Lung cancer remains a stubborn disease to treat. Even cutting-edge immuno-therapies have had limited success. Brian Wong, CEO of South San Francisco-based RAPT Therapeutics, believes that the company’s lead drug, FLX475, has potential to overcome the scientific challenges in treating this disease.
RAPT’S proprietary discovery platform has identified certain tumors in which the abundance of regulatory T (Treg) cells are likely to be a key cause of immune suppression. RAPT refers to these tumors as “charged” because of their expression of high levels of C-C motif chemokine receptor 4 (CCR4) ligands, Treg cells and CD8 positive effector cells. These charged tumors include tumor types such as non-small cell lung cancer. RAPT’s approach is designed to enable selective restoration of the immune response within tumors without systemically depleting Treg cells or broadly suppressing the immune system.
Dr. Wong is leading RAPT’s programs. He joined RAPT Therapeutics in 2015, bringing more than 15 years of experience leading research and translational medicine organizations. Most recently, he served as Senior Vice President, Research, and Head of Immuno-Oncology at Five Prime Therapeutics, where he led the discovery of novel therapeutics in cancer and inflammation. Prior to Five Prime, Dr. Wong served as Director of Research in the Inflammation Disease Biology Area at Roche Palo Alto from 2005 to 2009. From 2000 to 2005, he held various leadership roles at Rigel Pharmaceuticals, where he identified and developed clinical candidates for allergic, autoimmune and respiratory disorders, including Tavalisse™.
Dr. Wong received his M.D. from the Weill Cornell Medical College and his Ph.D. in Immunology from Rockefeller University.
WuXi AppTec: What is your opinion about the challenges of early diagnosis of lung cancer? Are there any specific biomarkers?
Dr. Brian Wong: The biggest challenges in the early diagnosis of lung cancer are determining which people to screen, and developing methods that can reliably diagnose the disease at a stage when it is still curable, or at least improve overall survival.
Finding the right biomarkers to identify and select patients who will best respond to specific immunotherapies is a constantly evolving area. PD-L1 expression and tumor mutational burden are among the most extensively studied and investigated, but are by no means perfect.
Through extensive computational analysis of cancer genetic signatures, we have identified tumor types characterized by high levels of effector cells, Treg cells, and CCR4 ligands as being tumors we believe have a higher chance of responding to our drug candidate (FLX475), which targets CCR4 and Treg cell recruitment. We call these “charged” tumors, and non-small cell lung cancer is one of those “charged” tumor types.
WuXi App Tec: What are the hot targets in the field of drug development for lung cancer?
Dr. Brian Wong: Relevant to immuno-oncology, the anti-PD-(L)1 antibody therapies have revolutionized lung cancer therapy and have become key treatment options for a subset of patients. However, it is clear that a majority of patients do not respond to these therapies, likely due to immune-resistance mechanisms such as Treg cells, which act to suppress the immune response.
At RAPT we are developing a novel oral small molecule that is designed to specifically target Treg cells associated with the tumor while not triggering widespread immune suppression, which has historically plagued the field.
WuXi App Tec: What treatment modalities show the most potential? Are there any with the potential to treat early stage disease?
Dr. Brian Wong: Immunotherapies are showing new potential in the treatment of lung cancer, both as monotherapies as well as in combination with different treatment modalities, including other novel immuno-oncology agents and chemotherapy. With that said, there is still room for significant improvement in this therapeutic area since still only a minority of lung cancer patients are benefiting from checkpoint inhibitors.
WuXi AppTec: How is your drug different from existing lung cancer treatments? Is it a new approach?
Dr. Brian Wong: We are developing FLX475, our lead drug candidate targeting CCR4, for the treatment of a broad range of “charged” tumors. These “charged” tumors are characterized by high levels of effector cells, Treg cells, and CCR4 ligands, the target for our immunotherapy. “Charged” tumor types include lung cancer and other cancer types we believe are most likely to respond to FLX475.
In cancer, the secretion of certain chemokines from tumor cells and tumor-resident immune cells is responsible for recruitment of immunosuppressive Treg cells to tumor sites. Treg cells represent a dominant pathway for downregulating the immune response, and thus may limit the effectiveness of currently available therapies such as checkpoint inhibitors. Therefore, blocking the migration of Treg cells has the potential to restore naturally occurring antitumor immunity as well as to synergize with a variety of both conventional and immune-based therapies, such as radiation, chemotherapy, checkpoint inhibitors, immune stimulators and adoptive T cell therapy.
We believe that the inhibition of CCR4 has the potential to bring therapeutic benefit to lung cancer patients (among other tumors) in a manner similar to other immuno-oncology therapies that have been shown to be effective against multiple tumor types, while also potentially deepening or broadening clinical responses to these therapies.
The company is conducting a Phase 1/2 study of FLX475 in patients with advanced cancer. The Phase 1 portion of the study will examine the safety and determine the Phase 2 dose of FLX475, both as a monotherapy and in combination with pembrolizumab. The Phase 2 portion will examine the efficacy of FLX475 both as monotherapy and in combination with pembrolizumab in selected types of cancer.
WuXi AppTec: What is the specific mechanism of action?
Dr. Brian Wong: FLX475 is an orally-available small molecule drug that blocks the CCR4 receptor on regulatory T cells and thus stops their ability to be recruited into tumors. By cutting off the supply of suppressive regulatory T cells to the tumor microenvironment, FLX475 is predicted to then shift the CD8 effector T cell to regulatory T cell balance toward the anti-tumor effector cells which should promote the eradication of tumor cells. FLX475 could be used either as monotherapy, or in combination with other therapies that can be limited by regulatory T cells such as checkpoint inhibitors, CAR-T cells, vaccines, chemotherapy, and radiation therapy.
WuXi AppTec: How did you choose to focus on lung cancer? It has been a very difficult disease to treat.
Dr. Brian Wong: Through our analysis of many types of cancer we identified specific tumors that appear to be much more likely to express high levels of CCR4 ligands and to have high numbers of regulatory T cells and effector CD8 T cells, which we believe have a higher chance of responding to FLX475. Non-small cell lung cancer (NSCLC), both adenocarcinoma and squamous subtypes, came up as being among the most “charged” tumor types in our analysis.
WuXi AppTec: Other than participating in clinical trials how have patients been involved in the development of your drug?
Dr. Brian Wong: We have incorporated our profiling of cancer patient genetic data to come up with the “charged” tumor profile, which has indicated that NSCLC patients may be more likely to respond to FLX475. So patient data have certainly helped shape our overall development plan.
WuXi AppTec: What major challenges have you faced in trying to bring a new drug for lung cancer to patients?
Dr. Brian Wong: It is a highly competitive field, with many clinical trials ongoing using all kinds of agents, both novel and follow-on. We see these dynamics as good for patients as it means that the industry is focusing on the unmet needs of this patient population, but it also can mean many clinical trials are recruiting the same types of patients.
WuXi AppTec: What lessons have you learned during the development process?
Dr. Brian Wong: It is crucial to engage with investigators early on in the process and to communicate the science behind your drug candidate. Patient selection and enrichment strategy as well as a comprehensive biomarker program are critical in increasing the probability of success.
WuXi AppTec: What other drug candidates do you have in the pipeline?
Dr. Brian Wong: For cancer we are developing inhibitors of general control nonderepressible 2 (GCN2) and hematopoietic kinase 1 (HPK1), both of which limit the immune systems’ ability to recognize and eliminate tumor cells. These programs are in the discovery stage. We are also developing a second CCR4 antagonist called RPT193 as an oral treatment for a broad array of allergic disorders.
WuXi AppTec: What are the top three major impediments in our delivery of “better” medicines “faster” and “better” to patients?
Dr. Brian Wong: First, identifying novel targets to meaningfully improve clinical outcomes. Second would be the identification of patient populations or subpopulations that have an increased probability of responding to these novel mechanisms of action, and the third impediment is the high number of clinical trials competing for the limited numbers of patients who actually participate in clinical trials.
WuXi AppTec: For lung cancer, what would be the one thing that would have the greatest potential to lead a paradigm shift “from treatment to cure?”
Dr. Brian Wong: Finding the right combinations of therapies that can both directly kill tumor cells while unleashing the full capacity of the immune system to develop, expand, and maintain an effective anti-tumor immune response.