cal evidence shows mice lacking A2A receptor have reduced tumor growth, implying tumor protection from T cells in the presence of the adenosine-A2A receptor interaction.7
Prostate cancer is a solid tumor that has FDA-approved cellular immunotherapy in sipuleucel-T.8 Yet, attempts with single-agent CTLA49, 10 and PD-(L)111, 12 checkpoint inhibition have not been very successful. This is likely due to the presence of an immune-exclusive tumor microenvironment. Relevant to the adenosine pathway, it has been shown that CD39 is strongly expressed in the stromal compartment of tumors. Prostatic acid phosphatase (PAP) is obviously upregulated in prostate cancer, and it also has ectonucleotidase activity which leads to conversion of AMP to adenosine.13, 14 Finally, A2B receptor is upregulated in prostate cancer,15-17 leading more support to the concept of adenosine-mediated immune exclusion.
Altogether, the above evidence offers potential for targeting the adenosine pathway to reduce the immune exclusive microenvironment in many solid tumors, including the prostate and other genitourinary malignancies. Manipulation of the microenvironment to retain ATP and avoid adenosine production and activation of specific adenosine receptors can be accomplished via multiple different mechanisms. This may include inhibiting the reduction of ATP through inhibition of CD39 and/or CD73, resulting in decreased adenosine accumulation. Additionally, inhibition of the adenosine receptors has the potential to minimize the impact of adenosine in the tumor microenvironment, by limiting immune checkpoint upregulation and suppression of innate immune system components. Hence, a tumor like prostate cancer, with an immune exclusive microenvironment, may be ideal for induction of anti-tumor inflammation, initiated by manipulation of the adenosine pathway. Clinical trials with novel therapeutics that manipulate the various components of the adenosine pathway are currently ongoing and in development. Below, I list relevant trials that are inclusive of patients with prostate cancer and other genitourinary malignancies.
Select trials that target the adenosine pathway
- Phase 2 trial of AZD4635 (A2A receptor antagonist) with durvalumab or with durvalumab and cabazitaxel for metastatic castration resistant prostate cancer (mCRPC) (AARDVARC) (NCT04495179)
- Phase 1/2 trial of etrumadenant (A2A and A2B receptor antagonist) plus zimberelimab (PD-1 antibody) combinations with or without standard of care treatments or etrumadenant plus AB680 (CD73 inhibitor) with or without zimberelimab for mCRPC (NCT04381832)
- Phase 1 trial of TTX-030 (CD39 inhibitor) with budigalimab (PD-1 inhibitor) with and without chemotherapy for solid tumors (including mCRPC and renal cell carcinoma) (NCT04306900)
- Phase 2 trial of AZD4635 (A2A receptor antagonist) with durvalumab, oleclumab (CD73 inhibitor) or both for mCRPC (NCT04089553)
- Phase 1/1b trial of NZV930 (anti-CD73 antibody) alone and in combination with PDR001 (PD-1 antibody) and/or NIR178 (A2A receptor antagonist) in advanced malignancies (including mCRPC and renal cell carcinoma) (NCT03549000)
- Phase 1 trial of CPI-006 (CD73 inhibitor) alone and in combination with ciforadenant (A2A receptor antagonist) and with pembrolizumab in advanced cancers (including mCRPC, bladder cancer and renal cell carcinoma) (NCT03454451)
- Phase 2 trial of NIR178 (A2A receptor antagonist) in combination with PDR001 (PD-1 antibody) in non-hodgkins lymphoma and solid tumors (including mCRPC, urothelial carcinoma and renal cell carcinoma) (NCT03207867)
- Phase 1/1b trial of ciforadenant (A2A receptor antagonist) alone and in combination with atezolizumab in advanced cancers (including mCRPC and renal cell carcinoma) (NCT02655822)
- Knowles JR. "Enzyme-catalyzed phosphoryl transfer reactions." Annu Rev Biochem 1980; 49:877-919.
- Mishra N, Tuteja R, Tuteja N. "Signaling through MAP kinase networks in plants." Arch Biochem Biophys 2006; 452:55-68.
- Di Virgilio, et al. "Extracellular ATP and P2 purinergic signalling in the tumour microenvironment." N