Oncolytic viruses induce immunogenic tumor cell death, which makes them ideal partners for combination with immunotherapies such as immune checkpoint inhibitors and adoptive T cell therapies. |
Effective combination therapies will depend on careful scheduling of the component parts. |
1 Oncolytic Virotherapy
2 Oncolytic Viruses (OVs) and Activation of Immune Responses
2.1 Innate Immune Responses
2.2 Immunogenic Tumor Cell Death
3 OVs and Immune Checkpoint Inhibitors
3.1 Immune Checkpoint Inhibition
3.2 Combination Therapy in Preclinical Models
Virus family | Virus | Indication | Combination drug | Virus RoA | Dosing schedule | Timing comment | References |
---|---|---|---|---|---|---|---|
Adenovirus | Ad-TK | GL261Luc2 glioma | Anti-PD1 | IC | Virus day 7, ICI days 10, 13, 16, 19 | Delayeda ICI administration improved survival | [105] |
Ad5 TNF-α or IL-2 | B16-OVA melanoma | Anti-PD1 | IT | Virus day 10, ICI day 10, q3d Virus days 11, 12, 14, q3d, ICI days 11, 12, 14, q3d Virus days 11, 12, 14, q3d, ICI day 14, q3d | Simultaneous or delayeda ICI (or ICI and ACT) administration improved survival over virus alone | [106] | |
hTertAd | CMT64 lung adenocarcinoma | Anti-PD1 | IT | Virus day 0, ICI days 0, 3, 6, 9 | Simultaneous administration improved survival and broadened T cell neoantigen response | [65] | |
ONCOS-102: GM-CSF and Ad5/3 capsid | A2058 melanoma | Pembrolizumab | IT | Virus days 15, 17, 19, ICI days 15, 17, 19, then q3–4d | Simultaneous ICI synergistically reduced tumor volume, no significance comparisons between combination and virus alone | [107] | |
HSV-1 | HSV-G47Δ IL-12 | 005 GSC glioma | Anti-PD1 Anti-PDL1 Anti-CTLA4 | IT | Virus day 12, anti-PD1 or anti-PD-L1 days 15, 18, 21 Virus day 8, anti-CTLA4 days 8, 11, 14 Virus day 8, combination anti-PD1 anti-CTLA4 days 8, 11, 14 | Earlier (day 8) virus and simultaneous ICI administration yielded best outcomes | [108] |
HSV1716 | M3-9-M and 76-9 rhabdomyosarcoma | Anti-PD1 | IT | Virus days 0, 2, 4, ICI days 4, 7, 11 | Delayeda ICI administration improved survival | [109] | |
Maraba | MG1 | 4T1, EMT6, E0771 breast cancer | Anti-CTLA4 Anti-PD1 | IT neoadjuvant | Virus days 7–11 (daily), combination anti-CTLA4 and anti-PD1 days 21–29 (q2d) | Delayedb combination anti-CTLA4 and anti-PD1 ICI administration improved survival | [71] |
NDV | NDV LaSota | B16 melanoma | Anti-CTLA4 | IT | Virus and ICI days 7, 10, 13, 16 | Simultaneous ICI administration improved survival | [64] |
NDV LaSota | B16F10 melanoma and CT26 colon cancer | Anti-PD1 Anti-PDL1 | IT | B16F10 model: virus and ICI days 3, 5, 7, 9 CT26 model: virus and ICI days 7, 9, 11, 13 | Simultaneous ICI administration improved survival | [110] | |
Reovirus | Reovirus | 5TGM1-luc multiple myeloma | Anti-PDL1 | IV | Virus days 7, 14, 21, ICI day 22, q2d × 8 | Delayedb ICI administration improved survival | [111] |
Reovirus | GL261 glioma | Anti-PD1 | IV | Virus days 5–10, 12–17, ICI days 19, 21, 23 | Delayedb ICI administration combined with GM-CSF improved survival over virus + GM-CSF | [14] | |
Vaccinia | vvDD-Fcu1 | MCA205 sarcoma | Anti-PD1 Anti-CTLA4 | IT | Virus days 0, 3, ICI days 6, 9, 12 or ICI days 0, 3, 6, virus days 7, 10 | Delayeda ICI administration and anti-PD1 pretreatment improved survival | [76] |
vvDD-fused IL-15/IL-15Rα | MC38-luc colon cancer | Anti-PD1 | IP | Virus day 7, ICI days 7, 9 11, 13 | Simultaneous ICI administration improved survival | [112] | |
vvDD-mIL2 | MC38-luc colon cancer | Anti-PD1 Anti-PDL1 Anti-CTLA4 | IP | Virus day 9, ICI days 9, 11, 13, 15 | Simultaneous ICI administration improved efficacy (not for anti-CTLA4 antibody) | [69] | |
vvDD or B18R | Renca renal adenocarcinoma | Anti-CTLA4 | IV | Virus day 0, ICI days 4, 7, 10 or ICI days 0, 3, 6 | Only delayeda ICI administration improved efficacy | [75] | |
VSV | VSV gp100 or OVA | B16 or B16-OVA melanoma | Anti-PD1 Anti-TIM3 | IV | Virus days 8–28 (3 ×/week), ICI days 14–28 (3 ×/week), ACT days 7, 21 | Delayeda/overlapping ICI administration had no effect on survival vs. virus + ACT | [73] |
VSV-HIF2a, Sox-10,or c-Myc | GL261 glioma | Anti-PD1 Anti-CTLA4 | IV | Virus days 6, 8, 10, 13, 15, 17, ICI days 13, 15, 17 | Delayedb dual-ICI combination with all 3 TAA-expressing viruses improved survival over virus or virus + a single ICI | [66] | |
VSV-IFNβ-NIS | C1498.GFP AML | Anti-PDL1 | IV | Virus day 12, ICI days 15, 18, 21 | Delayeda ICI administration improved survival | [68] |
3.3 Combination Therapy in Clinical Trials
Virus family | Virus | Indication | Combination drug | Virus RoA | Dosing schedule | Timing comment | ClinicalTrials.gov identifier |
---|---|---|---|---|---|---|---|
Adenovirus | Ad-p53 | HNSCC | Nivolumab | IT | 3 × virus (week 1), nivolumab day 5 Combination repeats on week 1 of each cycle q4w | Delayed ICI (4 days) | NCT03544723 |
DNX-2401 | GBM, gliosarcoma | Pembrolizumab | IT | Virus day 1 Pembrolizumab day ~ 8, q3w | Delayed ICI (1 week) | NCT02798406 | |
Enadenotucirev | Advanced epithelial tumors | Nivolumab | IV | Unknown virus schedule Unknown nivolumab schedule | Unknown | NCT02636036 | |
ONCOS-102 | Anti-PD1-refractory metastatic melanoma | Cyclophosphamide Pembrolizumab | IT | Cyclophosphamide day – 1 Virus days 1, 4, 8 Pembrolizumab day 22, q3w | Delayed ICI (3 weeks) | NCT03003676 | |
VCN-01 | R/M HNSCC | Durvalumab | IV | Arm 1: virus IV day 1, durvalumab IV day 1, q4w Arm 2: virus IV day 1, durvalumab IV day 15, q4w | Simultaneous ICI or delayed ICI (2 weeks) | NCT03799744 | |
CVA21 | Cavatak | Uveal melanoma with liver metastases | Ipilimumab | IV | Virus days 1, 3, 8, q3w (up to 19 ×) Ipilimumab day 8, q3w (up to 4 ×) | Delayed ICI (1 week) | NCT03408587 |
Cavatak | Advanced melanoma | Pembrolizumab | IT | Virus days 1, 3, 8, q3w (up to 19 ×) Pembrolizumab day 8, q3w (up to 2 years) | Delayed ICI (1 week) | NCT02565992 | |
Cavatak | NSCLC | Pembrolizumab | IV | Virus days 1, 3, 8, q3w (up to 8 ×) Pembrolizumab q3w (up to 24 months) | Uncertain | NCT02824965 | |
HSV1 | HF-10 | Resectable advanced melanoma | Nivolumab | IT neoadjuvant | 9 × virus (5 × virus q1w then 4 × virus q2w) Nivolumab q2w × 7, surgery, nivolumab q4w up to 1 year | Uncertain | NCT03259425 |
T-VEC | Early breast cancer | Atezolizumab | Unknown | Virus days 1, 21, q2w Atezolizumab day 21, q2w | Delayed ICI | NCT03802604 | |
T-VEC | TNBC, CRC with liver metastases | Atezolizumab | IT | Virus day 1, q3w Atezolizumab day 1, q3w | Simultaneous ICI | NCT03256344 | |
T-VEC | Refractory lymphoma Advanced or refractory non-melanoma skin cancer | Nivolumab | IT | Virus days 1, 21, q2w Nivolumab day 21, q2w | Delayed ICI (3 weeks) | NCT02978625 | |
T-VEC | Malignant pleural effusion | Nivolumab | Intrapleural | Virus (unknown schedule) ± nivolumab (same day as virus) | Simultaneous ICI | NCT03597009 | |
T-VEC | Advanced melanoma | Pembrolizumab | IT | Virus day 1, q3w Pembrolizumab day 1, q3w | Simultaneous ICI | NCT02965716 | |
T-VEC | Unresected melanoma | Pembrolizumab | IT | Virus days 1, 21, q2w Pembrolizumab week 5, q3w | Delayed ICI (5 weeks) | NCT02263508 | |
RP1 | Melanoma, bladder, skin, MSI-high solid | Nivolumab | IT | 3 × virus in escalating doses q2w Unknown nivolumab schedule | Unknown | NCT03767348 | |
Maraba | MG1-E6/E7 | HPV-associated cancer | Ad-E6/E7 Atezolizumab | IV or IT + IV | Prime IM Ad-E6/E7 (– 14 days) 4 × IV MG1-E6/E7 (spread over 2 weeks) OR IV MG1-E6/E7 day 1, IT MG1-E6/E7 days 4,14 Atezolizumab day 43, q3w | Delayed ICI (6 weeks) | NCT03618953 |
MG1-MAGEA3 | Metastatic melanoma, CSCC | Ad-MAGEA3 Pembrolizumab Cyclophosphamide | IV or IT + IV | Ad-MAGEA3 IM day 1 ± CPA day – 3 Virus IV days 15,18, or IV day 15, IT days 22, 29, 36 (+ day 43, q3w IT boosters) Pembrolizumab q3w (start either day 1 or week 6) | Pre-virus ICI (– 2 weeks) or delayed ICI (4 weeks) | NCT03773744 | |
Reovirus | Reolysin | Advanced pancreatic adenocarcinoma | Chemotherapy Pembrolizumab | IV | Virus days 1, 2 q3w Chemotherapy combination day 1 q3w Pembrolizumab day 8 q3w | Delayed ICI (1 week) | NCT02620423 |
Reolysin | Advanced pancreatic cancer | Pembrolizumab | IV | Virus days 1, 2, 3, 8 + days 1, 8 q3w (up to 24 months) Pembrolizumab day 1, q3w | Simultaneous ICI | NCT03723915 | |
Vaccinia | PexaVec | Unresectable RCC | Cemiplimab | IV or IT | 3 × virus IT q2w or 4 × virus IV q1w, cemiplimab q3w Cemiplimab q3w: @PD, 3 × virus IT q2w | Uncertain | NCT03294083 |
PexaVec | Refractory CRC | Durvaumab Tremelimumab | IV | Virus days 2, 12, 16 cycle 1, day 2 cycle 2 Durvalumab day 1 each cycle Tremelimumab day 1 cycles 1–4 | Simultaneous ICI | NCT03206073 | |
PexaVec | Advanced solid tumors | Ipilimumab | IT | Virus up to 5 × (weeks 1, 3, 5, 9, + week 12 if PD) Ipilimumab up to 4 × IT (weeks 3, 5, 9, + week 12 if PD) | Delayed ICI (3 weeks) | NCT02977156 | |
PexaVec | HCC | Nivolumab | IT | Virus days 1, 15, 29 Nivolumab day 15 q2w | Delayed ICI (2 weeks) | NCT03071094 | |
VSV | VSV-IFNβ-NIS | Solid Tumors | Avelumab | IV | Virus day 1, avelumab day 1, q3w | Simultaneous ICI | NCT02923466 |
VSV-IFNβ-NIS | HNSCC, NSCLC | Pembrolizumab | IV | Virus day 1, pembrolizumab day 1, q3w | Simultaneous ICI | NCT03647163 |