1. Why are T cells promising/exciting in cell therapy right now? What potential do you see?
“T cells play a central role in the immune response, as they have the potential to directly kill virus-infected or malignant cells, as well as modulate immune responses. With the development of the CAR T technology, T cells can be engineered to express antigen-specific TCRs (T Cell Receptors) or CARs (Chimeric Antigen Receptors) and thus be directed to kill any cells that express a particular antigen. This has proven to achieve long-lasting clinical effects in case of hematologic malignancies, while more development is needed to successfully apply CAR T cell therapy to solid tumor settings. The attractiveness of the T cell approach is clearly the potential of having complete and durable responses after a single treatment, with long-living T cells providing immune surveillance including across the blood brain barrier. Another exciting area are regulatory T cells, as initial Phase I clinical trials indicated both safety and efficacy in GVHD (Trzonkowski et al, 2009, Brunstein et al., 2010, Di Ianni et al. 2011), as well as type I diabetes (Marek-Tronzkowska et al., 2012, Bluestone et al, 2015). With improved methods to consistently isolate and expand these cells, an area in which PCT is actively working, regulatory T cells have potential therapeutic use in a large number of chronic autoimmune diseases.” – Ines
“T cells direct the immune system, and are potent and specific killers of malignant or virus-infected cells. They can be isolated efficiently from blood and expanded consistently in vitro for cell therapy, typically in oncology (leukemia and other blood cancers) or antiviral clinical indications (such as EBV). In the case of regulatory T cells (Tregs), they can be used to suppress autoimmune conditions such as asthma, diabetes, and inflammatory bowel disease.” – Cenk
“Throughout the industry, a great deal of clinical data is really starting to show significant T cell immunotherapy response rates in patients. A shining example would be data from Novartis’ Phase 2 study of CTL019 that showed 55/59 ALL patients experiencing complete remission. This is truly exciting, as this provides validation not only for the therapies but to the researchers, old and new, who have helped blaze the trail we are currently traveling down.” – Joseph
2. What do you see as the most significant discoveries or advancements in this field in the past few years? Why?
“The development of engineered TCR or CAR (chimeric antigen receptor) expressing T cells pioneered by Zelig Eshhar, Carl June, and others certainly is the most prominent, with previously unknown success rates for treatment of ALL (93% complete remission in CTL019 Phase II clinical trial) and potential applicability for treatment of a variety of tumors. While CARs recognize surface antigen, TCRs can potentially be specific to any expressed protein, irrespective of its cellular localization thus broadening the number of targetable proteins.” – Ines
“The development of CAR T cell therapies for B cell malignancies looks to be a major advance in cellular immunotherapy. The development of immune checkpoint inhibitors has been a major advance in the use of biologics to treat cancer.” — David
“I think the most significant advances have come from the NCI (Rosenberg et al), U Penn (June, Levine et al) and MSK (Sadelain et al) teams, using CAR and TIL (Tumor Infiltrating Lymphocyte) T cell therapy to achieve (among other spectacular clinical results) up to 90% response rates to blood cancers such as ALL, often in pediatric patients with no other viable option. In my opinion, this work clearly deserves a Nobel prize, and I hope to see one awarded to these investigators (as well as Zelig Eshhar, "father" of the CAR).” – Cenk
“For me it’s the next-generation CARs, as increased T-cell activation, expansion, and persistence will be essential in making additional therapeutic gains within the industry. I’m also very excited about CARs with inducible or constitutive release of IL-12. These ‘Armored CARs’ are targeted more towards solid tumors, which are really the next frontier in the immunotherapy field. The additional release of IL-12 from these T cells is expected to build up within the solid tumor and trigger a strong immune response in what was originally a very immune-suppressive tumor environment.” – Joseph
3. How have your previous work experiences and research impacted T cell work you have done for cell therapy clients since joining PCT?
“I am an immunologist by training with most of my academic research focused on the interactions between dendritic and T cells. I was always interested in the normal and pathologic biology of T cells, their characterization and function, including tumor-infiltrating lymphocytes. I did my postdoc in the laboratory of Dr. Engleman at Stanford, who is a co-founder of Dendreon, which further stimulated my interest in cell therapies using either dendritic cells or T cells. When clients bring their T cell processes to us, my prior experience and scientific knowledge allows me to quickly understand the client’s needs, facilitate the technology transfer and to suggest process optimization geared towards a more robust GMP manufacturing process.” – Ines
“My previous academic work on immune monitoring for patients receiving active immunotherapies (vaccines) for cancer has helped me design and develop methods at PCT for measuring T cell potency and suppressive activity of regulatory T cells.” — David
“I have been productively engaged in the T cell field for nearly 20 years, having worked in graduate school under the leadership of Mark Davis and Mike Dustin to establish the Immunological Synapse paradigm, with over 4,000 citations for my publications to date. I have also been involved in several technology development teams in industry to build tools to better understand, isolate, activate, track, image, and engineer these potent cells for pre-clinical and clinical applications. When clients bring us their T cell technology platforms, we are excited to leverage our deep understanding of these systems to build a T cell therapy manufacturing process with the best chance of clinical and commercial success.” – Cenk
“From a manufacturing perspective, the success and failure of your product depends on a few key variables. The first is successful enrichment of your T cells. The second is satisfactory gene delivery, most commonly viral transduction, and the third is proper expansion of the culture to meet the patient dose. My previous hematology research has positioned me so that I can not only develop these key unit operations but also troubleshoot issues that may arise, most commonly caused from unpredictable variations in incoming patient apheresis.” – Joseph
