Our current research demonstrates the great potential of CD73 inhibitor for clinical translation of cancer studies by analyzing the behavior and function of 3D tumor cells, and thus for more effective treatment protocols for GBM.

P2, N=147, Active, not recruiting, Jules Bordet Institute | Trial primary completion date: Sep 2024 --> May 2025

P1/2, N=129, Active, not recruiting, Jules Bordet Institute | Trial completion date: Apr 2025 --> Dec 2025 | Trial primary completion date: Aug 2024 --> Mar 2025

P1, N=48, Active, not recruiting, National Cancer Institute (NCI) | Suspended --> Active, not recruiting

P1, N=48, Completed, Symphogen A/S | Active, not recruiting --> Completed

P3, N=610, Recruiting, Arcus Biosciences, Inc. | Not yet recruiting --> Recruiting

This led to the identification interactions and similarities of PSK and the AB680 inhibitor in the active site of CD73. With the isoform of the K-RAS protein, PSK bonded to the TYR32 amino acid at switch 1, while with BAK it bonded to the region of the α1 helix, while PSP bonded to the activation site and the C-terminal and N-terminal ends of that helix. In Bcl-2, PSK interacted at the binding site of the Venetoclax inhibitor, showing similarities with the amino acids ASP111, VAL133, LEU137, MET115, PHE112, and TYR108, while PSP had similarities with THR132, VAL133, LEU137, GLN118, MET115, APS111, PHE112, and PHE104.

P1/2, N=227, Active, not recruiting, Arcus Biosciences, Inc. | Trial completion date: Oct 2024 --> Jul 2025 | Trial primary completion date: Oct 2024 --> Jul 2025

P1, N=87, Not yet recruiting, Akeso

P2, N=13, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=30 --> 13

Background Neo-CheckRay (NCT03875573) demonstrated high rates of pathological complete response (pCR) after immune-modulating stereotactic body radiation therapy (iSBRT) to the primary BC in combination with the anti-PD-L1 durvalumab (durva) in high-risk early-stage luminal BC...Pts were randomized 1:1:1 to ARM 1: paclitaxel q1w x12 with iSBRT at week 4 (3x8 Gy targeting the primary tumour, avoiding lymph nodes and normal breast tissue), followed by dose-dense epirubicin/cyclophosphamide q2w x4; ARM 2 : arm 1 + durva q4w x5; and ARM 3 : arm 1 + durva + oleclumab (anti-CD73) q2w x4 then q4w x3...Table: 2O All Arm 1 Arm 2 Arm 3 n 135 45 45 45 pts, % B: PD-L1 negative* 58.5 57.8 57.8 60.0 W6: no tumor 32.2 13.5 46.3 34.9 W6: TILs increase 14.0 16.2 12.2 14.0 W6: PD-L1 IC increase 42.7 31 48 48 pCR rate, % All pts 28.9 17.8 33.3 35.6 B: PD-L1 negative* 24.0 3.8 34.6 33.3 W6: no tumor 48.7 40.0 47.4 53.3 W6: TILs increased 17.6 0.0 20.0 33.3 W6: PD-L1 IC increased 24.0 0.0 46.0 40.0 TILs: pts, % B: TILs ≥ 1% 51.5 51.2 50.0 53.3 W6: TILs ≥ 1% 26.8 28.1 27.3 25.0 PD-L1: pts, % B: PD-L1 IC ≥ 1% 57.0 57.8 57.8 55.6 W6: PD-L1 IC ≥ 1% 70.5 48.3 85.7 82.1 B: PD-L1 TC ≥ 1% 22.2 24.4 17.8 24.4 W6: PD-L1 TC ≥ 1% 29.9 13.8 42.9 37.0 B: PD-L1 CPS ≥ 1% 39.3 37.8 40.0 40.0 W6: PD-L1 CPS ≥ 1% 54.5 37.9 66.7 63.0 B, baseline; pts, patients; W6, week 6. *Stratification factor.Conclusions In pts treated with iSBRT+durva, PD-L1 increase or absence of tumor at W6 is associated with higher pCR rate at surgery.

P2, N=30, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting

P1; Recruiting --> Suspended

P2, N=30, Not yet recruiting, AstraZeneca

P1/2, N=56, Recruiting, Jonsson Comprehensive Cancer Center | Suspended --> Recruiting

P3, N=610, Not yet recruiting, Arcus Biosciences, Inc.

P2, N=320, Recruiting, Gilead Sciences | Trial completion date: Sep 2026 --> Dec 2027 | Trial primary completion date: Sep 2026 --> Dec 2027

P1/2, N=173, Completed, Arcus Biosciences, Inc. | Active, not recruiting --> Completed

Among them, compounds 18 and 19 exhibited significant inhibition activities against hCD73 with IC50 values of 0.28 μM and 0.10 μM, respectively, suggesting the feasibility of replacing the benzotriazole moiety in the lead compound. This study explored the novelty and structural diversity of CD73 inhibitors.

Although the safety profile was acceptable, this study did not meet its primary efficacy endpoint.

To test our hypothesis, we used the KrasG12D; PdxCre1 (KC) genetically engineered mouse (GEM) model and tested the utility of AB-680, a small molecule inhibitor targeting CD73, to inhibit PanIN progression...The scRNA-seq analysis showed that CD73 inhibition reduced M2 macrophages, acinar, and PanIN cell populations. CD73 inhibition enhanced immune surveillance and expanded unique clonotypes of TCR and BCR, indicating that inhibition of CD73 augments adaptive immunity early in the neoplastic microenvironment.

P1/2, N=227, Active, not recruiting, Arcus Biosciences, Inc. | Trial completion date: Jul 2024 --> Oct 2024 | Trial primary completion date: Jul 2024 --> Oct 2024

P1, N=56, Active, not recruiting, ORIC Pharmaceuticals | Recruiting --> Active, not recruiting | Phase classification: P1b --> P1 | Trial completion date: Jun 2024 --> Sep 2024 | Trial primary completion date: Jun 2024 --> Sep 2024

Both agents demonstrated antitumor activity in early-phase trials. PACIFIC-9 (NCT05221840) is an international, double-blind, randomized, placebo-controlled, Phase III trial comparing durvalumab plus either oleclumab or monalizumab with durvalumab plus placebo in patients with unresectable, stage III NSCLC and no disease progression following cCRT.Clinical Trial Registration: NCT05221840 (ClinicalTrials.gov).

Specifically, ZIF-90, an ATP-responsive consumer, is synthesized as the core carrier to encapsulate AB680 (CD73 inhibitor) and then coated with an iron-polyphenol layer to prepare the ICD inducer (AZTF), which is further grafted onto prebiotic bacteria via the esterification reaction to obtain the engineered biohybrid (Bc@AZTF). Particularly, the designed Bc@AZTF can actively enrich in tumor sites and respond to the acidic tumor microenvironment to offload AZTF nanoparticles, which can consume intracellular ATP (iATP) content and simultaneously inhibit the ATP-adenosine axis to reduce the accumulation of adenosine, thereby alleviating adenosine-mediated immunosuppression and strikingly amplifying ICD effect. Importantly, the synergy of anti-PD-1 (αPD-1) with Bc@AZTF not only establishes a collaborative antitumor immune network to potentiate effective tumoricidal immunity but also activates long-lasting immune memory effects to manage tumor recurrence and rechallenge, presenting a new paradigm for ICD treatment combined with adenosine metabolism.

Neo-CheckRay (NCT03875573) is the first prospective, international, phase 2, randomized trial investigating this treatment. Eligible patients (pts) with newly diagnosed cT1c-3 (≥ 2 cm) cN0 or cT1c-3 (≥ 1.5 cm) cN1-3, grade 2 (Ki67 ≥ 15%) or grade 3, MammaPrint (MP) high risk, invasive ER+/HER2- BC were randomized 1:1:1 to arm 1: neo-adjuvant paclitaxel q1w x12 with SBRT at week 5 (3x8 Gy targeting the primary tumour, avoiding lymph nodes and normal breast tissue), followed by dose-dense epirubicin/cyclophosphamide q2w x4; arm 2: arm 1 + durva 1500mg q4w x5; and arm 3: arm 2 + ole 3000 mg q2w x4 then q4w x3. The addition of durva+/- ole numerically increases pCR and RCB 0/1 rates compared to NACT+SBRT. Final statistical analysis will be presented at the conference. Ongoing translational research will shed light on the mechanisms of response.

Live cell imaging demonstrated PBMC-mediated cytotoxicity against 1B3-transfected tumor cells. These data demonstrate for the first time that miR-193a-3p induces long-term immunity against tumor development via modulation of the tumor microenvironment and induction of immunogenic cell death.

CD73 inhibitor AB680 limits tumor progression and potentiates therapeutic efficacy of GC chemotherapy or anti-PD-1 treatment in iCCA. AB680 combined with anti-PD-1 therapy effectively elicits anti-tumor immune response.

P2, N=75, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Jun 2024 --> Jun 2026 | Trial primary completion date: Jun 2024 --> Jun 2026

Combined treatment with oleclumab and durvalumab was safe and demonstrated limited anti-tumor activity in patients with recurrent EOC.

Provided herein are novel heteroaryl compounds as CD73 inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.

P1/2, N=43, Active, not recruiting, MedImmune LLC | Trial completion date: Jan 2025 --> Jul 2025

P1, N=195, Recruiting, Arcus Biosciences, Inc. | Active, not recruiting --> Recruiting

Provided herein are novel CD73 inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.

P2, N=23, Recruiting, Catherine Spina | Trial primary completion date: Apr 2024 --> Dec 2025

The nanodrug, named as AptEM@CBA, is constructed by encapsulation of photothermal agent black phosphorus quantum dots (BPQDs) and selective CD73 inhibitor α, β-Methyleneadenosine 5'-diphosphate (AMPCP) in chitosan nanogels, which are further covered with aptamer AS1411 modified erythrocyte membrane (EM) for biomimetic camouflage...Meanwhile, the release of AMPCP suppress the adenosine generation via CD73 blockade, alleviating the impairment of adenosine to dendritic cells and suppressing regulatory T cells, synergically stimulate the activity of T cells. The combination of CD73 blockade with PTT, not only suppresses the growth of primary implanted tumors, but also boosts strong antitumor immunity to inhibit the growth of distal tumors, providing good potential for tumor photoimmunotherapy.

P1, N=16, Completed, Akeso | Recruiting --> Completed | N=48 --> 16

P1, N=48, Active, not recruiting, Symphogen A/S | N=100 --> 48

P1, N=100, Active, not recruiting, Symphogen A/S | Trial completion date: Jul 2024 --> Dec 2024 | Trial primary completion date: Jul 2024 --> Dec 2024

No abstract available

P1, N=165, Active, not recruiting, Arcus Biosciences, Inc. | Trial completion date: Jun 2024 --> May 2027 | Trial primary completion date: Jun 2024 --> May 2027

P2, N=360, Recruiting, Arcus Biosciences, Inc. | N=200 --> 360 | Trial completion date: Nov 2025 --> Jun 2027 | Trial primary completion date: Sep 2025 --> Sep 2026