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GENOS IMMUNE PLUS SYSTEMIC REBALANCING

Mechanism of Action of GENOS Immune Plus in Oncology

Integrative Mechanism of Action 

In oncology, GENOS Immune Plus does not pursue an isolated single-target approach, but rather a systems biology model of functional immune reactivation. The focus is on restoring the immune system’s ability to recognize, target, and eliminate damaged or malignant cells via cytotoxic mechanisms.

The clinical data to date reveal three key patterns in particular:

  • significant increase in NK cell cytotoxicity

  • restoration of IL-2 responsiveness

  • stabilization of systemic immune axes such as CD4/CD8 and inflammatory markers

GENOS Immune Plus, as an epigenetically active magistral recipe (§21 AMG), is unique and addresses multiple levels simultaneously. It does not produce linear immunosuppression, but rather a measurable rebalancing of inflammatory, angiogenic, and immunocellular signaling axes.

GENOS Immune Plus does not act as an isolated immunostimulator, but as a functional network modulator.

It addresses cellular immune function as well as the inflammatory microenvironment:

  1. NK cell reactivation via NKG2D/NCR activation and reduction of inhibitory dominance

  2. Restoration of IL-2 responsiveness as a sign of functional signal transduction

  3. Reactivation of cytotoxic effector mechanisms via perforin/granzymes, Fas/CD95, and TRAIL

  4. Stabilization of the adaptive immune axis via CD4/CD8 balance and checkpoint regulation

  5. Regulation of the inflammatory environment via IL-6R, TNFR, interferon axes, and CRP dynamics

  6. Improvement of immune cell distribution via chemokine and S1P receptors

  7. Cellular sensitization via preclinically described telomerase modulation

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1. NK cell axis: Restoration of cytotoxic competence

The natural killer cell is a central effector cell of tumor immune surveillance. Its activity depends not only on cell count but also on the balance between activating (NKG2D, NKp30, NKp44, NKp46) and inhibitory receptor signals (KIR receptors, NKG2A / CD94). 

In the observed cases, it was found that although NK cells were partially present prior to treatment, their function was significantly impaired. After administration of as few as 3 to 4 ampoules (7.0 ml) of GENOS Immune Plus intravenously, a significant increase in NK-mediated tumor cell apoptosis was observed. This suggests a functional shift in the NK cell axis toward activating signals.

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GENOS Immune Plus reactivates the functional cytotoxicity of NK cells. Functional immune reactivation combined with normalization of key immune axes rather than isolated stimulation. Enables coordinated tumor defense through restored cytotoxicity, immune balance and controlled inflammation.

2. IL-2 receptor axis: Restoration of stimulability

The IL-2 receptor (IL-2R) is central to the activation and expansion of T cells and NK cells. A lack of IL-2 responsiveness indicates a functional blockade of the cellular immune response. In several cases, the IL-2-stimulated NK response was significantly reduced or barely augmentable prior to treatment. Following treatment, a marked restoration of IL-2 responsiveness was observed.

  • Reactivation of intracellular signal transduction

  • Improved responsiveness to immunological stimuli

  • Restoration of adaptive immune reactivity

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The IL-2 axis demonstrates that GENOS Immune Plus not only activates cells but also restores their responsiveness.

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Summary diagram of NK cell reactivation and IL-2 activation
3. Cytotoxic effector mechanisms: perforin, granzymes, Fas/CD95, and TRAIL

Upon activation, NK cells kill target cells via clearly defined effector mechanisms such as the perforin/granzyme system, the Fas receptor/Fas ligand (CD95/CD95L) pathway, and TRAIL receptor signaling pathways. The observed improvement in NK cell cytotoxicity functionally indicates a reactivation of key cytotoxic effector mechanisms, including perforin/granzyme systems as well as Fas/CD95-mediated apoptotic signaling pathways.

What is crucial is not only that tumor cells are damaged, but that they can subsequently be immunologically eliminated. 

4. CD4/CD8 axis: systemic coordination of the immune response

NK cell function should not be viewed in isolation. It is closely linked to adaptive immunity. CD4 cells coordinate the immune response, while CD8 cells perform cytotoxic effector functions. A shifted CD4/CD8 ratio indicates systemic immune dysregulation.

In the observed cases, in addition to NK cell reactivation, a stabilization or functional re-establishment of the CD4/CD8 axis was also observed. Under GENOS Immune Plus, the CD4/CD8 ratio normalizes toward a functional equilibrium. This does not involve a one-sided increase or decrease, but rather a context-dependent rebalancing of the adaptive immune response

GENOS Immune Plus acts not only on NK cells but also on the coordination of the cellular immune response.

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5. Checkpoint axis: PD-1, CTLA-4, CD28, and TGF-βR

Tumor-associated immune dysfunction often arises from exhaustion, negative regulation, and a lack of co-stimulation.

The observed restoration of functional immune responses can be characterized as a rebalancing between activation and suppression.

The goal is not uncontrolled stimulation, but rather the restoration of a regulated antitumor immune response.

6. Cytokine and Inflammation Receptors: IL-6R, TNFR, IFNAR, and IFNGR

Tumor immunity is strongly influenced by the inflammatory environment. In addition to the NK cell and S1P receptor axis, GENOS Immune Plus also demonstrates significant modulation of inflammatory signaling pathways. Particularly notable are markers closely associated with classical inflammatory receptor systems:

  • IL-6 receptor axis (IL-6R)

  • TNF receptor axis (TNFR)

  • Interferon signaling axis (IFNAR / IFNGR)

  • VEGF-dependent inflammation and vascular regulation

 

These signaling axes play a key role in chronic inflammation, immune cell activation, vascular permeability, tissue infiltration, and the inflammatory microenvironment.

In vivo follow-up observation with GENOS Immune Plus

In the available follow-up data, the markers were documented following repeated administration of GENOS Immune Plus:

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IL-6 axis: functional attenuation of the IL-6-mediated inflammatory axis, without indicating general immunosuppression.

TNF-α / TNF receptor axis: In cases of initially significantly elevated TNF-α levels, a clear normalization toward the reference range is observed. Rebalancing of the TNF receptor-mediated inflammatory response.

VEGF axis: The available measurements show significant reductions in elevated VEGF levels: A marked decrease is observed in cases with highly elevated baseline values. Modulation of the inflammatory-angiogenic microenvironment. 

Interferon-γ axis (IFN-γ / IFNGR): IFN-γ remains stable within the low normal range across all measurement time points. The stable IFN-γ concentration, coupled with improved effector function of the immune system, argues against nonspecific proinflammatory overstimulation and instead supports functional immune modulation, in which cytotoxic activity is increased without inducing chronic inflammatory activation.

In oncology, an excessive increase in IFN-γ is associated with compensatory mechanisms such as PD-L1 induction and T-cell exhaustion. The stability observed here can therefore be interpreted as evidence of a controlled, regulated activation of the interferon axis.

GENOS Immune Plus modulates inflammatory and immunological signaling pathways not by blocking individual factors, but by restoring a regulated balance between activation, effector function, and control. The combination of reduced pro-inflammatory burden (IL-6, TNF-α, VEGF), a stable acute-phase response (CRP), and controlled interferon activity (IFN-γ) underscores the systemic, non-linear mechanism of action.

Thus, the inflammatory receptor axis complements the other GENOS Immune Plus areas of action:

  • NK cell reactivation

  • IL-2 responsiveness

  • CD4/CD8 stabilization

  • S1P-mediated cell distribution

  • Checkpoint and stress axes

  • Telomerase modulation as a preclinical vulnerability axis

7. Chemokine and S1P axis: Immune cell migration, tumor infiltration, and functional availability

An effective immune response does not depend solely on the activation of individual immune cells, but rather on whether these cells reach the target site—particularly the tumor microenvironment—in sufficient numbers and with adequate functional quality. The regulation of immune cell migration occurs primarily via chemokine receptors (e.g., CXCR3, CXCR4, CCR5, CCR7) as well as via the sphingosine-1-phosphate (S1P) axis, which controls the distribution of lymphocytes between blood, lymphoid organs, and tissues.

In the available clinical follow-up data from the 4 cases presented, no direct measurements of S1P receptors or chemokine profiles were performed. Nevertheless, indirect conclusions regarding improved systemic immune organization can be drawn from the observed functional changes.

The significant increase in NK cell cytotoxicity as well as the improved IL-2 responsiveness suggest that not only activation but also functional availability of effector immune cells is present. Furthermore, the stabilization of the CD4/CD8 balance indicates a reorganization of the adaptive immune response, which is typically accompanied by optimized cell distribution and interaction within immunological compartments.

Furthermore, the simultaneous reduction in inflammatory markers (IL-6, TNF-α, VEGF) alongside stable interferon-γ activity indicates a normalization of the immunological microenvironment. Such an environment is crucial for the efficient migration and infiltration of immune cells into target tissues.

Even without direct measurement of S1P and chemokine axes, the overall pattern of the data suggests a functional improvement in immune cell distribution. This likely includes optimized recruitment, retention, and interaction of effector cells in the target tissue, thereby supporting a more effective immune response.

  • GENOS Immune Plus does not act in isolation on individual immune parameters but promotes a systemic reorganization of immunological processes. In addition to the activation and functional improvement of effector cells, the data provide consistent evidence of improved spatial and functional coordination of the immune response.

8. Preclinical Telomerase Modulation as a Complementary Vulnerability Axis

Evidence base

In addition to immune rebalancing, telomerase modulation is a relevant mechanistic component. The available data are derived from preclinical studies of RM31 on the HL-60 cell line. A 99.5% reduction in telomerase activity was observed within 72 hours. 

https://pubmed.ncbi.nlm.nih.gov/35281585/

Telomerase is central to:

  • unlimited proliferative capacity

  • apoptosis resistance

  • cell persistence

  • malignant stabilization

Reduced telomerase activity can increase the vulnerability of malignant cells and thereby improve their immunological eliminability.

Clinical relevance

In oncology, GENOS Immune Plus acts not as an isolated immunostimulator, but as a functional network modulator.

The approach combines:

  • Immune reactivation

  • Receptor rebalancing

  • Cell migration

  • Inflammation regulation

  • Cytotoxic effector function

  • Potential cellular vulnerability

This results in an oncological mechanism of action that does not primarily focus on cell count or individual blockade, but rather on the functional restoration of a coordinated antitumor immune response.

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