Upgraded armed strategies for five oncolytic viruses!

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Upgraded armed strategies for five oncolytic viruses!

Upgraded armed strategies for five oncolytic viruses!  On June 11, Daiichi Sankyo Co., Ltd. announced that its oncolytic virus product Delytact (teserpaturev/G47∆) was approved by the Japanese Ministry of Health, Labour and Welfare (MHLW) for the treatment of malignant glioma.

This is the fourth oncolytic virus product approved globally and the first oncolytic virus product approved for the treatment of glioblastoma.

Oncolytic viruses have been proven to regulate the immune microenvironment, reduce suppressive immune phenotypes, and enhance anti-tumor immunity. This article analyzes several armed strategies of oncolytic viruses and combined with other tumor immunotherapy directions.

Oncolytic virus induces anti-tumor immunity (picture from literature 8)

1.  Armed strategy of oncolytic virus

1.1 Arming oncolytic viruses with tumor antigens

The oncolytic virus lyses the tumor locally and releases TAAs and TANs, which is similar to tumor vaccines. But sometimes it is not enough to induce tumor-specific T cell responses.

Ways to improve

Integrating the TAAs encoding gene into the genome of the oncolytic virus allows the oncolytic virus to express a larger amount of TAAs (such as HER2, HPV E6, E7, MAGE-A3, etc.) to induce tumor-specific T cell immune responses.

Clinical Trials

NCT02285816:MG1Maraba/MAGE-A3, With andWithout Adenovirus Vaccine With Transgenic MAGE-A3 Insertion in IncurableMAGE-A3-Expressing Solid Tumours, Canadian Cancer TrialsGroup/Ottawa Hospital Research Institute.

Using MG1 Maraba oncolytic virus, engineered to express melanoma-associated antigen-A3 (melanoma-associatedantigen-A3, MAGE-A3) to treat solid tumors expressing MAGE-A3. It is currently activated and not recruited.

NCT02879760:Oncolytic MG1-MAGEA3 WithAd-MAGEA3 Vaccine in Combination With Pembrolizumab for Non-Small Cell LungCancer Patients, Turnstone Biologics, Corp.

Use MG1-MAGEA3 combined with K drug to treat non-small cell lung cancer.

1.2 Arming oncolytic viruses with immune stimulating cytokines

The most commonly used cytokine is GM-CSF. The local release of GM-CSF by oncolytic virus can promote the maturation and migration of DC cells and enhance the immune response of T cells.

The first oncolytic virus product T-VEC (Talimogene Laherparepvec/T-VEC/Imlygic, BioVex Limited/Amgen) approved by the FDA and EMA is an oncolytic virus expressing GM-CSF. The phase III clinical trial (NCT00769704) showed obvious Improve DRR, ORR and PFS in patients with melanoma (Reference 2).

IL-12 is a multifunctional cytokine that activates innate immunity and adaptive immunity. It is the main coordinator of anti-tumor Th1 immunity and is also used to arm oncolytic viruses.

NCT02062827: Genetically Engineered HSV-1 Phase 1 Study for the Treatment of Recurrent Malignant Glioma (M032-HSV-1), the oncolytic virus HSV-1 genetically engineered to express IL-12 to treat recurrent malignant glioma.

Other cytokines IL-2, IL-15 and IL-18 are also under investigation.

1.3 Arming oncolytic viruses with immune activating ligands

i

CD40L is currently the most researched.

CD40 is a superfamily of tumor necrosis factor receptors. It is expressed on antigen-presenting cells such as DC, while CD40L is expressed on activated CD4+ T cells, B cells, NK cells, and memory CD8+ T cells.

At present, multiple CD40L oncolytic viruses are in clinical development, and the results show that: control tumor growth, induce tumor cell apoptosis, induce T cell response, up-regulate Th1 cell response, and effector T cell ratio.

NCT01455259: Phase I/IIa AdCD40LImmunogene Therapy for Malignant Melanoma and Other Solid Tumors, Uppsala University (Reference 3)

OX40 is another tumor necrosis factor receptor superfamily. Its ligand is OX40L. Through OX40L/OX40, it promotes the survival and homeostasis of effector and memory T cells, while controlling the differentiation and function of regulatory T cells.

NCT03714334:DNX-2440 OncolyticAdenovirus for Recurrent Glioblastoma, DNAtrix, Inc.

The dual ligand, currently in the clinical stage is Lokon Pharma’s LOAd703, which is genetically engineered into CD40L and 4-1BB, and two clinical trials are underway:

• NCT02705196: LOAd703 Oncolytic Virus Therapy for PancreaticCancer, LokonPharma AB;
• NCT03225989:TrialInvestigating an Immunostimulatory Oncolytic Adenovirus for Cancer, Lokon Pharma AB/UppsalaUniversity

1.4 Arming oncolytic viruses with chemokines

Chemokines are the largest subfamily of cytokines, which mediate immune cell migration and lymphatic tissue development. The chemokines under study include CCL5 (which can increase the local survival time of cell tumors), CLL19 (control tumor growth, increase DC, CD4+T cell migration to the tumor microenvironment), CCL20, CCL21, etc.

1.5 Arming oncolytic viruses with BiTE

BiTE is the most commonly used molecular design scheme for bispecific antibodies, which recruits and activates T cells through CD3 antibodies, thereby killing target cells. There are currently some designs in the preclinical stage, for example: EnAd-SA-EpCAM contains CD3scFv and EpCAM scFv (Reference 4).

2.  Oncolytic virus combined with other tumor immunotherapies

2.1 Combined immune checkpoint inhibitor

Ipilimumab combined with T-VEC

NCT01740297: Ipilimumab With or Without Talimogene Laherparepvec in Unresected Melanoma, Amgen, Phase 2.

Clinical results:

OR: 39% in combination and 18% with ipilimumab alone; lesion reduction rate: 52% in combination and 23% with ipilimumab alone. The combination significantly improved OR and reduced lesions (Reference 5).

Pembrolizumab combined with T-VEC

NCT02263508: Pembrolizumab With or Without Talimogene Laherparepvec or Talimogene Laherparepvec Placebo in Unresected Melanoma (KEYNOTE-034), Amgen/Merck Sharp & Dohme Corp. Phase1b/3. In previous clinical studies, the ORR of the combination was as high as 62%, and the CR reached 33% (Reference 6).

There are currently dozens of combined clinical trials in progress:

2.2 DC vaccine combined with oncolytic virus

Oncolytic viruses can improve the inhibitory environment of the tumor microenvironment, and recruit immune cells, and then add DC vaccine to activate T cells, which can greatly enhance T cell function.

Some clinical trials are underway:

• NCT03747744: Intratumoral Injection ofAutologous CD1c (BDCA-1)+ Myeloid Dendritic Cells Plus Talimogene Laherparepvec(T-VEC) (myDCTV), Universitair Ziekenhuis Brussel, Phase1
• NCT03514836:A Phase I/II, SafetyClinical Trial of DCVAC/PCa and ONCOS-102 in Men With MetastaticCastration-resistant Prostate Cancer, Sotio a.s. Phase1/2

Summary

Compared with other tumor immunotherapies, oncolytic viruses are still at a relatively early stage of development, but they also show synergistic enhancement with other immunotherapies. Compared with the slightly crowded antibody immune pipeline, oncolytic viruses may not be a good layout.

(source:internet, reference only)

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