The rapidly growing field of immunology is producing promising drug development candidates and has gained widespread attention among top pharma and biopharma firms. Numerous collaborations and alliances have been forged in this burgeoning field, along with acquisitions to gain immunotherapy pipeline assets. Immunotherapies, designed to elicit or amplify an immune response, have largely focused on oncology candidates, but are by no means limited to the field. However, to date, research challenges remain in properly evaluating what patient models are likely to best respond to an immunotherapy. Immunology models have been limited but recently released immunotherapeutic translational technology platforms representing both mouse and human immunity can help overcome today’s challenges to further advance discovery and development efforts. Dr. Jean-Pierre Wery, president at Crown Bioscience discusses immunology and its applications in medicine, specifically in targeting cancer, and this latest technology platform. --KB

Contract Pharma: What is immunotherapy and how can it be applied in oncology?

Dr. Jean-Pierre Wery: Broadly speaking immunotherapy involves treating disease by inducing, enhancing or suppressing an immune response. Each of these techniques can be employed to treat cancer and have shown considerable success in oncology research. There are several immunotherapeutic approaches to cancer treatments, including passive immunization, which fights cancer by modulating the host immune system or by harnessing the power of therapeutic antibodies in attacking tumor-associated antigens. Many promising results have also been observed in the use of combined antibody-drug conjugates (ADCs), where active compounds, combined with naturally occurring antibodies, deliver cytotoxic compounds directly into tumor cells. Active immunizations, or therapeutic vaccines, have also demonstrated efficacy in a variety of cancers.

CP: What has signified the coming of age of immunotherapy as a treatment paradigm for oncology?

JW: The ideal treatment for any disease is one that can cure or prevent the onset of a disease with the least impact on the quality of life of the patient. Surgery, irradiation and drug treatments in oncology and wider medicine have historically been associated with considerable side effects. This has fuelled the drive for less invasive, less aggressive treatments. In the case of drug delivery, the search for more advanced drug candidates has led to the development of immunotherapeutics, which have significantly fewer side effects.

Immunotherapy in oncology, offers a way to increase a patient’s comfort while also increasing the treatment efficacy of administered active compounds. The coming of age of immunotherapy as a treatment paradigm for oncology has really been signified by recent fast-track designations and regulatory approvals of immunotherapeutics (including the first FDA approval for an anti-PD-1 antibody). Immunotherapy is now a firmly established treatment paradigm that can bring both potential patient benefits and commercial success for the pharmaceutical industry.

CP:What are the advantages of utilizing immunotherapy in oncology?

JW: Traditional cancer treatments involve introducing systemic chemotherapy to the patient, or radiation to the area of the tumor. While these methods have some success killing cancerous cells, chemotherapy triggers a number of severe side effects, and radiation therapy can cause significant damage to surrounding healthy tissues. The advantages of cancer immunotherapy include improved safety margins and a prolonged effect due to the immune memory, preventing relapse and disease metastasis. Immunotherapy utilizes cell targeting, whereby treatments only attack cells carrying or expressing particular antigens. This significantly reduces the damage to healthy tissues and also increases the effectiveness of certain cytotoxic treatments, e.g., in the case of ADCs, they are only able to enter into cancerous cells before delivering the active compound. Certain immunotherapies also have the possibility of inducing a tumor-specific immunological memory, which could cause long-lasting disease regression and the prevention of disease relapse.

CP: In terms of developing effective new immunotherapeutics, what challenges must be overcome?

JW: The development of effective new immunotherapeutics in oncology still faces many challenges. As a research community we are still unsure why some patients and cancer types benefit from immunotherapeutic treatment while others do not. We also still need to determine how to maximize benefits from these agents. The major obstacle in overcoming these challenges is a lack of experimental immunology models.

At present, most commonly used experimental cancer models comprise of human tumors grown in immune compromised mice. The lack of a functional immune system in these models has significantly hindered the research and development of new immunotherapy agents. While syngenic and genetically engineered mutant mouse (GEMM) models with functional murine immunity are available and used in immunotherapy research, each model type has their own benefits and limitations. New models with functional immunity are essential in achieving a greater understanding of how current immunotherapeutics are functioning, and for future development of new agents and regimens.

CP: What is currently being done within preclinical research to overcome the lack of experimental immunotherapy models?

JW: As immunotherapy takes advantage of an individual’s immune system, it is important to simulate the immune response in the preclinical setting. Therefore, preclinical platforms that utilize both mouse and human immunity are now seen as a key requirement to achieving this.

To complement syngenic and GEMM models with functional murine immunity, one company is developing a collection of allografts of spontaneous murine tumors studied in mice with complete immunocompetency. These tumors have never been manipulated or adapted to grow in vitro and will cover a wide diversity of cancer types, enabling preclinical research into specific pathways and the discovery of new predictive biomarkers for targeted immunotherapy agents.

Together with this, human immunity platforms are being developed that can provide information on the function of the target as well as how the human immune response affects tumor growth using the most predictive type of preclinical xenograft model available – the patient-derived xenograft (PDX) model. These platforms can also provide models of transient human immunity (developed by mixing peripheral blood mononucleated cells with xenograft models), to provide a simple alternative to the full stem cell reconstitution approach.

CP: What benefits will new translational platforms provide for drug developers?

JW: As cancer research evolves, there is an ever-increasing need to develop methods of ascertaining the effectiveness of a compound before entering expensive clinical trials. With the cost of failure being so high, most drug developers simply cannot afford to support an ineffective candidate through the process of testing and authorization. The new platforms will be instrumental in providing accurate predictions of the success of immunotherapeutics in clinical trials, giving drug development companies invaluable indications as to which of their potential candidates should be backed all the way through to the clinic. The models can also provide answers to specific immunotherapy questions around maximizing agent benefit and identifying cancer indications of interest. By evaluating immune response to treatment, they can be used to assess where stimulation of the immune system is most beneficial for each specific disease type.
 
Prior to joining CrownBio, Dr. Wery was Chief Scientific Officer at Monarch Life Sciences, a company dedicated to the discovery and development of protein biomarkers. Prior to joining Monarch, Dr. Wery spent three years at Vitae Pharmaceuticals, Inc., where he was VP of Computational Drug Discovery. Before joining Vitae he worked for 12 years at Eli Lilly and Company in various scientific and management positions. Dr. Wery received his B.S. and Ph.D. in Physics from the U. of Liege, Belgium. Following his Ph.D., he did postdoctoral studies at Purdue University with Prof. Jack Johnson. Dr. Wery has authored more than 50 abstracts and publications.