Gene-Immune Therapy of Cancer: Approaches and Problems

Alekseenko, I. V.; Плешкан, В. В.; Kuzmich, A. I.; Kondratieva, Sofia A.

doi:10.1134/s1022795422040020

Cited by 4 publications

(5 citation statements)

References 93 publications

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“…A major disadvantage of currently approved immunotherapeutics is the systemic administration, which leads to severe (grade ≥ 3) systemic immune-related adverse events (irAEs), such as colitis, endocrinopathy, nephritis, liver toxicity, rash, pruritus or pneumonitis (16,27). Meanwhile the local intratumoral administration of immunotherapeutics as proteins (recombinant proteins, monoclonal antibodies) does not usually lead to pronounced antitumoral effects due to short protein half-life (hours) (28). One way to overcome these disadvantages is intratumoral geneimmune therapy, which allows for prolonged (days) and localized protein expression (29).…”

Section: Discussionmentioning

confidence: 99%

Non-viral-mediated gene transfer of OX40 ligand for tumor immunotherapy

Rakitina,

Kuzmich,

Bezborodova

et al. 2024

Front. Immunol.

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BackgroundImmune checkpoint blockade (ICB) is rapidly becoming a standard of care in the treatment of many cancer types. However, the subset of patients who respond to this type of therapy is limited. Another way to promote antitumoral immunity is the use of immunostimulatory molecules, such as cytokines or T cell co-stimulators. The systemic administration of immunotherapeutics leads to significant immune-related adverse events (irAEs), therefore, the localized antitumoral action is needed. One way to achieve this is intratumoral non-viral gene-immune therapy, which allows for prolonged and localized gene expression, and multiple drug administration. In this study, we combined the previously described non-viral gene delivery system, PEG-PEI-TAT copolymer, PPT, with murine OX40L-encoding plasmid DNA.MethodsThe resulting OX40L/PPT nanoparticles were characterized via gel mobility assay, dynamic light scattering analysis and in vitro transfection efficiency evaluation. The antitumoral efficacy of intratumorally (i.t.) administered nanoparticles was estimated using subcutaneously (s.c.) implanted CT26 (colon cancer), B16F0 (melanoma) and 4T1 (breast cancer) tumor models. The dynamics of stromal immune cell populations was analyzed using flow cytometry. Weight loss and cachexia were used as irAE indicators. The effect of combination of i.t. OX40L/PPT with intraperitoneal PD-1 ICB was estimated in s.c. CT26 tumor model.ResultsThe obtained OX40L/PPT nanoparticles had properties applicable for cell transfection and provided OX40L protein expression in vitro in all three investigated cancer models. We observed that OX40L/PPT treatment successfully inhibited tumor growth in B16F0 and CT26 tumor models and showed a tendency to inhibit 4T1 tumor growth. In B16F0 tumor model, OX40L/PPT treatment led to the increase in antitumoral effector NK and T killer cells and to the decrease in pro-tumoral myeloid cells populations within tumor stroma. No irAE signs were observed in all 3 tumor models, which indicates good treatment tolerability in mice. Combining OX40L/PPT with PD-1 ICB significantly improved treatment efficacy in the CT26 subcutaneous colon cancer model, providing protective immunity against CT26 colon cancer cells.ConclusionOverall, the anti-tumor efficacy observed with OX40L non-viral gene therapy, whether administered alone or in combination with ICB, highlights its potential to revolutionize cancer gene therapy, thus paving the way for unprecedented advancements in the cancer therapy field.

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Section: Discussionmentioning

confidence: 99%

Non-viral-mediated gene transfer of OX40 ligand for tumor immunotherapy

Rakitina,

Kuzmich,

Bezborodova

et al. 2024

Front. Immunol.

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“…The usual mode of delivery for immunomodulators is systemic because this route provides predictable pharmacokinetics and is considered to ensure full receptor occupancy in the tumor [ 54 ]. However, there is a problem in achieving therapeutic intratumoral concentrations in the absence of systemic toxicity, which is especially important for solid tumors [ 48 ]. Systemic toxicity that occurs during systemic administration often does not allow the use of optimal doses of drugs [ 55 ].…”

Section: “Act Locally—think Globally”mentioning

confidence: 99%

“…Due to many advantages—such as high local concentration, the possibility of the induction of the abscopal effect, and reduced off-target toxicity—intratumoral administration has been actively developed recently, as evidenced by the growing number of preclinical and clinical trials of drugs administered intratumorally. We have previously discussed this principle as applied to gene therapy [ 48 ], showing that the current development of gene therapy drugs may well follow this path. As applied to MNPs, this principle can be strengthened due to their innate properties, i.e., MNPs as exogenous agents, which activate the innate immune system through PRRs—in other words, acting as an adjuvant.…”

Section: “Act Locally—think Globally”mentioning

confidence: 99%

“…Since all the advantages of intratumoral administration in terms of basic principles to their use in gene therapy are considered in the above works [ 48 , 53 ], we will not repeat the previously analyzed examples. However, we will proceed to review data from clinical studies in which intratumoral administration was used.…”

Section: “Act Locally—think Globally”mentioning

confidence: 99%

“…Instead of trying to bypass the protective barriers of the tumor, we can deliver the drug to its very heart by intratumoral administration. In cancer patients, the immune cycle is inefficient, whereby cancer cells manage to implement the mechanisms of protection against the immune system [48,49]. Immune interactions in a cancer patient are wider than can be described by single steps and components; they comprise an emergent system in which exposure to individual agents can lead to unpredictable results [50], suggesting that such affectations should be carried out very carefully.…”

Section: The Cancer-immunity Cycle As a Target For Metal-based Adjuvantsmentioning

confidence: 99%

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Prospects for the Use of Metal-Based Nanoparticles as Adjuvants for Local Cancer Immunotherapy

et al. 2023

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Immunotherapy is among the most effective approaches for treating cancer. One of the key aspects for successful immunotherapy is to achieve a strong and stable antitumor immune response. Modern immune checkpoint therapy demonstrates that cancer can be defeated. However, it also points out the weaknesses of immunotherapy, as not all tumors respond to therapy and the co-administration of different immunomodulators may be severely limited due to their systemic toxicity. Nevertheless, there is an established way through which to increase the immunogenicity of immunotherapy—by the use of adjuvants. These enhance the immune response without inducing such severe adverse effects. One of the most well-known and studied adjuvant strategies to improve immunotherapy efficacy is the use of metal-based compounds, in more modern implementation—metal-based nanoparticles (MNPs), which are exogenous agents that act as danger signals. Adding innate immune activation to the main action of an immunomodulator makes it capable of eliciting a robust anti-cancer immune response. The use of an adjuvant has the peculiarity of a local administration of the drug, which positively affects its safety. In this review, we will consider the use of MNPs as low-toxicity adjuvants for cancer immunotherapy, which could provide an abscopal effect when administered locally.

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