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Page 618 Laubach et al. Cancer Drug Resist 2023;6:611-41 https://dx.doi.org/10.20517/cdr.2023.60

compounds have shown limited toxicity in Phase I clinical trials [85,86] , with iTeos Therapeutics’ compound
[86]
demonstrating initial signs of clinical benefit . Dizal Pharmaceuticals’ compound was also evaluated in
murine models of prostate cancer, where treatment with the novel antagonist and anti-PD-1 significantly
[85]
reduced tumor volume compared to monotherapy .

There are several pre-clinical and clinical studies that demonstrate promising results for targeting CD39 or
CD73 in combination with anti-PD-1 or PD-L1. Cancer exosomes expressing CD39 and CD73 drive
adenosine accumulation and were also found to promote CD39 expression on macrophages .
[87]
Macrophage-derived CD39 cooperates with tumor-derived CD73 to increase adenosine levels in the TIME,
which drives anti-PD-1 resistance . Targeting CD39 on macrophages in combination with anti-PD-1
[87]
therapy abrogated therapeutic resistance and synergistically reduced the volume of murine hepatocellular
[87]
carcinoma tumors and increased CD8 T cell infiltration and granzyme B production . Moreover, a first-
+
in-human Phase I clinical trial was conducted in 2020 to assess the efficacy of an anti-CD39 antibody
(IPH5201) in combination with anti-PD-L1 treatment , and the first patient for the Phase II study was
[88]
dosed in June 2023 . A poster presentation at the European Society for Medical Oncology Immuno-
[89]
Oncology Summit in 2022 showed pre-clinical data for IPH5201, wherein treatment alone reduced
adenosine levels in the TIME of mouse fibrosarcoma tumors . The data also demonstrated that combining
[90]
anti-CD39, the chemotherapeutic agent gemcitabine, and anti-PD-L1 controlled tumor growth and
increased survival better than monotherapy or anti-PD-L1 with gemcitabine in murine colorectal carcinoma
tumors . In a clinical study of 44 patients, researchers found no major toxicities when combining an anti-
[90]
CD39 monoclonal antibody with anti-PD-1 and the chemotherapy regimen FOLFOX for the treatment of
gastric cancer or gastroesophageal junction adenocarcinoma . These data are critical first steps in the
[91]
approval and use of anti-CD39 therapies in combination with anti-PD-1/PD-L1 treatment. The results from
a first-in-human Phase I clinical trial with anti-CD73 and anti-PD-L1 recently reported tolerable safety and
[92]
moderate efficacy . Further, targeting CD73 has also recently been shown to be a promising therapeutic
strategy, wherein Phase II clinical trials combining anti-CD73 with anti-PD-L1 elicit increased response rate
and progression-free survival compared to anti-PD-L1 monotherapy in patients with non-small cell lung
cancer . One thing to consider when targeting CD39 or CD73 is that anti-CD39 treatments not only
[93]
inhibit adenosine production, but also promote accumulation of immunostimulatory ATP.

In addition to more conventional treatment methods, several unique approaches for inhibiting adenosine
metabolism and PD-1 have recently been discovered. Because of the ubiquitous expression of A2AR on T
+
cells, localizing inhibition of A2AR signaling to tumor-infiltrating CD8 T cells would likely mitigate off-
target effects. In this approach, researchers increased tumor oxygenation to relieve the hypoxic conditions
[94]
that promote tumor-derived adenosine production . Using a photo-modulated nanoreactor, hydrogen
peroxide is converted to oxygen within the TIME, leading to decreased adenosine production and abrogated
A2AR signaling in CD8 T cells . Moreover, combination with anti-PD-1 therapy synergistically reduced
[94]
+
[94]
tumor growth and increased CD8 T cell infiltration in triple-negative murine breast cancer tumors . In
+
another tumor-targeting approach, researchers utilized cancer-derived exosomes packaged with both a
CD39 antagonist and AMPK agonist to inhibit adenosine and promote ATP production, respectively .
[95]
This method increased CD8 T cell infiltration and production of granzyme B and IFNg, reduced
+
intratumoral adenosine and Treg populations, and synergized with anti-PD-1 treatment in mouse
melanoma models . The final targeted approach used ROS-producing nanoparticles to deliver a CD39
[95]
[96]
inhibitor . Inducing ROS accumulation in the TIME seems counterintuitive, but like hypoxia, ROS trigger
the release of ATP. Therefore, ROS would increase ATP concentration and inhibiting CD39 would prevent
[96]
adenosine formation, thus remodeling the TIME away from an immunosuppressive state . This method