Cancer immunotherapy new technology - lysolytic tumor fake virus.

Since immuno-checkpoint inhibitors were first successfully applied to melanoma patients, anti-cancer immunotherapy has become diversified, and combined radiotherapy and chemotherapy have become the standard of treatment for a variety of malignant tumor adaptations.
currently approved immunotherapy includes monoclonal antibodies for immunosuperials and tumor-related antigens, immunostulation cytokines, CAR-T cells, cancer vaccines based on dexterous cells, and locally applied lysovirus therapies.
A growing body of preclinical evidence supports the view that not only local viral therapies, but also non-viral therapies (laser, microwave, radio frequency or photothermal therapy; high-intensity focused ultrasound; cryotherapy; photodynamic therapy; and cytotoxins used in tumors) can also promote systemic anti-tumor immunity by inducing immunogenic cell death (immunogenic cell death, ICD), which leads to long-lasting damage to treated lesions and far-end anti-tumor effects.
, however, the clinical success of these "viral-free" approaches has been limited, prompting calls for new and more effective ways to turn tumors into their own "vaccines".
co-stimulating ICD, inflammation and immune activation are important research directions for cancer immunotherapy.
, however, even multidrruprocial therapies often fail to trigger all the steps needed for self-sustaining anti-tumor immunity.
August 10, scientists from the Massachusetts Institute of Technology published a paper in the journal Nature Cancer that proposed a platform for prosthetic viruses that can stimulate local and systemic cancer responses by activating multiple immune stimulation pathfects at the same time.
photo source: Nature cancer Specifically, they designed synthetic lipid nanoparticles that simulate certain characteristics of the virus but are not at risk of infection. LNP) fake virus platform - LNP-Rep-(IL-12), which combines three key elements: (1) an LNP component that effectively promotes ICD;
LNP-Rep-(IL-12) carries self-replicating RNA, which promotes innate immune stimulation and induces ICD in tumor cells through Tol-like subject 3-sensing viral RNA.
in the ICD process, dead cancer cells release damage-related molecular patterns (DAMP), such as ATP, high-migration family protein B1 (HMGB1) and calcium mesh protein.
DAMP is an important auxiliary signal that actes on pattern recognition subjects expressed by dexterity cells to facilitate their collection and activation, and then the dexterity cells ingest tumor antigens and cross-deliver antigens to cytotoxic lymphocytes in a three-stage lymphatic structure constructed within the tumor microenviron environment (see figure below).
combination, which aims to kill cancer cells and identify receptors through the DAMP stimulation pattern, constitutes a clever strategy for "igniting" cancer immunity.
Photo Source: Nature cancer In this new study, mouse melanoma model experiments show that the treatment of LNP-Rep-12 can cause tumors in mice to subside and improve their survival rate, but not with blank LNP treatment.
further evidence that cancer cells ingest the fluorescent marker LNP-Rep-(IL-12).
addition, the presentation of THEMP calcium mesh protein and the expression of type I interferon after intra-tumor injection of LNP-Rep-(IL-12) led to the remodeling of immuno-immersion in the tumor microenvironment.
this jointly supports the conclusion that LNP-Rep-(IL-12) induces ICD in the body.
the possibility of equipping fake viruses with RNA-coded immunostulation cytokines will help them continue to optimize for greater effectiveness.
MIT scientists chose to bind IL-12 to the surface of cancer cells by using a single-stranded variant fused into collagen binding protein lumican (rather than using the natural soluble form of IL-12), which avoids systemic inflammatory side effects of cytokines and ensures local immunostatulation.
The LNP-Rep-(IL-12) platform used in the study further promoted the expression of inflammatory cytokines, including IFN-cytokines, in tumor microenvironments and amplified the anti-tumor T-cell response, allowing melanoma and colon cancer model mice to completely alleviate and improve survival.
interestingly, when used in association with PD-1 inhibitors, synthetic proviral-mediated tumor eradication can effectively induce tumor subsidion (far-fluor effect) farther away from the injection site.
showed that the LNP-Rep-(IL-12) platform's intra-tumor injection-induced immunomodulation transcended the local environment and stimulated a systemic response from T-cells.
Injecting LNP-Rep-(IL-12) into multiple patient models of the same line of transplanted mice by intra-tumor injection can cause the tumor to subside and have a distant effect on the distant un-injected tumor, while producing immune memory to protect the mouse from tumor re-attack.
(Photo Source: Nature cancer) It is worth noting that T-VEC, the only lysovirus clinically approved for the treatment of melanoma( talimogene laherparepvec; a gene-modified herpes virus type 1 that expresses cytokine GM-CSF), can induce an anti-tumor immune response, resulting in far-end metastasis in patients who also receive systemic immunopsychase inhibitors.
this, the application of lysovirus in cancer treatment is limited by the complexity of its manufacturing process, the regulatory restrictions on potential sources of infection, and the protection of its clinical drug flow.
platform solves some of the problems of lysovirus treatment.
, however, local immunotherapy must consider another limitation based on cancer biology, namely that tumor metastasis often loses the expression of the main tissue-compatible complex class I (MHC1) so that it cannot be identified by cytotoxic T lymphocytes.
the relationship between the immune system and natural viruses is complex as a result of the co-evolution of host-pathogens.
immune system has evolved to recognize and eliminate infectious microorganisms, but viruses can only exist if they are not identified by the host defense system.
, for example, auto-responses to the most primitive cells of viral infections include blocking the synthesis of viral proteins and mobilizing autophagy mechanisms to isolate and destroy pathogens in cells.
both events depend on the activation of the "integrated stress response", the e-core translation starting factor eIF2 alpha is the key to the phosphatization of specific kinases.
is not surprising that viruses have evolved strategies to suppress integrated stress responses, thus avoiding cellular autologic responses and immune identification.
T-VEC has been designed to inhibit eIF2 alpha phosphorylation.
, by contrast, the other advantage of fake viruses is that they do not have the burden of "carving" into the natural course of the virus gene, which avoids unnecessary immunosuppression due to the integration of stress responses, interferon reactions, or other circuit damage.
in short, it would be tempting to speculate that the lysolytic false virus platform would have a therapeutic effect on solid tumors that can be injected into the tumor.
in future clinical trials, the method may be used in therapeutic applications that can be injected into solid tumors.
(Photo: Nature cancer) Looking ahead, it will be important to explore preclinical studies of tumor models that use fake viruses to fight antigen heterogenic carcinogens rather than transplants.
addition, there is growing preclinical and clinical evidence that chemotherapy, which induces ICD, is better than these monotherapy drugs in combination with immuno-checkpoint inhibitors.
, the platform proposed by MIT scientists also provides an opportunity to combine strategies with local or systemic immuno-checkpoint inhibitors.
, for example, RNA that encodes immune checkpoint inhibitors may be introduced into LNP to release local immune responses in an unprecedented manner.
reference: 1 singzhong Liet al. Multifunctional oncolytic nanoparticles deliver self-replicating IL-12 RNA to eliminate seted tumors and prime systemic immunity. Nature Cancer (2020) 2 s Oliver Kepp et al. Pseudovirus for immunotherapy. Nature Cancer (2020) 3 .Cong Luo et al. 4y and tumor immunogenic cell death. Journal of International Oncology (2017)