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Adenosine And Imunosuppression

Decent Essays
• Immune system cells can target and attack cancer cells, preventing tumor growth and metastasis. Tumors that have greater levels of immune cell infiltration often lead to better outcomes. However, cancer cells can adapt to inhibit the proliferation and promote the apoptosis of cells of the immune system. Treatments that prevent the mechanism of immunosuppression are used as oncological therapeutics to reactivate the immune system towards the cancer.
• Adenosine is a naturally occurring metabolite found inside and outside cells.
A high extracellular concentration of adenosine can have immunosuppressive effects, inhibiting activation of immune cells capable of attacking tumor cells and increasing the number of T-regs (regulatory
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Study Conducted
• Phase 1/1B clinical trial testing both the single agent (CPI-444) and combination (CPI-444 with atezolizumab) treatments on an expanded cohort of patients with progressive RCC (renal cell cancer) or NSCLC (non-small cell lung cancer), with a large number of patients exhibiting resistant/refractory response to prior anti-PD-L1 exposure (NSCLC 82%, RCC 73%) and testing as PD-L1 negative (NSCLC 54%, RCC 95%). Significant Findings
• Baseline tumor biopsies from the CPI-444 phase 1 trial demonstrate that CD73 is upregulated in anti-PD-1 naïve as compared to anti-PD-1 resistant/refractory tumors. Tumor cells adapt to overcome blockage of the PD-1 signaling using adenosine-mediated immunosuppression through increased expression of CD73. This indicates CPI-444 could potentially be more effective for patients with anti-PD-1 resistant/refractory tumors or in combination with atezolizumab.
• Patients on the higher dose of CPI-444 (100mg BID/200mg QD vs. 50mg BID) had both higher plasma levels of CPI-444 and decreased A2AR pathway activity when stimulated with NECA (an adenosine analog). The negative correlation between CPI-444 concentration and A2AR pathway activity confirms that CPI-444 is an effective antagonist of the A2A receptor in patients and decreases pathway activation.
• The single-agent and combination treatments were well tolerated. Treatment-related adverse effects with either treatment were mostly mild or
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