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Pan-PI3K inhibition with copanlisib overcomes Treg- and M2-TAM-mediated immune suppression and promotes anti-tumor
Simon Heller1, Sarah Glaeske2, Katja Gluske2
1Nuvisan ICB GmbH, Berlin, Germany.
Abstract:
The PI3K pathway is one of the most frequently altered signaling pathways in human cancer. In addition to its function in cancer cells, PI3K plays a complex role in modulating anti-tumor immune responses upon immune checkpoint inhibition (ICI). Here, we evaluated the effects of the pan-Class I PI3K inhibitor copanlisib on different immune cell types in vitro and on tumor growth and immune cell infiltration in syngeneic murine cancer models. Intermittent treatment with copanlisib resulted in a strong in vivo anti-tumor efficacy, increased tumor infiltration of activated T cells and macrophages, and increased CD8+ T cell/regulatory T cell and M1/M2 macrophage ratios. The strong in vivo efficacy was at least partially due to immunomodulatory activity of copanlisib, as in vitro these murine cancer cells were resistant to PI3K inhibition. Furthermore, the combination of copanlisib with the ICI antibody anti-PD-1 demonstrated enhanced anti-tumor efficacy in both ICI-sensitive and insensitive syngeneic mouse tumor models. Importantly, in an ICI-sensitive model, combination therapy resulted in complete remission and prevention of tumor recurrence. Thus, the combination of ICIs with PI3K inhibition by intermittently dosed copanlisib represents a promising new strategy to increase sensitivity to ICI therapies and to treat human solid cancers.
Insights
Intermittent PI3K inhibition with copanlisib shows strong anti-tumor effects by boosting immune cell activity. Combining copanlisib with immune checkpoint inhibitors (ICIs) enhances efficacy, offering a promising strategy for treating solid cancers.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- The phosphoinositide 3-kinase (PI3K) pathway is frequently altered in human cancers.
- PI3K signaling influences anti-tumor immune responses, particularly during immune checkpoint inhibition (ICI).
Purpose of the Study:
- To evaluate the effects of the PI3K inhibitor copanlisib on immune cells, tumor growth, and immune cell infiltration.
- To assess the combination therapy of copanlisib and anti-PD-1 in murine cancer models.
Main Methods:
- In vitro assessment of copanlisib effects on immune cells.
- In vivo studies using syngeneic murine cancer models with intermittent copanlisib treatment.
- Evaluation of tumor growth, immune cell infiltration, and ratios (CD8+/Treg, M1/M2).
- Combination therapy with copanlisib and anti-PD-1 antibody.
Main Results:
- Intermittent copanlisib treatment demonstrated significant in vivo anti-tumor efficacy.
- Copanlisib increased the infiltration of activated T cells and macrophages, improving CD8+/Treg and M1/M2 ratios.
- In vitro, cancer cells showed resistance to PI3K inhibition, suggesting immunomodulatory mechanisms for in vivo efficacy.
- Combination therapy with copanlisib and anti-PD-1 enhanced anti-tumor activity in both ICI-sensitive and insensitive models.
- Complete remission and prevention of tumor recurrence were observed in an ICI-sensitive model with combination therapy.
Conclusions:
- Intermittent PI3K inhibition with copanlisib exhibits potent anti-tumor activity through immunomodulation.
- Combining copanlisib with ICIs is a promising strategy to overcome ICI resistance and treat solid tumors.
- This combination therapy holds potential for increasing sensitivity to existing ICI treatments.
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