Oncolytic Viruses and Immune Checkpoint Inhibitors: The “Hot” New Power Couple
Abstract
:Simple Summary
Abstract
1. Introduction
2. Oncolytic Viruses
Turning Cold Tumours Hot: The OV Immune Response
3. Oncolytic Virus Monotherapy
4. Combined OV and ICI Therapy
4.1. Neoadjuvant Therapies
4.1.1. Markers of Response
Virus | OV | ICI | Indication | Key Findings | Ref. |
---|---|---|---|---|---|
Ad | CG0070 (IVS) | PD-1: Pembrolizumab | NMIBC Phase II | Disease control: 82% 6-month CR; 81% 9-month CR; 68% 12-month CR | |
DNX-2401 (IT) | GBM Phase II | Survival: 52.7% 12-month survival; 12.5 months median OS; 3 patients alive > 45 months Disease control: ORR 10.4%; 42.9% SD; 4.8% CR; 7.1% PR; | [59] | ||
EnAd (IT) | PD-1: Nivolumab | mCRC Phase I | Survival: median OS 15.4 months (5 months placebo) Disease control: median PFS 2.8 months Immune response: 85% demonstrated increased CD8+ TILs; 77% increased CD4+ TILs; 62% increased PD-L1+ TILs | [64,65,66] | |
ONCOS-102 (IT) | PD-1: Pembrolizumab | Melanoma progressing post-PD-1 blockade Pilot | Disease control: 35% ORR; 64% SD; 27% demonstrated CR in injected tumour 53% demonstrated reduction in ≥1 non-injected tumour Immune response: increased CD4+ & CD8+ TILs | [62] | |
HSV | T-VEC (IT) | PD-1: Pembrolizumab | Melanoma Phase Ib | Disease control: 82% demonstrated >50% reduction of injected tumours; 43% in non-injected tumours Immune response: 67% demonstrated increased CD8+ TILs; demonstrated increased systemic proliferating CD8+ T cells | [67] |
Melanoma Phase III T-VEC + Pemb vs Pemb | Disease control: T + P: 17.9% CR; 48.6% ORR (CR/PR); 14.3 months PFS P: 11.6% CR; 41.3% ORR; 8.5 months PFS | [60] | |||
Sarcoma Phase II | Disease control: 21% PR; 47% SD; median PFS 17.1 months Immune response responders saw increased CD8+ TILs and CD8+ aggregates at tumour edge; non-responders saw no increase in CD8+ TILs or aggregates | [63] | |||
CTLA-4: Ipilimumab | Melanoma Phase II TVEC + Ipi vs Ipi | Disease control: T + I: 13% CR; 26% PR; 39% ORR (CR/PR); 8.2 months median PFS; 52% non-injected visceral tumour reduction I: 7% CR; 11% PR; 18% ORR; 6.4 months median PFS; 23% non-injected visceral tumour reduction | [61] | ||
HF10 (IT) | CTLA-4: Ipilimumab | Melanoma Phase II | Survival: Median OS 26 months Disease control: median PFS 19 months; 68% SD Immune response: increased CD8+ and decreased CD4+ TILs | [34] | |
VV | JX-594 (IT) | CTLA-4: Tremelumab PD-L1: Durvalumab | ICI refractory CRC Phase I/II | Survival: J + D: Median OS 7.5 months J + D + T: Median OS 5.2 months Disease control: J + D: median PFS 2.3 months; 12.5% DCR J + D + T: median PFS 2.1 months; 16.7% DCR Immune response: Increased proliferating CD3+ TILs after OV treatment and again after ICI treatment; increased M1 macrophages in tumours | [68] |
4.1.2. Adverse Events
4.2. OVs Encoding ICIs
OV | Target | ICI Format | Indication | Key Findings | Ref. |
---|---|---|---|---|---|
Ad5 | CTLA-4 mouse | IgG2 | Melanoma NSCLC SCLC | Subcutaneous mouse xenograft model with intravenous OV injection: Disease control: significant 72% reduction in tumour growth compared to untreated tumours Subcutaneous mouse xenograft model with intra-tumoural OV injection: Disease control: significant 3-fold decrease in tumour growth compared to untreated tumours | [71] |
Ad5/3 | CTLA-4 human | IgG2 | NSCLC Prostate | Subcutaneous T-cell-deficient mouse xenograft model with intra-tumoural OV injection: Disease control: significantly decreased tumour growth compared to untreated Immune response: 43-fold increase in tumour anti-CTLA-4 antibody concentrations compared to systemic plasma In vitro human T cell activation assay: PBMCs from advanced solid cancer patients cultured in the presence of supernatant from OV-infected cells saw increase in T cell IL-2 and IFN-γ production | [72] |
HSV-1 | CTLA-4 & GM-CSF mouse | scFv fused to mouse IgG1 | Lymphoma | Bilateral subcutaneous mouse xenograft model with single-sided intra-tumoural OV injection: Disease control: decreased tumour growth in both injected and non-injected tumours (not significant) | [73] |
IAV | CTLA-4 mouse | scFV | Melanoma | Bilateral subcutaneous mouse xenograft model with single-sided intra-tumoural OV injection: Disease control: significantly decreased tumour growth in both injected and non-injected tumours and prolonged survival compared to parental virus | [74] |
IAV | CTLA-4 mouse | scFV | HCC | Spontaneous homograft model with intra-tumoural OV injection: Survival: prolonged survival compared to parental OV Disease control: significantly decreased tumour compared to parental OV | [85] |
NDV | CTLA-4 mouse | scFV | Melanoma | Intradermal mouse tumour model with intra-tumoural OV injection: Survival: prolonged survival compared to systemic CTLA-4 treatment plus parental NDV Disease control: comparable tumour growth inhibition | [93] |
MV | CTLA-4 mouse | scFV-IgG1 Fc fusion | Melanoma | Subcutaneous synergic mouse tumour model with intra-tumoural OV injection: Disease control: significantly decreased tumour growth compared to parental virus and untreated Immune response: significant increase in tumour T cell infiltration and a decrease in Treg infiltration compared to parental OV and untreated; increased splenocyte IFN-γ release upon re-stimulation with tumour cells in vitro compared to parental OV and untreated | [91] |
Ad68 | PD-1 | IgG4 | Colorectal | Bilateral subcutaneous humanised PD-1 transgenic mouse tumour model with single-sided intra-tumoural OV injection: Survival: prolonged survival compared to parental OV and untreated Disease control: significantly decreased tumour growth compared to parental OV and untreated, with successful tumour rejection upon rechallenge Immune response: significantly increased systemic CD8+ T cell and effector and central memory T cell proportions; significantly decreased PD-1+ CD4+ and CD8+ T cell proportions | [75] |
HSV-1 | PD-1 mouse | scFv | HCC | Bilateral subcutaneous synergic mouse tumour model with single-sided intra-tumoural OV injection: Disease control: significantly decreased tumour growth in both injected and non-injected tumours and greater long-term tumour growth inhibition compared to parental OV and untreated; successful tumour rejection upon rechallenge Immune response: significantly increased activated CD4+ and CD8+ cell tumour infiltration compared to parental OV; however, also saw significantly greater MDSC infiltration compared to parental OV | [76] |
HSV-1 | PD-1 human | scFv | HCC | Orthotopic HCC xenograft tumour model with intravenous OV injection in humanised PD-1 transgenic mice: Survival: and increased overall survival compared to parental OV and untreated mice Disease control: significantly decreased tumour growth compared to parental OV and untreated mice, with all anti-PD-1 OV treated mice tumour free at 12 weeks Bilateral subcutaneous mouse xenograft tumour model with single-sided intra-tumoural OV injection in humanised PD-1 transgenic mice: Disease control: significantly decreased tumour growth in both injected and non-injected tumours compared to parental OV and untreated Immune response: anti-PD-1 OV treated tumours demonstrated significantly reduced proportions of exhausted CD8+ T cell populations and increased effector memory CD8+ T cell populations compared to parental OV and untreated | [77] |
HSV-1 | PD-1 human | scFv | Melanoma | Bilateral subcutaneous mouse xenograft tumour model with intra-tumoural OV injection in humanised PD-1 transgenic mice: Disease control: significantly decreased tumour growth compared to untreated and parental OV Immune response: significantly increased tumour CD4+ and CD8+ T cell infiltration compared to untreated; RNA-seq analysis demonstrated significant enrichment in anti-viral, IFN and antigen presentation and processing pathways compared to untreated | [78] |
HSV-1 | PD-1 human | scFV | GBM | Orthoptic GBM synergic mouse tumour model with intra-tumoural OV injection: Survival: increased median survival time compared to untreated (significant) and parental OV (not significant) Disease control: successful tumour rejection following rechallenge | [89] |
HSV-2 | PD-1 human | IgG | Melanoma | Subcutaneous mouse xenograft tumour model with intra-tumoural OV injection in humanised PD-1 transgenic mice: Survival: prolonged survival compared to untreated; improved tumour-free survival compared to parental OV and untreated Disease control: significantly decreased tumour growth compared to untreated; successful tumour rejection following rechallenge Immune response: increased systemic percentages of CD4+, CD8+ and CD3+ T cells and significant increase in T cell activation markers compared to parental OV and untreated; significant reduction in Tregs and MDSCs compared to untreated | [79] |
VV | PD-1 mouse | IgG & scFV | Fibrosarcoma Melanoma | Subcutaneous synergic mouse tumour model with intra-tumoural OV injection: Survival: prolonged survival (IgG significant; scFV not significant) compared to parental OV and untreated Disease control: significantly decreased tumour growth compared to parental OV and untreated Immune response: IgG-OV significantly increased tumour infiltration of CD4+ and CD8+ T cells, the proportion of activated CD8+ T cells, and the CD8+/Foxp3+ T cell ratio compared to systemic anti-PD-L1 treatment, but to a lesser extent than parental OV alone | [86] |
NDV | PD-1 and PD-L1 mouse & IL-2 | scFV | Melanoma | Unilateral subcutaneous synergic mouse tumour model with intra-tumoural OV injection: Survival: prolonged survival compared to parental OV Disease control: significantly decreased tumour growth compared to parental OV Bilateral subcutaneous synergic mouse tumour model with single-sided intra-tumoural OV injection: Survival: when combined with systemic anti-CTLA-4 treatment, PD-1 and PD-L1 OV demonstrated significantly prolonged survival compared to parental OV Disease control: when combined with systemic anti-CTLA-4 treatment, PD-1 and PD-L1 OV demonstrated significantly inhibited tumour growth in non-injected tumours compared to parental OV | [87] |
MV | PD-1 & PD-L1 mouse | scFV-IgG1 Fc fusion | Melanoma | Subcutaneous synergic mouse tumour model with intra-tumoural OV injection: Survival: significantly prolonged survival compared to parental OV and untreated Disease control: significantly decreased tumour growth compared to parental OV and untreated; successful tumour rejection following rechallenge Immune response: significantly increased activated CD8+ T cell and reduced Foxp3+ Treg tumour infiltration; higher effector memory T cell: central memory T cell ratio for PD-1 (significant) and PD-L1 (not significant) OVs compared to untreated | [84,91] |
Ad5/24 | PD-L1 mouse | scFV | Colorectal | Bilateral subcutaneous synergic mouse tumour model with intra-tumoural OV injection: Survival: significantly prolonged survival compared to parental OV and untreated Disease control: significantly decreased tumour growth compared to parental OV and untreated Immune response: significantly increased tumour CD8+ T cell infiltration compared to parental OV | [88] |
Chimeric poxvirus | PD-L1 human | scFv | Breast cancer Gastric cancer PDAC | Orthotopic synergic mouse breast cancer model with intra-tumoural or intravenous OV injection: Survival: significantly prolonged survival compared to untreated Disease control: significantly decreased tumour growth compared to untreated Orthotopic mouse breast cancer xenograft model with intra-tumoural OV injection: Survival: significantly prolonged survival compared to untreated Disease control: significantly decreased tumour growth compared to untreated Peritoneal mouse GC and PDAC xenograft tumour model with intraperitoneal OV injection: Survival: significantly prolonged survival compared to untreated Disease control: significantly decreased tumour growth compared to untreated | [80,81,82,90] |
VSV | PD-L1 human | scFV | Lung carcinoma | Subcutaneous mouse hPD-L1 knock-in synergic tumour model with intra-tumoural OV injection: Survival: significantly prolonged survival compared to untreated Disease control: significantly decreased tumour growth compared to untreated successful tumour rejection following rechallenge Immune response: significant systemic increase in total number of CD8+ effector memory and CD8/CD4+ central memory T cells | [83] |
VV | PD-L1 & GM-CSF human | Soluble PD-1 ED fused to IgG1 Fc | Melanoma | Bilateral subcutaneous synergic mouse tumour models with intra-tumoural OV injection: Survival: significantly decreased prolonged survival upon tumour rechallenge compared to untreated and parental OV Disease control: decreased tumour growth in 3 solid tumour models; significantly decreased tumour growth and prolonged survival upon tumour rechallenge compared to untreated and parental OV Immune response: significantly increased CD45+, DC, CD4+ and CD8+ T cell, and decreased MDSC and Treg tumour infiltration in injected tumours; untreated distant tumours also demonstrated increased infiltration and activation of lymphocytes and other immune cells | [92] |
Additional Targets
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Virus | Diameter | Genome | Genome Size | Transgene Capacity |
---|---|---|---|---|
Adenovirus | 90–100 nm | dsDNA | 30–36 kb | ~2.5 kb |
Herpes simplex virus | 200 nm | dsDNA | ~152 kb | ~30 kb |
Vaccinia virus | 350 nm | dsDNA | ~192 kb | ~25 kb |
Influenza A virus | 80–120 nm | ss(–)RNA | ~13.5 kb | ~2.4 kb |
Newcastle disease virus | 100–500 nm | ss(–)RNA | ~15 kb | ~4.5 kb |
Measles virus | 100–200 nm | ss(–)RNA | ~16 kb | ~6 kb |
Vesicular stomatitis virus | 70–200 nm | ss(–)RNA | ~11.1 kb | ~4.5 kb |
Coxsackie virus | 22–30 nm | ss(+)RNA | ~7.5 kb | <1 kb |
Reovirus | 80 nm | dsRNA | 24 kb | ~1.5 kb |
Virus | OV | Engineered Specificity | Transgene | Indication | Delivery | Key Findings | Ref. |
---|---|---|---|---|---|---|---|
Adenovirus | CG0070 | Ad5 with E1a under E2F-1 promoter | GM-CSF | NMIBC Phase II | IVS | Disease control: 47% 6-month CR; 29% 12-month CR | [49] |
DNX-2401 | Ad5 with 24 bp E1a deletion; RGD integrin-binding motif | GBM Phase I | IT | Survival: 20% >3-year survival Disease control: 12% demonstrated >95% tumour reduction Immune response: increased tumour CD8+ and T-bet+ cells; decreased TIM-3+ cells | [31] | ||
EnAd | Ad11p/3 chimera generated through directed evolution | Ovarian Phase I | IV | Survival: 64% PFS Disease control: 10% ORR; 35% achieved stable disease; 65% saw reduction in tumour burden; Immune responses: 83.3% demonstrated increased CD8+ TILs | [42] | ||
LoAd-703 | Ad5 with 24 bp E1a deletion; Pseudo-typed Ad35 knob | TMZ-CD40L; 4-1BBL | PDAC Phase I/II | IT | Survival: OS 8.7 months Disease control: 44% ORR; 94% DCR Immune response: increased effector memory T cells; decreased Tregs and MDSCs | [40] | |
ONCOS-102 | Ad5 with 24 bp E1a deletion; Pseudo-typed Ad3 knob | GM-CSF | Solid tumours Phase I | IT | Immune response: increase in TILs; increase in systemic tumour-specific CD8+ T cells; increased tumour PD-L1 expression | [33] | |
Telomelysin | Ad5 with E1a under hTERT promoter | Oesophageal Phase I | IT | Disease control: 91.7% ORR; 83.3% Stage I and 60% Stage II/III CRR Immune response: increased tumour CD8+ T cells; increased tumour PD-L1 expression | [39] | ||
VCN-01 | Ad5 with 24 bp E1a deletion; E2F1 promoter insertion; RGDK integrin-binding motif | Hyaluronidase | PDAC Phase I | IT | Disease control: injected tumours reduced in size or remained stable; reduction in tumour stiffness | [43] | |
IV | Disease control: 40–45% ORR including 1 complete response Immune response: CD8+ T cell tumour infiltration and IDO upregulation in 64% of patients | [48] | |||||
Coxsackie virus | CVA21 | NMIBC Phase I | IVS | Disease control: 1/15 demonstrated CR; viral protein detected in 86% of tumours with no viral protein seen in stroma Immune response: CR patient demonstrated increased immune infiltration; RNA-seq demonstrated increased intrinsic apoptotic cell death pathway and PD-L1, LAG-3 and IDO within the TME | [41] | ||
Herpes simplex virus | T-VEC | HSV1 with ICP34.5 deletion; US11 deletion | GM-CSF | Melanoma Phase III | IT | Survival: median OS 23.3 months Disease control: 19% DRR; 31.5% ORR; 50% demonstrated CR of which 88.5% were estimated to survive at 5-years; median time to CR 8.6 months Approved for the local treatment of unresectable metastatic stage IIIB/C–IVM1a melanoma in Europe and US | [26] |
G207 | HSV1 with ICP34.5 deletion; UL39 deletion; | GBM Phase I (+Rad) | IT | Survival: median OS 7.5 months Disease control: median PFS 2.5 months; 67% demonstrated stable or partial response at ≥ 1 time point | [37] | ||
Paediatric glioma Phase I | IT | Survival: Median OS 12.2 months; 36% still alive at 18 months Disease control: 18% demonstrated stable disease at 12 months Immune response: increased CD4+ and CD8+ T cell tumour infiltration | [44] | ||||
G47Δ | G207 with additional α47 deletion; US11 promoter deletion | GBM Phase II | IT | Survival: median OS 20.2 months; 84.2% survival at 12 months Disease control: median PFS 4.7 months; stable disease in 18 patients at 2 years Immune response: increased CD4+, CD8+ and decreased Foxp3+ TIL Conditional and time-limited approval for treatment of GBM in Japan | [27] | ||
HF10 | HSV1 with UL43, UL49.5, UL55 & UL56 deletions; Latency-associated transcripts deletions; UL53 & UL54 overexpression | Pancreatic cancer Phase I | IT | Survival: median OS 15.5 months; 2 patients were alive at 3 year follow up Disease control: median PFS 6.3 months; 33.3% PR; 44.4% SD; 2 patients demonstrated surgical CR Immune response: increased CD4+, CD8+ TILs | [45] | ||
Superficial solid tumours Phase II | IT | Disease control: 33.3% SD; 1 patient demonstrated pathological CR after 4 months; 30–61% reduction in tumour size in those demonstrating responses | [36] | ||||
Seprehvir | HSV1 with ICP34.5 deletion | Paediatric solid tumours Phase I | IT | Survival: median OS 7 months Disease control: 80% demonstrated SD at 14 days; 43% SD at 28 days | [30] | ||
OrienX010 | HSV1 with ICP34.5 deletion; US12 deletion | GM-CSF | Melanoma Phase I | IT | Survival: median OS 19.2 months Disease control: median PFS 2.9 months; 54.6% of injected tumours regressed, 25.8% of which regressed by ≥30%; 54.1% of non-injected regional tumours regressed, 32.8% of which regressed by ≥30%; 1 distant non-injected metastases regressed by 58% | [38] | |
OH2 | HSV2 with ICP34.5 & ICP47 deletion; | GM-CSF | Solid tumours Phase I/II | IT | Disease control: 1 PR; 33% stable disease Immune response: 79% saw increased CD8+ TILs; 86% increased CD3+ TILs; 71.4% increased PD-L1+ cells | [46] | |
Newcastle disease virus | PV701 | Solid tumours Phase I | IV | Disease control: 61% PFS at 4 months; 33% OR; 1 CR cervical cancer; 2 PRs colorectal; 1 PR melanoma | [8] | ||
Measles virus | MV-CEA | Carcinoembryonic antigen | Ovarian cancer Phase I/II | IP | Survival: median OS 12.15 months Disease control: 67% SD; 36% demonstrated >30% tumour reduction | [9] | |
GBM Phase I | IT | Survival: median OS 11.6 months Disease control: 59% 3-month PFS; 23% 6-month PFS | [47] | ||||
MV-NIS | Sodium iodide symporter | Ovarian cancer Phase I | IP | Survival: median OS 26.2 months Disease control: 81% SD | [32] | ||
Vaccinia virus | GL-ONC1 | Β-galactosidase; β-glucuronidase | Ovarian cancer Phase I | IP | Disease control: median PFS 11.6 months; 78% 6-month PFS; 63% ORR; 52% CR Immune response: increased CD4+ & CD8+ TILs | [29] | |
JX-594 | TK1 deletion | GM-CSF | HCC Phase II | IT | Survival: median OS 9 months; ~35% alive at 2 years Disease control: 46% demonstrated tumour control at 8 weeks; average 32.2% decrease in tumour size Immune response: increased tumour specific CD8+ TILs | [28] | |
HCC Refractory to Sorafenib treatment Phase IIb | IT | Survival: no significant increase in survival compared to BSC Disease control: 13% DCR compared to 18% DCR with BSC Immune response: OV treated patients demonstrated a significant increase in vaccinia-specific T cells; 21.7% OV treated patients demonstrated tumour associated antigen-specific T cells | [50] | ||||
Vesicular stomatitis virus | VSV- IFNβ-NIS | IFN-β; sodium iodide symporter | TCL Phase I | IV | Disease control: 1 6-month PR; 1 20-month CR; 71.4% reduction in ≥1 tumour | [35] |
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Lovatt, C.; Parker, A.L. Oncolytic Viruses and Immune Checkpoint Inhibitors: The “Hot” New Power Couple. Cancers 2023, 15, 4178. https://doi.org/10.3390/cancers15164178
Lovatt C, Parker AL. Oncolytic Viruses and Immune Checkpoint Inhibitors: The “Hot” New Power Couple. Cancers. 2023; 15(16):4178. https://doi.org/10.3390/cancers15164178
Chicago/Turabian StyleLovatt, Charlotte, and Alan L. Parker. 2023. "Oncolytic Viruses and Immune Checkpoint Inhibitors: The “Hot” New Power Couple" Cancers 15, no. 16: 4178. https://doi.org/10.3390/cancers15164178
APA StyleLovatt, C., & Parker, A. L. (2023). Oncolytic Viruses and Immune Checkpoint Inhibitors: The “Hot” New Power Couple. Cancers, 15(16), 4178. https://doi.org/10.3390/cancers15164178