Targeted "high energy" tumor immunotherapy flx475 is expected to benefit specific gastric cancer / lung cancer patients

Recently, in 2018, rapid therapeutics (formerly known as FLX bio), a biotech company, announced that it would reach an R & D cooperation of up to $118 million with Hanmi pharmaceutical in South Korea Hanmi company will obtain the R & D rights and interests of flx475, the main oral cancer immunotherapy of rapt company, in South Korea and China It will conduct 1 / 2 phase clinical trials of flx475 and 2 phase clinical trials of gastric cancer patients in South Korea and China, and assist the global clinical trials launched by rapt company How does flx475 stimulate the immune system to destroy cancer cells? Why are specific cancer patients in China particularly likely to benefit from this treatment? Recently, the content team of Wuxi apptec made an exclusive interview with Dr Brian Wong, the CEO of rapid He shared the unique features of this "first in class" oral cancer immunotherapy, as well as the patients it might benefit Immune system and cancer cells -- the game of "cat and mouse" people who have seen the classic animation "cat and mouse" (also known as Tom and Jerry, Tom and Jerry) may still remember the endless means of confrontation between the two protagonists of the animation, Tom cat and Jerry Mouse To some extent, there is also a cat and mouse game between cancer cells and the immune system After the discovery of cancer cells, the immune system will take a variety of measures to eliminate cancer cells, one of the important means is to activate CD8 positive T lymphocytes to recognize cancer cells These lymphocytes can migrate to cancer tissue and kill cancer cells Cancer cells also "use all their powers" to escape the "pursuit" of immune cells For example, they express immune checkpoint proteins (such as PD-L1) that inhibit T cell activation and inactivate T lymphocytes Inhibitors developed for immunocheckpoint proteins (such as keyturda and opdivo, PD-1 inhibitors, tecentriq and imfinzi, PD-L1 inhibitors) have brought revolutionary changes to cancer treatment and become one of the pillars of cancer treatment However, there are many ways to inhibit immune response in cancer cells Tumor microenvironment is another important factor to inhibit T cell activity Cancer cells can release chemokines and recruit regulatory T cells (Tregs) to migrate from the blood to the tumor microenvironment Treg's function is to inhibit the activation of CD8 positive T cells They and other immunosuppressive cells are important reasons for the immunosuppressive characteristics of tumor microenvironment Researchers at the rapid company found that although some tumor tissues were full of CD8 positive T cells, they also gathered many Treg cells They call them "charged" tumors If we can reduce the number of Treg cells, can we "detonate" these "high-energy" tumors and let CD8 positive T cells exert their power? Flx475 is such a "first in class" oral cancer immunotherapy Flx475 - cancer immunotherapy for "high energy" tumors, Dr Brian Wong said flx475 is an oral small molecule drug that blocks CCR4 receptors on the surface of Treg cells In order to attract Treg cells to migrate from blood to tumor microenvironment, tumor cells release trend factors CCL22 and CCL17 By binding to CCR4 receptor, these trend factors attract Treg cells to migrate to tumor microenvironment and inhibit the activity of CD8 positive T cells Flx475 reduces the migration of Treg cells to tumor microenvironment by binding with CCR4 receptor, changes the balance between Treg cells and CD8 positive T cells in tumor microenvironment, and recovers the ability of CD8 positive T cells to kill cancer cells Unlike other targeted Treg cell therapies, this treatment does not kill Treg cells and cause Treg cell depletion, so it does not affect the function of Treg cells in other parts of the body So which cancer patients carry the "high energy" tumor targeted by flx475? The ability to find these patients is one of the reasons for the R & D cooperation between rapt and Hanmi More than 50 years ago, British scientists Anthony Epstein, Yvonne Barr and Burt Achong published a landmark study in the lancet, describing the first human virus that can cause cancer The virus was later named Epstein Barr virus (EBV) Subsequent studies have found that EBV is associated with a variety of specific cancer types, including NPC and gastric cancer, which are more common in China Moreover, one way for EBV to escape the pursuit of human immune system is to recruit Treg cells For example, EBV can enhance the expression of CCL17 and CCL22 in infected human B cells, so as to construct "high energy" tumors Therefore, gastric cancer and nasopharyngeal cancer patients with "high energy" tumors are particularly likely to benefit from flx475 treatment, which is more common in Asian countries "Although we are conducting global clinical trials, we still have limited access to 'high-energy' cancer patients," said Dr Wong, "and this collaboration will allow us to bring this treatment to more patients." Virus related cancer patients are an important group of patients carrying "high-energy" tumors, so which other cancer patients may carry these "high-energy" tumors? March into lung cancer: how to change treatment to cure? Dr Wong said that rapt used its unique technology platform to analyze the genetic information of patients with different types of cancer The results showed that NSCLC patients are one of the most likely cancer types to carry "high-energy" tumors Lung cancer is the leading cause of cancer death in the world and China Cancer immunotherapy has made remarkable progress in the treatment of lung cancer Keytruda, a blockbuster PD-1 inhibitor developed by MSD, has been approved for first-line treatment of NSCLC patients for three times in China in the past year However, PD-1 / PD-L1 inhibitors can increase the expression of CCL17 and CCL22 in cancer cells, thus attracting more Treg cells into tumor microenvironment and inhibiting the activity of CD8 positive T cells This is an adaptive way for tumor cells to evade the attack of immune system, and also provides an opportunity for flx475 to further improve its efficacy The combination of flx475 and PD-1 inhibitor is expected to further enhance the anti-tumor immune response Currently, the clinical trials planned by rapt include the combination of flx475 and keytruda to treat specific cancer patients In addition to flx475, the company is also developing other innovative therapies to enhance the immune response to cancer, including Gcn2 and HPK1 inhibitors Talking about how to develop better therapies for patients faster, Dr Wong said that it is very important to find innovative targets that can bring significant clinical efficacy However, using biomarkers to analyze patient groups and find out the patient subsets that can benefit most from innovative therapies is also one of the key factors to improve the success rate of clinical development These principles are reflected in the development path of flx475 It is found that the right combination of therapies can not only directly kill cancer cells, but also release the full potential of the immune system, stimulate and maintain an effective anti-cancer immune response Dr Wong said that this is the most promising way to change the treatment mode of lung cancer from treatment to cure.