Oncolytic virus immunotherapy (HSV, oncolytic adenovirus)
and cancer therapy

Oncolytic virotherapy is a novel therapeutic modality utilizing oncolytic viruses (such as herpes simplex-, pox-, parvo-, or adenoviruses), which selectively replicate in cancer cells, to directly induce tumor cell lysis or indirectly reactivate human immune system to mediate tumor destruction (Fig. 7) [64]. Through decades’ optimization, a great number of oncolytic virus therapies have been put into clinical trials, such as ONYX-015 (E1B-deleted adenovirus) [65], DNX-2401 (Ad5) [66], CG0070 (Ad5 carrying GM-CSF gene) [67], OBP-301 (Ad5-hTERT-E1A/B) [68], G207 (a conditionally-replicative HSV-1 with ICP34.5 deletion and UL39 disruption) [69], and JX-594 (Pexa-Vec, GM-CSF-enhanced vaccinia virus with TK gene disruption) [67]. Among them, Amgen's T-VEC (a modified HSV-1 with expression of GM-CSF but deletions in ICP34.5 and ICP47 genes) was the first oncolytic virus approved by America Food and Drug Administration (FDA) for the treatment of melanoma in 2015 [70]. Moreover, when combined with the other therapy, such as Anti-PD-1 immunotherapy, oncolytic virus can significantly promote immune recognition of cancer cell as well as T cell infiltration, and lead to high response rate in patients with advanced melanoma [71].

Figure 7 Oncolytic viruses-induced anti-tumor immunity [64]. Oncolytic viruses mediate direct cancer lysis and indirect activation of anti-tumor immune responses.

Taken together, different kinds of immune-oncology cell therapy show great variety in their curative effects. Although promising therapeutic outcomes in acute lymphocytic leukemia (ALL) and large B cell lymphomas have been achieved by CAR-T [80,81], little therapeutic effects were acquired in solid tumors as well as tumors with intracellular antigens, and multiple side effects, such as cytokine release syndrome, prohibited the broad application of CAR-T [82-84]. TCR-T displays better effects for the treatment of hematopoietic cancers and solid tumors, but requires MHC and co-stimulatory or co-inhibitory signals to combat tumors [45]. Without the drawback of CAR-T, CAR-NK is safer than CAR-T and presents excellent tumor elimination ability in both hematopoietic cancers and solid tumors via CAR-dependent and NK receptor-dependent mechanisms [53]. DC-CIK immunotherapy shows improved immunologic function, reduced mortality, and mild adverse effects in both hematologic malignancies and solid tumors, and may be suitable for patients that are intolerance to radiotherapy and chemotherapy [62,85]. Without the need of defined antigens included in the vectors, oncolytic viruses show a durable anti-tumor effects by directly infecting and lysing tumor cells in situ and also activating the host immune response to eliminate tumor cells, thus displaying curative effects on both hematopoietic cancers [86,87] and solid tumors [64]. Moreover, these immune-oncology cell therapies can also be combined with programmed cell death protein 1 (PD-1) antibody or PD-1 inhibitor, showing reduced drug toxicity and enhanced the tumor cytotoxicity [88]. For example, CD19-CAR-T cell carrying the single-chain variable fragment (scFv) of antibody against PD-1 exhibited potent therapeutic effects superior to those of conventional CAR-T cells [89]; oncolytic Herpes Simplex Virus Type 2 encoding an antibody against PD-1 presented an enhanced therapeutic efficacy with a durable antitumor response both in the tumor microenvironment and in the systemic immune system [90].

View Knowledge Base - Landscape of Advanced cell therapy>>