Abstract 5827
Background
Immunotherapies are considered the most promising therapeutic approach for cancer and the immunosuppressive activity of ARG1 has been recognized as an important mechanism of the tumor immune evasion. This prompted the development of arginase inhibitors, which in preclinical models, enhanced antitumor immunity as a monotherapy and in combination with other immune checkpoint inhibitors. On the other hand, ARG2, but not ARG1, is highly expressed in neoplastic cells in many tumors and its expression is correlated with malignant phenotype. Preclinical studies confirmed that ARG2 promotes the proliferation of cancer cells and the growth of tumor xenografts independently of its immunosuppressive activity. Generation of polyamines to facilitate the growth of hypoxic and nutrient-deprived tumors, as well as specific metabolic adaptations including increased reliance on protein catabolism are the major mechanisms underlying the tumorigenic activity of ARG2. Hence, the tumor cell intrinsic activity of ARG2 represents an attractive intracellular target for novel therapies with arginase inhibitors.
Methods
The compound activity was determined using human ARG1 and ARG2, and in CHO-K cells expressing ARG1 and ARG2. ARG1 and ARG2 expression in cancer cell lines and dissected tumors was assessed by WB and qPCR. CellTiter-Glo was used to assess the antiproliferative activity of the compound. In vivo antitumor activity was evaluated in murine CT26 (syngeneic) and human K562 (xenograft) subcutaneous mouse models.
Results
The expression of the endogenous ARG2 was confirmed in multiple human cancer cell lines and xenografts. We developed a highly potent dual ARG1 and ARG2 inhibitor, OATD-02, with a good cellular activity. We demonstrated that OATD-02 inhibited proliferation of multiple human cancer cell lines expressing ARG2 and suppressed the growth of human xenografts. OATD-02 also strongly inhibited the growth of the syngeneic CT26 tumors.
Conclusions
OATD-02, a potent ARG1 and ARG2 inhibitor, exerts its antitumor efficacy not only by the reactivation of the immune response but also by directly suppressing the ARG2-dependent proliferation of cancerous cells. Thus, OATD-02 is a very promising compound for the treatment of hypoxic tumors which are particularly resistant to therapies.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
OncoArendi Therapeutics SA.
Funding
National Centre for Research and Development in Poland.
Disclosure
M.M. Grzybowski: Full / Part-time employment: OncoArendi Therapeutics SA. J. Pęczkowicz-Szyszka: Full / Part-time employment: OncoArendi Therapeutics SA. P. Wolska: Full / Part-time employment: OncoArendi Therapeutics SA. P.S. Stańczak: Full / Part-time employment: OncoArendi Therapeutics SA. M. Welzer: Full / Part-time employment: OncoArendi Therapeutics SA. E. Nikolaev: Full / Part-time employment: OncoArendi Therapeutics SA. A.M. Siwińska: Full / Part-time employment: OncoArendi Therapeutics SA. R. Błaszczyk: Full / Part-time employment: OncoArendi Therapeutics SA. B. Borek: Full / Part-time employment: OncoArendi Therapeutics SA. M. Dzięgielewski: Full / Part-time employment: OncoArendi Therapeutics SA. A. Gzik: Full / Part-time employment: OncoArendi Therapeutics SA. J. Nowicka: Full / Part-time employment: OncoArendi Therapeutics SA. J. Brzezińska: Full / Part-time employment: OncoArendi Therapeutics SA. K. Jędrzejczak: Full / Part-time employment: OncoArendi Therapeutics SA. J. Chrzanowski: Full / Part-time employment: OncoArendi Therapeutics SA. A. Gołębiowski: Leadership role, Full / Part-time employment: OncoArendi Therapeutics SA. J. Olczak: Leadership role, Full / Part-time employment: OncoArendi Therapeutics SA. P. Dobrzański: Leadership role, Full / Part-time employment: OncoArendi Therapeutics SA. All other authors have declared no conflicts of interest.
Resources from the same session
4600 - Patterns and outcomes related to rapid progressive disease in a cohort of advanced solid tumors treated with immune checkpoint inhibitors (ICIs).
Presenter: Lucio Ghiglione
Session: Poster Display session 3
Resources:
Abstract
3547 - Real World Outcomes of Immune-Related Adverse Events (irAEs) among Patients Receiving Immune Checkpoint Inhibitors (ICIs) in Hospital Settings
Presenter: Saby George
Session: Poster Display session 3
Resources:
Abstract
1124 - Sex-based heterogeneity of efficacy of anticancer immunotherapy
Presenter: Fabio Conforti
Session: Poster Display session 3
Resources:
Abstract
4133 - Comparative efficacy and safety of PD-1/PD-L1 inhibitors for patients with solid tumors: a systematic review and Bayesian network meta-analysis
Presenter: Qingyuan Huang
Session: Poster Display session 3
Resources:
Abstract
2548 - Excess weight and efficacy of anti-PD-1 antibodies in advanced cancer patients
Presenter: Jacobo Rogado
Session: Poster Display session 3
Resources:
Abstract
2228 - Safety and efficacy of anti-PD-1 inhibitor ABBV-181 in lung and head and neck carcinoma
Presenter: Antoine Italiano
Session: Poster Display session 3
Resources:
Abstract
2333 - Efficacy and safety of immune checkpoint inhibitors (ICIs) for treatment of advanced solid tumours in octogenarian patients
Presenter: Soraya Mebarki
Session: Poster Display session 3
Resources:
Abstract
4847 - Association of programmed cell death 1 (PD-1) inhibitor therapy with overall survival (OS) in stage IV melanoma treated with targeted therapies
Presenter: Aracelis Torres
Session: Poster Display session 3
Resources:
Abstract
2215 - Clinical outcomes of immune checkpoint inhibitors in older and younger patients with advanced solid tumours in a real-life setting
Presenter: Pauline Corbaux
Session: Poster Display session 3
Resources:
Abstract
2881 - Impact of corticosteroids and antibiotics on efficacy of immune-checkpoint inhibitors in advanced non-small cell lung cancer
Presenter: Joaquin Mosquera Martinez
Session: Poster Display session 3
Resources:
Abstract