On April 3, 2019 Aprea Therapeutics reported the results of studies with APR-246 in combination with immune checkpoint blockade presented by researchers from Memorial Sloan Kettering Cancer Center at the 2019 AACR (Free AACR Whitepaper) Annual Meeting in Atlanta (Press release, Aprea, APR 3, 2019, View Source [SID1234534946]). The studies collectively support a role for p53 activity in the tumor microenvironment and suggest that stabilization of the tumor suppressor protein, p53, by APR-246 can enhance anti-tumor immune response, particularly when combined with immuno-oncology agents.
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The studies characterized changes in the tumor immune microenvironment in melanoma and colorectal cancer in vivo models when treated with APR-246 and immuno-oncology agents, either alone or in combination. APR-246 monotherapy treatment of melanoma tumors induced a pro-inflammatory tumor microenvironment. The analysis of tumor infiltrating immune cells demonstrated a pattern of gene expression suggesting that stabilization of p53 by APR-246 alters the immune tumor microenvironment and enables the immune system to target tumor cells more effectively. Anti-tumor activity was observed with APR-246 monotherapy; the combination treatment with APR-246 and anti-PD-1 enhanced the effects of PD-1 blockade in a T cell-dependent manner, as assessed by reduced tumor growth and improved survival. Also, the administration of APR-246 together with anti-PD-1 and anti-CTLA-4 dual immune checkpoint blockade significantly augmented anti-tumor control.
Abstract: 4843
Poster Title: TP53-stabilization with APR-246 enhances antitumor effects of immune checkpoint blockade in preclinical models.
Session Title: Targeted Therapies and Immunological/Tumor Microenvironment Effects
Poster Presentation Date and Time: Wednesday April 3, 2019, 8:00 am – 12:00 pm EDT
About p53 and APR-246
The p53 tumor suppressor gene is the most frequently mutated gene in human cancer, occurring in approximately 50% of all human tumors. These mutations are often associated with resistance to anti-cancer drugs and poor overall survival, representing a major unmet medical need in the treatment of cancer.
APR-246 has been shown to reactivate mutant and inactivated p53 protein – by restoring wild-type p53 conformation and function – and thereby induce programmed cell death in human cancer cells. APR-246 has demonstrated pre-clinical anti-tumor activity in a wide variety of solid and hematological (blood) tumors, including MDS, AML, and ovarian cancer, among others. Additionally, strong synergy has been seen with both traditional anti-cancer agents, such as chemotherapy, as well as newer mechanism-based anti-cancer drugs and immuno-oncology checkpoint inhibitors. In addition to pre-clinical testing, a Phase I/II clinical program with APR-246 has been completed, demonstrating a favorable safety profile and both biological and confirmed clinical responses in hematological malignancies and solid tumors with mutations in the TP53 gene.