid Leukemia

“…Combined with PD-L1 blockade, VSV-mIFNβ-NIS further augments antitumor activity with enhanced infiltrating T-cells reducing leukemia burden in an AML-murine model [ 169 ]. OVs armed with bi- and tri-specific T-cell engagers to locally boost T-cell-mediated tumorgenicity are currently under investigation [ 171 ].…”

Recent Advances in the Molecular Design and Applications of Multispecific Biotherapeutics

“…Besides recent new designs on CiTE [136,137] and the costimulatory receptor for sustained T-cell proliferation [133,134], combining TCEs/KCEs with CAR-T/CAR-NK cells, iPSC-NK cells, checkpoint blockages or ADCs has opened up future investigations [5,6,225,226]. For cancer therapy, TCEs and KCEs-armed oncolytic viruses (OVs) have shown impressive efficacy in various tumor models [227] (Figure 2A). With the recent FDA approval of T-VEC (Imlygic TM ) for the treatment of advanced melanoma patients in the US in 2015 [229], OVs' potential as potent anti-cancer biologics are established, despite the challenges such as antiviral immunity and insufficient delivery.…”

“…TCEs-and KCEs-encoded OVs produce and secrete the multispecific drugs into tumor tissues so that endogenous T cells can be activated and directed to kill tumor cells and stromal cells for improved efficacy [27,[230][231][232]. This combined strategy has significant advantages such as converting immunologically cold tumors into hot ones [233,234], minimizing on-target off-tumor toxicities [227,235], and enhancing T-cell infiltration into solid tumors [27]. To increase the therapeutic window of TCEs, high potency and low CRS toxicity can be achieved through next-generation protein engineering by decoupling tumor cell killing from cytokine release [23,236].…”

Oncolytic Virotherapy and Microenvironment in Multiple Myeloma

“…New perspectives in the cure of the disease including CAR-T cells, drug-conjugate mAbs and bispecific Abs have been recently developed for MM treatment. However, the use of these agents in combination with oncolytic viruses has been explored only in solid tumors [ 102 , 103 ]. In this setting there are some evidences that, for example, the combination of oncolytic virus and CAR-T could improve patients outcome boosting immune system and facilitate the CAR-T trafficking [ 104 , 105 ].…”