Activating the immune system for therapeutic benefit in cancer patients has long been a goal in the scientific community. After decades of disappointment, this intriguing approach has come to the forefront of cancer research, showing promising results in several malignancies. To keep abreast of this rapidly advancing field, The ASCO Post recently spoke with one of the nation’s leading immunology experts, Michel Sadelain, MD, PhD, Director of the Center for Cell Engineering and the Gene Transfer and Gene Expression Laboratory at Memorial Sloan Kettering Cancer Center, New York.
Innovation and Clinical Translation
Please tell the readers a bit about your background and how you arrived at the Center for Cell Engineering, Memorial Sloan Kettering Cancer Center.
After obtaining a medical degree and a PhD in Immunology, I went to MIT in 1989 to conduct research on gene-transfer biology, which was then very rudimentary. My goal was to unravel whether T lymphocytes could be genetically engineered and, if so, whether one could “instruct the immune system” to perform any task we deemed useful. In 1994, I started a stem cell and T-cell engineering program at Memorial Sloan Kettering, where I later (in 2008) founded the Center for Cell Engineering with the support of then-President Harold E. Varmus, MD.
The Center for Cell Engineering primarily focuses on cancer immunotherapy, as well as stem-cell therapies for blood and neurologic disorders. The two hallmarks of the program are innovation, as best seen in the chimeric antigen receptor (CAR) field, and clinical translation, with major strengths in patient cell manufacturing and clinical trial implementation. These enable us to bring the novel concepts and methods we devise to the bedside. We invent, develop, and translate engineered cell-based therapies.
Current Research
Please describe your current line of inquiry in immunotherapy and chimeric antigen receptor therapy.
It has taken over 2 decades to establish the technologic platform for human T-cell engineering (based on the use of retroviral vectors) and to design and test synthetic receptors that effectively direct potent, targeted immune responses. These receptors for antigen, which we eventually called chimeric antigen receptors, went through a series of evolutionary steps. The most critical of these, perhaps, was the incorporation of costimulatory domains into the receptors, which we termed second-generation CARs.
This design extends the function and lifespan of the engineered T cells. This functionality is, in turn, the key to creating “living drugs” that persist long enough in the body to induce complete remissions, as we see today in patients with B-cell malignancies, especially in acute lymphoblastic leukemia (ALL).
We proposed CD19 as a CAR target over 10 years ago1 because of its relevance to several cancers—ALL, other leukemias, several lymphomas, Waldenstrom’s macroglobulinemia, etc—and its very restricted expression in other tissues. CD19 is now the paradigm for CAR therapy, and ALL, the CD19-linked disease where current CARs work the best.
The results achieved in adults with chemorefractory, relapsed ALL patients have exceeded any forecast. Most important, our early results in 5 patients, reported in 2013,2 are holding up in larger cohorts of patients (16 reported earlier this year).3 We are developing further-enhanced CD19 CARs for those B-cell malignancies that require them.
We are also making rapid progress in understanding the occasional toxicities that we see in patients treated with CAR T cells. The unknown frontier is whether CARs will work in solid tumors, which I firmly believe will be the case. To attain this goal, we need to identify the right targets and tackle the microenvironmental resistance mechanisms that are found in different tumor types.
Dendritic Cell Therapy
Dendritic cell therapy is garnering significant attention in a wide range of malignancies. What is your opinion on the research being done in this area of immunotherapy?
Dendritic cells are the most effective cells in the body to initiate the immune responses that are carried out by T cells, which the dendritic cells specifically activate. The potency of dendritic cells in preventive interventions, such as vaccines against infectious diseases, is well established. The question has long been whether their ability to elicit and amplify T-cell responses is sufficient after the disease is diagnosed, ie, as a therapeutic intervention rather than a prevention step, and especially against cancer, where most of the antigens are typically less immunogenic than those found in infectious organisms.
So while the tolerability of dendritic cell therapy is high, questions remain as to its suitability for treating patients with advanced cancer, immune dysfunction, and/or rapidly progressing disease. This is why we chose to bypass this natural immune-stimulatory pathway and focused on the rapid generation of large cohorts of ready-to-fight targeted T cells using CARs. Fortunately, cancer immunotherapy offers many approaches to tackling cancer, which will ultimately give us the flexibility to select or combine the better approaches to meet each patient’s needs.
Stem Cell Engineering
Stem cell engineering is a relatively new field. Please shed light on how this intriguing science could translate into clinical therapeutic approaches in cancer.
Stem cell engineering is the foundation for regenerative medicine, which many of us anticipate will bring another revolution in patient care in the years to come. The isolation, expansion, differentiation, genetic engineering, and large-scale manufacturing of stem cells still pose significant biologic and technical challenges, but research is advancing at a steady pace.
In some regards, the development of T-cell therapies is laying the groundwork for the advent of stem cell–based regenerative medicines. Stem cell therapies will benefit cancer patients in several ways, ranging from tissue repair (eg, bones) to organ regeneration (eg, liver) to immune reconstitution. The latter will be especially important in aging populations.
One area that we are actively pursuing is how to use cultured stem cells (“in a dish”) to generate T cells that are ready and ideally suited to fight cancer. We were the first to succeed in making T cells—CAR T cells, of course—from human pluripotent stem cells and to cure tumor-bearing mice with such “artificial” T cells.4
Closing Thoughts
Immunotherapy has had a long and, at times, difficult road in oncology. Please share a few last thoughts about this field’s future in the fight against cancer?
Immunotherapy is not monolithic. It is a rich field encompassing multiple approaches. The immunotherapies that have taken oncology by storm in the very recent years are different from those that had been tried earlier. Both checkpoint blockade and T-cell engineering approaches act on the patient’s T cells, not the tumor.
Our work on CAR T-cell engineering targeting CD19, complemented by studies from the National Cancer Institute and University of Pennsylvania, where other researchers were eventually attracted to pursue this intriguing approach, demonstrates the feasibility and efficacy of CD19 CAR therapy. The fact that three centers independently reported promising results has given enormous credibility to the potential of CAR therapy.
The second-generation CAR design opened the door to T-cell potency and impressive therapeutic responses. We now need to better harness this powerful tool and tailor the design of CAR T cells to take on the challenge of solid tumors. ■
Disclosure: Dr. Sadelain reported no potential conflicts of interest.
References
1. Brentjens RJ, Latouche JB, Santos E, et al: Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nat Med 9:279-286, 2003.
2. Brentjens RJ, Davila ML, Riviere I, et al: CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 5:177ra38, 2103.
3. Davila ML, Riviere I, Wang X, et al: Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 6:224ra25, 2014.
4. Themeli M1, Kloss CC, Ciriello G, et al: Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy. Nat Biotechnol 31:928-933, 2013.
