Cancer of the pancreas is a deadly disease. It is rarely diagnosed at early stages where treatment could be more helpful, and there are few effective treatments for patients with advanced disease. So far, academic and industry research has failed to find a solution for early diagnosis or an effective therapy to improve survival. Despite the efforts from large pharma, biotech and academic researchers to target this cancer, only 25 % of the patients diagnosed with pancreatic cancer will live more than one year.
Bellicum Pharmaceuticals, based in Houston, TX, is developing a new approach to dealing with this devastating disease, utilizing a new platform based on a unique CAR-T activation “switch” that increases the potency of pancreatic cancer-targeted T cell therapies by direct tumor killing and stimulation of the patient’s immune system – a double barrel tumor killer. Bellicum is a clinical-stage cell therapy company focused on discovering and developing novel cellular immunotherapies by modulating T cell function via controllable molecular switches. The company is using a proprietary Chemical Induction of Dimerization, or CID, technology platform to engineer product candidates with switch technologies that are designed to control components of the immune system in real time by administration of small molecules to turn gene-modified immune cells (e.g., CAR-T cells) on or off to maximize efficacy and limit potential toxicities.
BPX-601 is an autologous GoCAR-T product candidate containing a proprietary inducible MyD88/CD40 (iMC) activation switch, designed to treat solid tumors expressing prostate stem cell antigen, or PSCA. PSCA is a cancer antigen expressed in several solid tumor indications, including pancreatic, gastric and prostate cancers. Preclinical data has shown that MC augments T cell proliferation and persistence, enhances host immune activity, and modulates the tumor microenvironment to improve the potential to treat solid tumors compared to traditional CAR-T therapies.
Last month at ASCO, Bellicum announced positive updated safety and activity data for BPX-601, from a Phase1/2 study in patients with metastatic pancreatic cancer expressing prostate stem cell antigen (PSCA).
As part of WuXi Communications program to highlight innovative solutions to develop drugs that can make a difference in patients’ lives, WuXi spoke with Bellicum President and CEO Rick Fair about his company’s new technology and how it might work to solve the pancreatic conundrum – one where so many others have failed.
Rick Fair has a 20+-year track record as a strategist and commercial leader in the biopharmaceutical industry. He joined Bellicum as President and CEO in January 2017 from Genentech/Roche where he most recently served as Senior Vice President, Head of Oncology Global Product Strategy. In this role, he oversaw the global launch of five new molecular entities and numerous line extensions. Prior to Genentech, Mr. Fair spent nine years at Johnson & Johnson, holding leadership roles in marketing, managed care and reimbursement strategy. Mr. Fair received his B.S. from the University of Michigan and his M.B.A. from Columbia Business School.
WuXi: What is your opinion about the challenges in pancreatic cancer early screening and diagnosis? Are there any specific biomarkers?
Rick Fair: Early detection of pancreatic cancer is challenging with current methods, and unlike colorectal or prostate cancer, there is not a standardized screening strategy for the disease. For patients diagnosed with pancreatic cancer, serum biomarkers such as CA19-9, CA125 and CEA can be used to track cancer progression and response to treatment. There are a variety of other assays in development, including cell-free (e.g. miRNA, lcRNA), circulating tumor cells and exosome testing, but they have not been universally adopted by treatment centers.
WuXi: What are the hot targets in the field of drug development for pancreatic cancer?
Rick Fair: There are a number of trials exploring inhibitors to EGFR, VEGF, and PARP pathways in combination with chemotherapy or cancer immunotherapies. In addition, there has been an increased focus on altering the tumor microenvironment with modulators to encourage the patient’s own immune cells to kill the cancer, including inhibitors to chemokine pathways, activators of macrophages and other immune agonists. In addition to our PSCA targeting CAR-T study, there are also some trials targeting different antigens in pancreatic cancer, such as mesothelin, CEA, Claudin 18.2, etc.
WuXi: In recent years, what breakthroughs have been made in drug development for pancreatic cancer?
Rick Fair: Immunotherapies aimed at stimulating the immune system are starting to show promise in treating pancreatic cancer. For example, a CD40L immune agonist, when used in combination with standard of care chemotherapy and nivolumab induced a response in patients with advanced disease, which suggests that immunotherapies that alter or boost the immune system may be effective.
WuXi: How is your drug different from existing pancreatic cancer treatments? Is it a new approach? What have been the results of your research so far?
Rick Fair: CAR-T cells are T cells genetically engineered to target a specific protein expressed on the surface of tumor cells. In this case, our product candidate BPX-601 targets PSCA, which is expressed at a high level in approximately 50% of pancreatic cancers.
CAR-T cells have demonstrated promising results in hematologic malignancies, including two products (Yescarta and Kymriah) which have been approved to treat certain types of CD19+ B-cell leukemias and lymphomas. Results to date in solid tumors have been more limited. BPX-601 is a next generation CAR-T cell product that includes a drug-dependent activation switch (iMC), that is more potent than current CAR-T designs, and may address some of the limitations of CAR-T cell therapies in solid tumors.
In the most recent early Phase 1 results, presented at the ASCO Annual Meeting (June 2019), we reported on the first 18 patients treated in the dose escalation portion of the study. To date, our key findings indicate that BPX-601 has been well tolerated, with no dose-limiting toxicities observed. The majority of adverse events related to BPX-601 were mild to moderate and resolved with or without supportive care. And, in spite of a conservatively designed clinical experiment, evidence of encouraging biologic activity has been observed early in the study. Of 13 efficacy-evaluable patients reported, 8 (62%) achieved stable disease, and 3 patients had tumor shrinkage ranging from 10-24%. In the next phase of the study, iMC will be triggered to activate BPX-601 cells each week, which is designed to deepen and extend the treatment effect. We intend to report first results from this cohort of patients around year-end 2019.
WuXi. What is the specific mechanism of action?
Rick Fair: BPX-601 is designed to kill tumors through two mechanisms: First, direct tumor cell killing through binding of the PSCA CAR-T cells to the PSCA antigen expressed on pancreatic tumor cells; and second, through the recruitment and activation of the host immune response through the production of pro-inflammatory cytokines and chemokines.
WuXi: How did you choose to focus on pancreatic cancer, considering that it has been a very difficult disease to treat?
Rick Fair: The target PSCA that is addressed by BPX-601 is expressed on several tumors of the gastrointestinal and genitourinary tracts. While challenging, pancreatic cancer is viewed as an attractive area for exploration given the large percentage that express PSCA and the very high unmet need.
WuXi: Are you planning to develop the drug through regulatory approval and market it?
Rick Fair: We continue to enroll the Phase 1/2 study in pancreatic cancer, and intend to expand the study to include patients with other tumors that express PSCA. In the event we observe clinically meaningful activity, we will expand this study and/or initiate a new trial to enable regulatory approval.
WuXi: What major challenges have you faced in trying to bring a new drug for pancreatic cancer to patients?
Rick Fair: Pancreatic cancer is a difficult tumor to treat. The tumor microenvironment has many different factors inhibiting immune responses to tumors, such as tumor stroma, an absence of tumor infiltrating lymphocytes, the presence of immunosuppressive cell types and other factors. Additionally, many pancreatic cancer patients who are relapsed or refractory to other treatments are in poor health with a very limited life expectancy; ensuring patients have adequate performance status and sufficient life expectancy to receive treatment under the clinical trial protocol is a challenge for participating trial investigators.
WuXi: What lessons have you learned during the development process?
Rick Fair: It is critical to collect relevant samples, such as blood and on-treatment tumor biopsies for correlative studies. It is important once the appropriate dose and schedule of BPX-601 and rimiducid has been determined, to treat a relatively homogeneous group of patients to understand the impact of treatment our therapy.
WuXi: Have you benefited from FDA initiatives, such as breakthrough therapy and fast track designations? If so how?
Rick Fair: We have not applied for breakthrough designation thus far. Depending on future clinical data, that could be considered in the future.
WuXi: What other drug candidates do you have in the pipeline?
Rick Fair: In addition to BPX-601, we are developing rivo-cel, an allogeneic polyclonal T cell product genetically modified with our CaspaCIDe safety switch to improve immune reconstitution and reduce the rate of relapse and mortality in patients with hematologic malignancies and orphan blood disorders undergoing hematopoietic stem cell transplantation. We recently announced results from a Phase 1/2 study in pediatric patients who have had stem cell transplants that will serve as the basis for filings for regulatory approval in Europe.
Other candidates include BPX-603 a dual-switch HER2 targeted CAR-T cell product that incorporates both the iMC activation switch and our CaspaCIDe safety switch. We expect to clear our IND application and initiate a Phase 1/2 study in patients with solid tumors expressing HER2 by the end of 2019. We are also developing BPX-802 a dual switch GoCAR-T targeting an antigen expressed in certain hematologic malignancies. We expect to file an IND application by the end of 2019 and initiate a Phase 1/2 study in 2020.
WuXi: Looking at the entire drug development process, from discovery all the way to drug approval, what would be the key areas or processes you would change or improve in order for companies to bring more and better drugs to pancreatic cancer patients each year?
Rick Fair: For the discovery and development of cell therapies in pancreatic cancer, I would highlight several areas of opportunity.
- First, identification of target antigens that are highly and homogeneously expressed in tumor cells.
- Second, development of mechanisms to penetrate or circumvent tumor stroma to allow CAR-T and endogenous T cell access to enable tumor cell killing.
- Third, development of more robust biomarkers to diagnose and track the response of pancreatic cancer to immunotherapies.
WuXi: And finally, what will be the one or two most significant technological advances in pancreatic cancer drug development over the next year or two?
Rick Fair: In cell therapies for pancreatic cancer, I would say initially the identification of effective cell therapies and combination therapy strategies that synergize with them. As we do that, then the focus will be on the development of off-the-shelf cell therapies to improve the scalability and cost of these treatments.