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Why can Oncolytic virus (OV) boost the tumor immunity?
Why can Oncolytic virus (OV) boost the tumor immunity? Oncolytic virus (OV) has the ability to infect, replicate and dissolve malignant transformed tumor cells. This oncolytic activity enhances the therapeutic advantage and induces immunogenicity after tumor cell death, which increases the infiltration of CD8+ T cells into the tumor microenvironment.
This important feature of oncolytic viruses can heat up immune “cold” tumors, and its combination with other immunotherapies presents an attractive prospect.
1. Oncolytic virus
Oncolytic viruses have been widely developed as anti-cancer drugs. OV based on adenovirus, herpes simplex virus, reovirus, vaccinia virus, measles virus, Coxsackie virus and Newcastle disease virus has proven its efficacy and effectiveness in animal models. For safety, some OVs are undergoing clinical trials.
OV achieves its anti-tumor effect mainly through the dual mechanism of infecting and selectively killing tumor cells and inducing systemic anti-tumor immunity. Among them, strict control of tumor selectivity is a key consideration. The uptake of OV by healthy cells will cause it to flow to “non-targeted” tissues, thereby limiting the bioavailability of OV for tumor targeting. In recent years, with the development of “precision virus therapy”, OV has made significant progress in achieving stricter tumor selectivity.
In addition, another attractive feature of oncolytic viruses is the ability of the viral genome to encode therapeutic transgenes. Early research focused on transgenes with indirect toxicity to tumor cells, such as nitroreductase. However, due to many reasons, including low transfection/transduction efficiency of the vector, non-specific toxicity, and slow prodrug-drug conversion rate, the curative effect is limited.
Currently, more research is focused on adding transgenes encoding cytokines (such as IL-12, IL-2, IL-15 and GM-CSF) to stimulate the recruitment of immune cells to the tumor microenvironment (TME). The FDA and EMA have approved talimogenelaherparepvec (T-VEC, Imlygic™), a modified herpes simplex virus (HSV) expressing GM-CSF, for the local treatment of malignant melanoma, indicating their potential.
However, the efficacy of OV as a monotherapy is still limited, and the induction of tumor cell death by OV to release immunogenicity is of great significance for other immunotherapies. Based on this, OVs have been used in combination with other immunotherapies to further stimulate the host’s anti-tumor immune response.
2. OV and immune checkpoint inhibitors
Immune checkpoints, especially cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), are key components for maintaining peripheral tolerance and regulating immune response homeostasis. Although the therapeutic potential of ICIs has been fully demonstrated, the percentage of people who can benefit from this treatment is still very low. In this case, the oncolytic virus may provide a significant immune-enhancing effect.
Preclinical studies have proven that OV mJX-594 can sensitize ICI-resistant tumors and promote T cell infiltration in mouse tumors. Combined with anti-PD-1 therapy, tumor growth can be reduced by 70%. Similarly, another study demonstrated that the combined treatment of NDV and anti-CTLA-4 doubled the protection against tumor recurrence and enhanced tumor lymphocyte infiltration compared with mice treated with anti-CTLA-4 alone.
Similar results have also been confirmed in human trials. During the clinical trial for the treatment of stage IIB-IV melanoma, the immune response of patients receiving T-VEC and the treatment of ipilimumab was studied. Compared with the limited response observed with ipilimumab monotherapy, the combined treatment demonstrated increased CD4+ICOS+ T cells are associated with significantly improved treatment outcomes. The potential synergy of OVs and ICIs has made their combined application in clinical trials very popular, and multiple combinations are currently being evaluated.
In addition, oncolytic viruses are excellent candidates for increasing antibodies produced locally at tumor sites. OVs transgenic encoding ICI antibody has entered clinical evaluation. Although the number is limited, with the advancement of technology, the number of clinical trials will certainly increase rapidly.
3. OV and CAR-T cells
Chimeric antigen receptor (CAR) T cells have also achieved remarkable success in hematological malignancies. However, due to TME’s inhibition of CAR-T cell transport and penetration, and the current lack of excellent targets in solid tumors, its therapeutic efficacy in solid tumors is limited.
However, recent studies have used a uniquely designed OV to express truncated form of CD19 on infected tumor cells, and “mark” these cells to facilitate the killing of tumor cells by CD19-CAR-T cells, which increases The tumor infiltration of T cells improves the survival rate of mouse melanoma and colorectal cancer models.
In addition, some people have explored the use of CAR-T cells as OV vectors to direct the virus to tumor cells. These examples show that OV can also provide additional benefits for CAR-T therapy.
4. OV and bispecific antibodies
Bispecific antibody T cell targeted therapy activates T cells or NK cells by binding to CD3/CD16 or tumor-specific antigens, leading to tumor cell lysis. Bispecific antibody drugs have achieved preclinical and clinical success, and are currently one of the hottest research fields.
Nevertheless, bispecific antibodies are still limited by toxicity, half-life, tumor retention ability, and the inability to produce durable immune memory. In response to this situation, an oncolytic adenovirus (ICOVIR-15K) was developed, which was designed to express BiTE (cBITE) that targets EGFR. In the co-culture test, oncolysis caused T cell activation and proliferation, and enhanced cytotoxicity. ICO15K-cBITE has been proven to be tumor-selective. Compared with the parental virus, intratumoral injection increased the persistence and accumulation of tumor-infiltrating T cells in the body, and showed enhanced anti-tumor activity in animal models.
Another example is an oncolytic virus expressing Fibroblast Activation Protein (FAP) targeted BiTE (fBiTE). In this way, immune cells are redirected to tumor stromal fibroblasts to improve tumor permeability and help virus spread.
A new form of bispecific antibodies is immune mobilization anti-tumor monoclonal TCRs (ImmTACs), which use TCRs to specifically bind to target cells. General bispecific antibodies are limited by the recognition of cell surface antigens. In contrast, IMMTAC can recognize intracellular antigens through peptide fragments provided by human leukocyte antigen (pHLA). Although the current data on the combined application of ImmTACs and OV are limited, the tumor-specific expression of ImmTACs of OV may have significant advantages in improving efficacy and reducing toxicity.
In addition, oncolytic viruses can easily be designed as a combination of different immunotherapies, including BiTE, cytokines, and ICIs. CAdTrio is an adenovirus that encodes IL-12, anti-PD-L1 antibody and specific BiTE against CD44v6. It is used in combination with HER-2-CAR-T cells to significantly improve tumor control in mouse animal models. And survival rate.
A large amount of evidence indicates that OVs and other immunotherapies have the potential to work synergistically, whether as a combination therapy or as a transgene into the OV genome.
At present, more and more combinations of OV and immunotherapy are appearing in the pre-clinical and clinical research phases. However, in view of the existence of multiple OV types, targeting strategies, and immune killing methods, finding the optimal combination of this combination therapy is still the first choice. Challenges.
It is believed that with the continuous deepening of clinical research, OV will bring more possibilities and better prospects for tumor immunotherapy.
(source:internet, reference only)