One of the reasons why cancers arise or recur is their ability to evade the immune surveillance. Breakthrough discoveries over the past 3 decades revealed immune checkpoints molecules, such as PD-1, as key mechanism suppressing tumor-killing T cell function and thus enabling cancer evasion from immune surveillance. Immune checkpoint blockade therapy (ICBT), such as PD-1 inhibitor pembrolizumab, can fully awaken the dysfunctional T cells inside the tumors to destroy the constantly changing cancer cells. However, majority of triple-negative breast cancers (TNBC), the most aggressive form of breast cancer, have little or no T cells inside the tumors, a term called immune-cold. These patients ca...

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One of the reasons why cancers arise or recur is their ability to evade the immune surveillance. Breakthrough discoveries over the past 3 decades revealed immune checkpoints molecules, such as PD-1, as key mechanism suppressing tumor-killing T cell function and thus enabling cancer evasion from immune surveillance. Immune checkpoint blockade therapy (ICBT), such as PD-1 inhibitor pembrolizumab, can fully awaken the dysfunctional T cells inside the tumors to destroy the constantly changing cancer cells. However, majority of triple-negative breast cancers (TNBC), the most aggressive form of breast cancer, have little or no T cells inside the tumors, a term called immune-cold. These patients cannot benefit from ICBT because they don't have the army inside their tumors that can be invigorated and deployed by the drug. We discover that the immune-cold TNBC tumors take advantage of an important stress response molecule, called IRE1a, to protect the cancer cells from being recognized by the immune system, and thus preventing T cell activation and infiltration. Inhibiting IRE1a with a highly selective drug ORIN1001 rips off the protection shield, allowing T cells infiltration into the tumors, and renders them hyper-sensitivity to ICBT. We show that while immune-cold TNBC tumors do not respond to the standard of care pembrolizumab-chemotherapy at all, adding ORIN1001 renders them hyper-sensitivity and long-term remission. Importantly, ORIN1001 has demonstrated safety, tolerability and promising preliminary efficacy in our ongoing Phase I clinical trial. This proposal will test the highly innovative immunotherapy with ORIN1001, taxane and pembrolizumab in a Phase II clinical trial in parallel with preclinical trial to establish the efficacy and define predictive biomarkers. If successful, this project will have immediate clinical impact and result in a paradigm shifting breakthrough in the treatment of immune-cold cancers.

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