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November 19, 2022 / eMedClub News / -- November 17, 2022, Nature Cancer In an article titled "An armed oncolytic virus for GBM destruction," an oncolytic herpes simplex virus (oHSV) that carries a bispecific EGFR-CCL5 antibody fusion protein that activates innate and adaptive anti-tumor immune responses has shown extremely high efficacy in preclinical models of glioblastoma (GBM).
。
.
At present, the most basic means of treating GBM is still surgical resection and the combination of radiotherapy and chemotherapy to remove residual tumor cells after surgery, but this treatment option has not made major breakthroughs
in the past four decades.
Factors hindering the therapeutic effect of GBM include the presence of glioma stem cells (GSCs) with drug resistance and stem cell properties, tumor heterogeneity, treatment resistance, immunosuppressive tumor microenvironment (TME) and blood-brain barrier (BBB), which together promote tumor growth and inhibit anti-tumor immune response
。 Previous nivolumab, pembrolizumab, and durvalumab for gliomas did not meet the primary endpoint in clinical trials, and overall survival did not improve
.
In this issue of Nature Cancer, City of Hope researchers also describe a multimodal treatment for GBM, similarly expressing a bispecific antibody-chemokine fusion protein with an oHSV, consisting of a single-stranded variable fragment (s) of the EGFR antibody cetuximab cFv) is linked by immunoglobulin G1 (IgG1) Fc fusion with the chemokine C-C motif ligand 5 (C CL5), an oncolytic virus the researchers refer to as OV-cmab-CCL5
.
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in mice that receive in situ GBM xenotransplantation and allogeneic transplantation of humans and mice respectively, This oncolytic virus successfully "heats" the immunity of "cold" tumors and leads to significantly longer
survival.
To further confirm the immunomodulatory capacity of this OV-cmab-CCL5 oncolytic virus, the researchers established an isogenic mouse tumor model
in immunocompetent mice.
The in vitro activity of OV-cmab-CCL5 in mouse cells is similar to that in human cells, and in vivo, OV-cmab-CCL5 significantly prolongs survival time in mouse models and is more effective
than OV-Q1 (oncolytic virus blank control) and recombinant OV-cmab-CCL5.
The results of unilateral treatment of mouse models implanted with bilateral GBM showed that OV-cmab-CCL5 likewise significantly prolonged the survival of mice and could induce immune cell infiltration into untreated contralateral tumors
.
Overall, this armed oHSV caused six different antitumor activities with a single viral structure:
- oHSV infection of tumor cells induces inflammatory response and immune stimulation;
- direct tumor-selective cytotoxic effect of oHSV;
- Locally expressed CMAB blocks EGFR signaling and precisely targets CCL5 to tumor cells.
- Secretes CCL5 (cbab - CCL5), recruits and activates T cells, macrophages and NK cells;
- Fc binds to tumor cells to induce NK-mediated ADCC;
- Fc binds to tumor cells to induce macrophage-mediated ADCP
.
▲ OV-CCAB-MCCL5 antitumor activity Image source: Reference 1
for patients through further studies and clinical trials.
The "armament" of oncolytic viruses
In recent years, oncolytic viruses have attracted more and more attention as a treatment that can be successful in the field of solid tumors, but oncolytic viruses must be able to enter tumor target cells to exert their anti-tumor activity, and the virus itself may cause the patient's own immune response, and viruses that induce a strong immune response may mediate strong anti-tumor immunity, but they may also be clearedfaster by the immune system.
The combination of oncolytic virus with other immunotherapies can synergistically overcome the limitations of single administration, and another improvement is to arm the oncolytic virus with therapeutic transgenes so that it is locally expressed and targeted to non-infected tumors and normal cells
.
At present, a number of oncolytic virus therapies equipped with other therapeutic genes are under development, including macrophage colony spike factor (GM-CSF), IL-12 or PD-1 antibodies
.
Oncolytic herpes simplex virus (oHSV)
Talimogene laherparepvec (T-vec), also known as Imlygic and developed by Amgen's subsidiary Biovex, is the first oncolytic virus approved for marketing in the United States and Europe for the treatment of advanced melanoma.
The virus inserts the GM-CSF gene, which induces lysis of tumor cells, while GM-CSF promotes an anti-tumor immune response
.
Oncolytic adenovirus (OAds)
Ad5-yCD/mutTKSR39rep-hIL12 is a replicating oncolytic adenovirus expressing the human IL-12 gene and two suicide genes, HSV-TK and yCD.
Both suicide genes expressed by this oncolytic virus were successfully converted to their respective prodrugs, inducing irreversible inhibition of DNA synthesis and producing potent antitumor effects, while improving the induction
of anti-tumor immune responses by expressing hIL-12.
There are currently two Phase 1 clinical trials underway to evaluate its efficacy and safety
in patients with prostate cancer or metastatic pancreatic cancer.
ONCOS-102, developed by Targovax, is an oncolytic adenovirus (Ad5/3-D24-GMCSF) expressing GM-CSF, and the latest data from the Phase 1/2 clinical trial of Pemetrexed/cisplatin (P/C) in patients with unresectable malignant pleural mesothelioma were presented at this year's ASCO Conference.
Median OS was prolonged in patients; There is also a clinical trial underway in combination ONCOS-102 and Keytruda
.
Oncolytic vaccinia virus (VV)
Pexa Vec (pexastimogene devacirepvec, JX-594), developed by Transgene, expresses the human GM-CSF gene and is well tolerated in patients with refractory solid tumors, showing a good safety profile.
In a Phase 3 clinical trial of PHOCUS, Pexa-Vec plus Nexavar failed to meet the desired endpoint
.
However, several other clinical studies are evaluating the efficacy and safety
of Pexa-Vec in other solid tumors.
brief summary
Oncolytic virus is a century-old tumor immunotherapy method, but only in recent years through the "east wind" of genetic engineering technology to break through the original limitations, with high killing efficiency, good targeting, small side effects, a variety of tumor killing pathways and low cost and other advantages, has become one of the most promising tumor therapies, according to Sullivan predicts, by 2025, the overall global oncolytic virus market size will reach 6.79 billion US dollars
.
With the development of gene editing technology, oncolytic viruses equipped with cytokines and antibody drugs have become one of the hot areas of research and development, and the combination of administration with other immunotherapies to enhance killing has also achieved the result
of one plus one greater than two in clinical trials 。 At present, the research and development of oncolytic viruses at home and abroad is in full swing, many companies are actively deploying in this field, and the fastest domestic drug candidates have also advanced to clinical phase 3, and in the future, oncolytic virus therapy will be promoted to the clinic more rapidly and diversified, so as to better meet the clinical needs
of patients.
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