On February 20, 2024 Theratechnologies Inc. ("Theratechnologies" or the "Company") (TSX: TH) (NASDAQ: THTX), a biopharmaceutical company focused on the development and commercialization of innovative therapies, reported the publication of a peer-reviewed article in Frontiers in Immunology that enhances understanding of the molecular mechanism of action of sudocetaxel zendusortide (also known as TH1902) as a potential anticancer treatment (Press release, Theratechnologies, FEB 20, 2024, View Source [SID1234640291]). Sudocetaxel zendusortide is an investigational, first-in-class peptide-drug conjugate (PDC) that targets the sortilin receptor (SORT1) and expedites the internalization and delivery of the cytotoxic payload (docetaxel) directly into cancer cells.
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The article, "Sudocetaxel Zendusortide (TH1902) triggers the cGAS/STING pathway and potentiates anti-PD-L1 immune-mediated tumor cell killing" appears in the "Cancer Immunity and Immunotherapy" section of the February (Volume 15) issue of the journal. It reports on preclinical research in which sudocetaxel zendusortide induced complete and prolonged tumor regression in a triple-negative breast cancer (TNBC)-derived xenograft tumor model and demonstrated tumor regression associated with growth inhibition and immune cell infiltration in a "cold" murine (syngeneic) tumor model. Additionally, combining sudocetaxel zendusortide with an anti-PD-L1 checkpoint inhibitor led to increases in tumor growth inhibition and median animal survival.
"The results published in Frontiers in Immunology demonstrate that sudocetaxel zendusortide exerts its antitumor activity, in part, through modulation of the immune tumor microenvironment," said Christian Marsolais, Ph.D., Senior Vice President and Chief Medical Officer at Theratechnologies, and one of the paper’s co-authors. "Our findings reinforce that combining this novel peptide-drug conjugate with anti-PD-L1 checkpoint inhibitor therapy may yield improved clinical outcomes, with potentially profound implications for patients across various cancer types."
"An important aspect of our research is the activation of an antitumor immunity process through involvement of the cGAS/STING pathway, a key regulator in the cancer-immunity cycle," commented Prof. Borhane Annabi, Chair in Cancer Prevention and Treatment in the Chemistry Department at the Université du Québec à Montréal, and a co-author of the Frontiers in Immunology paper. "Although the animal tumor model we worked with is considered a non-immunogenetic, or ‘cold’ tumor model, we observed a net increase in leukocyte infiltration within sudocetaxel zendusortide-treated tumors, especially for tumor-infiltrating lymphocytes and tumor-associated macrophages. This realization supports the rationale for further exploration of the combination of sudocetaxel zendusortide with immunotherapy."
The article can be accessed online here.
About Immunotherapy in Cold and Hot Tumors
Immunotherapies have significantly improved the treatment of cancer. Researchers continue to explore the power of the immune system to find and destroy cancer cells. "Hot" tumors show signs of inflammation, meaning the tumor has already been infiltrated by immune cells rushing to fight the cancerous cells. Only a few types of cancers are considered to be hot. "Cold" tumors have not yet been infiltrated with T cells. This signals that the immune response is not working, making it difficult to provoke an immune response with immunotherapies. Most cancers of breast, ovary, prostate, pancreas, and brain (e.g., glioblastoma [GBM]) are cold tumors, and are largely treated with traditional therapies like radiation and chemotherapy. As a result, researchers have sought to understand how to turn cold tumors hot by reversing the suppressive microenvironment surrounding cold tumors and by attracting more of the "right" anti-tumor lymphocytes.
About Sudocetaxel Zendusortide (TH1902) and SORT1+ Technology
Sudocetaxel zendusortide is a first-of-its-kind sortilin receptor (SORT1)-targeting PDC, and the first compound to emerge from the Company’s broader licensed oncology platform. As a new chemical entity, sudocetaxel zendusortide employs a cleavable linker to conjugate (attach) a proprietary peptide to docetaxel, a well-established cytotoxic chemotherapeutic agent used to treat many cancers. The FDA granted Fast Track designation to sudocetaxel zendusortide as a single agent for the treatment of all sortilin-positive recurrent advanced solid tumors that are refractory to standard therapy. Sudocetaxel zendusortide is currently being evaluated in a Phase 1 clinical trial in individuals with advanced ovarian cancer.
Theratechnologies has established the SORT1+ TechnologyTM platform as an engine for the development of PDCs that target SORT1, which is expressed in multiple tumor types. SORT1 is a "scavenger" receptor that plays a significant role in protein internalization, sorting, and trafficking. Expression of SORT1 is associated with aggressive disease, poor prognosis, and decreased survival. It is estimated that SORT1 is expressed in 40% to 90% of endometrial, ovarian, colorectal, triple-negative breast (TNBC), and pancreatic cancers, making this receptor an attractive target for anticancer drug development.