A new Phase I clinical trial will assess the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of TRX518, a monoclonal antibody designed to enhance the immune system by enabling T cells to more effectively attack cancer cells.

TRX518 is a unique targeted T cell immunotherapy that activates GITR (glucocorticoid-induced tumor necrosis factor receptor) found on multiple types of T cells and other immune cells. Activated GITR plays a role in directing the anti-tumor immune response via activating tumor-antigen-specific T effector cells, as well as abrogating the suppression induced by inappropriately activated T regulatory cells.

GITR was ranked 12th in a list of agents with high potential for use in treating cancer at a National Cancer Institute (NCI) workshop in 2007

Preclinical proof of concept studies established that administration of an anti-GITR antibody together with chemotherapeutic drugs was synergistic in multiple models of established and metastatic cancer. In preclinical studies, TRX518 achieved its targeted effect without compromising normal immune function, and preclinical models suggest TRX518 may have a reduced risk of causing serious inflammatory side effects that can result from cytokine release. TRX518 is designed to have activating and sustaining effects on T cells for enhancing the immune system’s responses against cancer cells, including responses that may occur with TRX518 alone, as well as complementary responses in combination with other cancer therapies including vaccines.

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GITR-activating immunotherapeutics are expected to be more potent than cancer vaccines, because they have the ability to induce both the activation of tumor-antigen-specific T effector cells, as well as abrogate the suppression induced by inappropriately activated T regulatory cells.

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The Phase I trial will evaluate ascending single doses of TRX518 in patients with malignant melanoma. Leading cancer researchers at the Memorial Sloan-Kettering Cancer Center will conduct the trial which is is supported by research funding from the Cancer Research Institute and clinical trials management expertise from the Ludwig Institute for Cancer Research Ltd., through its Cancer Vaccine Acceleration Fund (CVAF).

“We are very enthusiastic about leading the clinical study of TRX518 and evaluating this innovative immunotherapy, which offers a new approach to help cancer patients,” said Jedd Wolchok, MD, PhD, director of immunotherapy clinical trials at Memorial Sloan-Kettering Cancer Center. “In collaboration with Tolerx and the leadership team at the CVAF, we have assisted with the unique aspects of immunotherapy trials in cancer, including patient enrollment criteria, dosing strategy, trial endpoints, and other considerations to ensure the highest standards and quality results for the TRX518 Phase 1 study.”

This open label, non-randomized, ascending dose design will assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending intravenous doses of TRX518 in up to 40 patients with advanced stage III and IV malignant melanoma. The goal is to determine the maximum tolerated dose of TRX518 as patients are assessed over the 18-week core study period. In future clinical programs, Tolerx plans to evaluate TRX518 for the treatment of other cancers, building on the broad potential of GITR as a fundamental mechanism involved in cancer as well as preclinical proof of concept studies of TRX518 in multiple models of established and metastatic cancer.

“Starting this first-in-human study with TRX518 in an oncology indication is an important milestone for Tolerx. TRX518 has a novel mechanism of action and has the potential to enhance an anti-tumor immune response, regardless of tumor type, and this has tremendous potential for a broad variety of malignancies,” said Louis Vaickus, MD, Chief Medical Officer at Tolerx. “TRX518 works through GITR (glucocorticoid-induced tumor necrosis factor receptor), a molecule that has been recognized by the National Cancer Institute and other experts as one of the most promising targets in cancer immunotherapy.”

Tolerx Inc, the biotechnology copmay developing novel therapy, has an open IND from the US FDA for TRX518.

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