Table 2 Clinical trials of cancer therapy involving RLRs activation

5′-pppRNA

MK-4621

Pembrolizumab

Solid tumors

I

OR with MK-4621 monotherapy, 0; SD, 4 (27%). PR with combination therapy, 3 (10%)

NCT03065023 NCT03739138

[280]

Synthetic dsRNA

BO-112

Nivolumab or pembrolizumab

Tumors that had primary resistance to anti-PD-1

I

PR and SD with combination therapy at 8–12 weeks, 3/28 (10.7%) and 10/28 (35.7%), respectively

NCT02828098

[287]

Peptide-complexed ssRNA with poly-U repeats

CV8102

HepaVac-101 (therapeutic vaccine)

HCC

I/II

Immune responses against ≥ 1 vaccinated HLA class I and II TAA, 37% and 53%, respectively

NCT03203005

[282]

ssRNA

CV8102

Anti-PD-1 therapy

Advanced melanoma; squamous cell carcinoma of the skin, head and neck; adenoid cystic cancer

I

Estimated study completion date, February 2023

NCT03291002

[281]

Oncolytic virus

T-VEC

Pembrolizumab

Advanced/metastatic sarcoma

II

Best ORR at 6 mo: 30%. ORR overall, 35%

NCT03069378

[291]

Oncolytic virus

VSV

Ruxolitinib phosphate

Advanced treatment-refractory T cell lymphoma

I

3/7 patients with T-cell lymphoma had responses: 2 PR at 3 mo and 6 mo, respectively; 1 CR ongoing at 20 mo

NCT03017820

[292]

Oncolytic virus

Pexa-Vec/ JX-594

Metronomic cyclophosphamide

Advanced/metastatic soft tissue sarcoma

II

Combination therapy is not superior to metronomic cyclophosphamide alone (median PFS, 1.7 mo vs 7 mo; OS, 14.2 mo vs not reached

NCT02630368

[297]

Oncolytic virus

Pexa-Vec

Avelumab

Soft tissue sarcoma

I/II

Ongoing

NCT02630368

/

Oncolytic virus

Pexa-Vec

Surgical treatment

Colorectal cancer liver metastases or metastatic melanoma

II

Presurgical treatment with Pexa-Vec was associated with IFNα and chemokine induction, resulting in transient innate and long-lived adaptive anticancer immunity

EudraCT number 2012–000,704-15

[298]

Oncolytic virus

Pelareorep (reovirus)

Paclitaxel

Metastatic breast cancer

II

Median adjusted PFS (combination therapy vs paclitaxel alone), 3.78 mo vs 3.38 mo; Median OS (combination therapy vs paclitaxel alone), 17.4 mo vs 10.4 mo

NCT01656538

[303]

Oncolytic virus

Pelareorep

Pembrolizumab, and either 5-fluorouracil, gemcitabine, or irinotecan

Advanced pancreatic adenocarcinoma

Ib

Partial response for 17.4 mo, 1/10; SD, 2/10, lasting 9 and 4 mo, respectively

NCT02620423

[305]

Viral mimicry

Azacitidine

Nivolumab

Relapsed/refractory AML

Ib/II

ORR,33%; CR, 22%; 1 PR, 10% with hematologic improvement maintained > 6 mo. SD (> 6 mo), 10%; ORR was 58% and 22%, in hypomethylating agent-naïve and HMA-pretreated patients, respectively

NCT02397720

[307]

Viral mimicry

Azacitidine

Camrelizumab

Relapsed/refractory classical Hodgkin lymphoma

II

CR, 79% in the decitabine-plus-camrelizumab group vs 32% in camrelizumab group. Median PFS with decitabine-plus-camrelizumab therapy, 35.0 mo; 15.5 mo with camrelizumab monotherapy

NCT02961101

NCT03250962

[311]

Viral mimicry

Decitabine

Camrelizumab

Relapsed/refractory classical Hodgkin lymphoma after prior anti-PD-1 monotherapy

II

ORR, 52%; CR, 36% in the test cohort. ORR, 68%; CR, 24% in the expansion cohort. Median PFS in the test cohort and expansion cohort, 20 and 21.6 mo, respectively

NCT02961101

NCT03250962

[312]

Viral mimicry

Guadecitabine

Pembrolizumab

Advanced solid tumors

I

ORR, 7% with 37% achieving disease control (PFS) for ≥ 24 weeks. 5/12 (42%) NSCLC patients have disease control ≥ 24 weeks

NCT02998567

[314]

Viral mimicry

Entinostat

Pembrolizumab

Metastatic uveal melanoma

II

ORR,14%. CBR 18 weeks, 28%; median PFS2.1 months; median OS, 13.4 months. Toxicities were manageable, and there were no treatment-related deaths

NCT02697630

[316]

Chemotherapy

Capecitabine and oxaliplatin

Pembrolizumab

Advanced biliary tract carcinoma

II

PR, 27.3%; SD, 54%. Disease control rate, 81.8%. Median PFS, 4.1 mo with a 6 mo PFS rate of 45.5%

NCT03111732

[319]