ONCOS-102

Together, our data suggests that oncolytic adenoviruses encoding ICOSL may enhance functional activity of tumor-specific BsAbs thereby opening a novel avenue for clinical development in immunotherapeutics.

ONCOS-102 plus pemetrexed and cisplatin/carboplatin was well tolerated by patients with MPM. In injected tumors, ONCOS-102 promoted a proinflammatory environment, including T-cell infiltration, which showed association with survival at month 18.

P2, N=0, Withdrawn, Targovax Oy | N=63 --> 0 | Not yet recruiting --> Withdrawn

P2, N=63, Not yet recruiting, Targovax Oy | Initiation date: Dec 2022 --> Jan 2024

Intratumoral injection of ONCOS-102, a chimeric oncolytic adenovirus expressing GM-CSF, into anti-PD-1 resistant melanoma with administration of pembrolizumab was safe and effective. Response to therapy was associated with increased lymphocyte infiltration and expression of cytotoxicity and co-stimulatory genes.

ONCOS-102 plus pembrolizumab was well tolerated and led to objective responses in patients with anti-PD-1 resistant advanced melanoma. ONCOS-102 promoted T-cell infiltration, particularly cytotoxic CD8+ T cells, which persisted at Week 9, driving clinical benefit. Further investigation of ONCOS-102 plus PD-1 blockade is warranted.

We recently completed phase I/II testing of ONCOS-102, a GM-CSF-encoding oncolytic adenovirus (Ad5/3-D24-GMCSF), for therapeutic efficacy and capacity to remodel tumor micro-environment (TME) in combination with pembrolizumab (pem) in patients (pts) with non-resectable, stage III-IV, anti-PD-1 resistant/refractory (R/R) melanoma (NCT03003676). ONCOS-102 drives pro-inflammatory modulation of the TME in PD-1 R/R melanoma tumors. Clinical response ONCOS-102 is associated with efficient viral gene expression and strong, sustained activation of immune-related genes, which may be targets for future combinations of ONCOS-102 and immune-modulators beyond PD-1/PD-L1 inhibitors.

This review focuses on the current status of IT agents currently under clinical trials in melanoma. Reviewed therapies include T-VEC, T-VEC with immune checkpoint inhibitors including ipilimumab and pembrolizumab or other agents, RP1, OrienX010, Canerpaturev (C-REV, HF10), CAVATAK (coxsackievirus A21, CVA21) alone or in combination with checkpoint inhibitors, oncolytic polio/rhinovirus recombinant (PVSRIPO), MAGE-A3-expressing MG1 Maraba virus, VSV-IFNbetaTYRP1, suicide gene therapy, ONCOS-102, OBP-301 (Telomelysin), Stimulation of Interferon Genes Pathway (STING agonists) including DMXAA, MIW815 (ADU-S100) and MK-1454, PV-10, toll-like receptors (TLRs) agonists including TLR-9 agonists (SD-101, CMP-001, IMO-2125 or tilsotolimod, AST-008 or cavrotolimod, MGN1703 or lefitolimod), CV8102, NKTR-262 plus NKTR-214, LHC165, G100, intralesional interleukin-2, Daromun (L19IL2 plus L19TNF), Hiltonol (poly-ICLC), electroporation including calcium electroporation and plasmid interleukin-12 electroporation (pIL-12 EP), IT ipilimumab, INT230-6 (cisplatin and vinblastine with an amphiphilic penetration enhancer), TTI-621 (SIRPαFc), CD-40 agonistic antibodies (ABBV-927 and APX005M), antimicrobial peptide LL37 and other miscellaneous agents.

To date, Talimogene laherparepvec is the only FDA approved oncolytic virus (OV), however, many other types of OVs are showing promising results in clinical studies. One example is ONCOS-102, an adenovirus serotype 5/3 chimera expressing GM-CSF as a transgene, which recently reported 33% ORR in advanced anti-PD1 refractory melanoma.Genetically engineered OVs can be armed with different co-stimulatory molecules in order to boost the anti-tumour immune responses...The double transgenes were shown to act synergistically in vivo, in line with the design hypotheses and proposed mode of action to induce cell lysis and prevent tumor growth. Moreover, the vectors were able to increase tumor infiltration of various immune subsets including CD4+, CD8+, CD8+ expressing PD1+ or CD8+ expressing Granzyme B T cells and reduction of regulatory T-cells and MDSC in the tumour microenvironment, suggesting an ability to prime immune-suppressive tumors to better respond to immunotherapy.These encouraging preclinical findings will be further investigated to elucidate the mode of action and perform toxicological studies to bring ONCOS-210 and ONCOS-212 towards clinical testing.

Furthermore, retrospective analyses of a phase I clinical trial of ONCOS-102 treatment of 12 patients with varied tumors indicated a correlation between viral genomes in blood and DSG2 RNA expression. These data support the role of DSG2 expression on cancer cells in virus infectivity and the continued development of ONCOS-102 for ovarian cancer treatment (NCT02963831).

Combination of durvalumab and IP ONCOS-102 was safe, and no DLTs were observed. Preliminary analyses demonstrate evidence of biologic and clinical activity. Phase 2 enrollment is ongoing.

This cavity-localized cancer lends itself to local administration of modalities, such as the oncolytic adenovirus (Ad) Ad5/3-D24-GM-CSF virus (ONCOS-102)...Furthermore, retrospective analyses of a phase I clinical trial of ONCOS-102 treatment of 12 patients with varied tumors indicated a correlation between viral genomes in blood and DSG2 RNA expression. These data support the role of DSG2 expression on cancer cells in virus infectivity and the continued development of ONCOS-102 for ovarian cancer treatment.

4 pts had previous anti-CTLA4, 3 T-VEC, 2 BRAFi/MEKi, 1 IL-2 and 1 TLR9 agonist. ONCOS-102 combined with pembrolizumab is tolerable and appears to induce systemic and lesional immune activation that can lead to objective responses in anti-PD-1 refractory melanomas. An expansion cohort is currently enrolling pts to receive up to 24 weeks of ONCOS-102 injections.