On April 18, 2023 Theratechnologies Inc. ("Theratechnologies" or the "Company") (TSX: TH) (NASDAQ: THTX), a biopharmaceutical company focused on the development and commercialization of innovative therapies, reported preclinical data that demonstrate the potential utility of its lead investigational peptide drug conjugate (PDC) candidate, sudocetaxel zendusortide (TH1902) — both as a single agent and in combination with other anticancer therapies — in targeting tumors that express the sortilin (SORT1) receptor (Press release, Theratechnologies, APR 18, 2023, View Source [SID1234630263]). The new data were presented in poster sessions at the 2023 annual meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) in Orlando, Fla.
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In two separate posters presented at AACR (Free AACR Whitepaper), sudocetaxel zendusortide demonstrated increased anti-cancer efficacy in combination with programmed cell death-ligand 1 (PD-L1) checkpoint inhibitor therapy in a melanoma mouse model; and as a single agent against SORT1-positive TNBC or HER2+ breast cancer models, resulting in complete tumor regression. Furthermore, sudocetaxel zendusortide generated superior activity in comparison to a combination of Herceptin and docetaxel in the HER2+ Herceptin-resistant tumor model. A third poster showed high expression of SORT1 in multiple tumor types, compared to healthy tissues, bolstering the rationale for SORT1 inhibition as a potential therapeutic approach.
"It’s particularly exciting to see in the melanoma animal model that using the SORT1 receptor with sudocetaxel zendusortide in combination with immunotherapy shows greater tumor inhibition and longer survival compared to immunotherapy alone," said Christian Marsolais, Ph.D., Senior Vice President and Chief Medical Officer of Theratechnologies. "Collectively our three AACR (Free AACR Whitepaper) poster presentations reinforce the potential of sudocetaxel zendusortide, on its own and in combination, to enable targeted delivery of anticancer therapy. We look forward to further characterizing this novel investigational agent as we seek partners and advance our clinical development program."
Induction of immune cell infiltration and improvement of anti-tumoral activity of anti-PD-L1 checkpoint inhibitor
In the first AACR (Free AACR Whitepaper) poster, researchers reported that sudocetaxel zendusortide induces immune cell infiltration and potentiates the anti-tumoral activity of anti-PD-L1 therapy in a melanoma mouse model. Surprisingly, in this non-immunogenic, or "cold," tumor type, immunohistochemistry (IHC) analysis showed a net increase in total leukocyte infiltration within sudocetaxel zendusortide-treated tumors compared with docetaxel-treated tumors, especially with regard to marked increases in tumor-infiltrating lymphocytes and tumor-associated macrophages. Researchers also observed elevated cytotoxic T and natural killer cells in the sudocetaxel zendusortide-treated tumors.
Next, the researchers halved the doses of sudocetaxel zendusortide and docetaxel and combined each agent with an anti-PD-L1 checkpoint inhibitor. Notably, sudocetaxel zendusortide alone showed greater tumor growth inhibition than docetaxel, anti-PD-L1 or anti-PD-L1/docetaxel combination. In addition, the sudocetaxel zendusortide/anti-PD-L1 combination significantly increased tumor growth inhibition and median survival over either anti-PD-L1 or sudocetaxel zendusortide as single agents (21 days compared to 2.5 and 12.5 days, respectively). The investigators attributed the superior anticancer activity of sudocetaxel zendusortide over docetaxel, in part, to the modulation of infiltrating immune cells within the tumor microenvironment.
"Our data are the first to demonstrate that immune cell infiltration patterns could play a pivotal role in the sudocetaxel zendusortide-associated anti-tumoral response," commented Dr. Marsolais. "Given that preclinical results showed a statistically significant improvement in the efficacy of an anti-PD-L1 inhibitor for tumors treated with sudocetaxel zendusortide in contrast to docetaxel, we are hopeful that further research with combination therapy may also lead to improved clinical outcomes."
Breast cancer data
The second AACR (Free AACR Whitepaper) poster reported high expression of SORT1 in several TNBC and HER2-positive breast cancer cell lines as well as in more than 60-75% of cases from commercial breast cancer tissue microarrays. Researchers further observed that SORT1 is involved for both cell surface recognition and internalization of the peptide, TH19P01, without payload. Fluorescence microscopy showed rapid uptake and co-localization of both TH19P01 and sudocetaxel zendusortide in the late endosomal and lysosomal compartments at the perinuclear region, indicating that both compounds are internalized through a receptor-mediated endocytosis (a cellular process in which substances are brought into the cell) pathway.
In a murine MDA-MB-231 TNBC tumor model, weekly administration of sudocetaxel zendusortide at a dose (35 mg/kg) equivalent to the maximally tolerated dose (MTD) of docetaxel (15 mg/kg) led to complete and sustained tumor regression, while docetaxel only inhibited tumor growth by half. Furthermore, in mice bearing HER2-positive breast tumor tissue grafts, sudocetaxel zendusortide induced complete tumor regression, unlike docetaxel, Herceptin and Herceptin/docetaxel combination.
Based on the demonstrated high anticancer properties of sudocetaxel zendusortide against SORT1-positive TNBC and Herceptin-resistant HER2-positive breast cancer models, as well as its higher tolerability compared to docetaxel, the researchers concluded that sudocetaxel zendusortide can be a promising avenue for further evaluation in the treatment of patients with SORT1-positive breast cancers.
SORT1 expression data
To better understand SORT1 expression, the Theratechnologies research team used IHC to screen 19 cancer tissue microarrays with 1394 evaluable cancer cores. They scored each cancer core using an H-score ranging from 0 to 300, whereby a score of 0 indicates no cell staining for SORT1 and a score of 300 corresponds to strong SORT1 staining in all cells. The table below summarizes the percentage of cancer cores with moderate to high SORT1 expression (defined as H-score ≥ 100) as well as the average H-score for each cancer type evaluated:
Cancer type No. evaluable cores % with H-score ≥ 100 Average H-score
Endometrial 94 90 197
Thyroid 108 92 188
Melanoma 155 83 184
Bladder 118 81 156
Testis 40 100 116
Lung 152 58 112
• Small cell lung 44 95 183
• Non-small cell lung 108 43 82
Small intestine 54 63 102
Eye 26 46 83
Cervix 376 38 75
Prostate 150 39 71
Liver 121 23 52
Results of the three presentations at AACR (Free AACR Whitepaper) 2023 validate and build upon previous reports on the pattern and prevalence of SORT1 expression in common tumor types, underscoring the promise of SORT1 as a target for the delivery and internalization of anticancer therapeutic agents.
Full posters can be found on Theratechnologies’ website.
About Immunotherapy in Cold and Hot Tumors
Immunotherapies have significantly improved the treatment of cancer. Researchers continue to explore the power of the body’s own 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 (GBM) are cold tumors, and are largely treated with traditional therapies like radiation and chemotherapy. As a result, much research has been done to understand how to turn cold tumors hot by reversing the suppressive microenvironment surrounding cold tumors and attracting more of the right anti-tumor lymphocytes.
About SORT1+ Technology and Sudocetaxel Zendusortide (TH1902)
Theratechnologies is currently developing a platform of proprietary peptides called SORT1+ TechnologyTM for cancer drug development targeting SORT1 receptors. The SORT1 receptor plays a significant role in protein internalization, sorting and trafficking. It is highly expressed in cancer cells compared to healthy tissue, which makes SORT1 an attractive target for cancer drug development. Expression of SORT1 is associated with aggressive disease, poor prognosis and decreased survival. It is estimated that the SORT1 receptor is expressed in 40% to 90% of cases of endometrial, ovarian, colorectal, triple-negative breast and pancreatic cancers.
Sudocetaxel zendusortide (TH1902) is currently Theratechnologies’ lead investigational PDC candidate for the treatment of cancer derived from its SORT1+ Technology. It is the Company’s proprietary peptide linked to docetaxel – a commonly used cytotoxic agent used to treat many cancers. The FDA granted fast track designation to TH1902 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, although patient recruitment was voluntarily paused on December 1, 2022. In alignment with this decision, the FDA placed the trial on partial clinical hold. The Company is currently preparing a protocol amendment, which includes recommendations from the Scientific Advisory Committee meeting held in March 2023.