Renier J. Brentjens, MD
Renier J. Brentjens, MD, PhD, focuses on the development of new therapies for patients with acute and chronic leukemias, in particular on novel immunotherapies such as chimeric antigen receptor (CAR) T cells. He is one of the founders of Juno Therapeutics, a start-up company launched in 2013 to expand cell-based immunotherapies, including CD19-targeted CAR T cells, into multiple cancer types. Brentjens, who is the director of Cellular Therapeutics at Memorial Sloan Kettering Cancer Center, discussed his research in this interview with OncologyLive
Could you briefly describe your own research interest in CD19-targeted therapies?
For the last 15 years we’ve been developing CD19-targeted T cells, which we generate through introduction of a gene created in the laboratory that is part antibody—recognizing CD19—and part T-cell receptor, which activates the T cell. By using retroviral gene transfer, we can extract a patient’s own T cells, which don’t recognize CD19-positive tumors, genetically modify them, and then inject them back into the patient, with the idea that the T cells now fight and kill the tumor cells.
How is CD19 being targeted for cancer therapy and, in your opinion, what is the most successful approach to date?
There are bispecific antibodies, which have specificity to CD19 and specificity to T cells. The idea behind these is that they bring a B cell that would otherwise not recognize a tumor cell together with the tumor cell. That strategy has seen some success.
But right now most of the attention has been focused on CAR T-cell technology, where the T cells are genetically modified with a chimeric antigen receptor. The data that we, and others at the University of Pennsylvania and the National Cancer Institute have generated to date, suggest that this is a novel and very potent treatment approach for patients with lymphoblastic leukemia.
Why does CD19 make such an attractive target?
The most attractive feature of CD19 is its restricted expression. When utilizing immune-based therapies, a significant consideration is whether the antigen we are targeting is also on normal tissues. Besides its expression on most B-cell cancers, the only other place that CD19 is expressed is on normal B cells. So the worst that can happen if you successfully target CD19 is that the tumor goes away, but also the normal B cells are eliminated; but that is a condition that is essentially compatible with life and one can always administer intravenous immunoglobulins to patients if they have long-term B-cell aplasia as a consequence of this type of therapy.
Why has CAR T-cell therapy focused on CD19 thus far?
It’s going to be interesting in the coming years to see whether the data that we have with these CD19-targeted CAR T cells in acute lymphoblastic leukemia (ALL) are the proof of principle for this technology or whether that is the only disease that this therapy will work in. What has to happen now, and is already happening, is that our group and others are targeting antigens on solid tumors. There is now a strong push to move this technology forward to see if we can get some promising clinical results in solid tumors, like breast cancer, prostate cancer, ovarian cancer, and so on. Time will tell whether similar striking results can be obtained in other tumors. I suspect we will see that, but I also suspect that we need to understand more about tumor biology and tumor immunology to find ways to make the T cells more potent than they currently are to have success in solid tumors.
What are the most significant limitations to CD19-targeted therapy?
The CAR T-cell technology does have significant side effects, specifically what we call cytokine release syndrome. So there are some issues regarding management of toxicity with this therapy that need to be addressed.
Then, I think there is also the issue of how well this technology works in other B-cell cancers. In our hands, it doesn’t work anywhere near as well in patients with chronic lymphocytic leukemia, especially if they have bulky disease. So, although I think the technology is extremely promising, to be universally applicable to all CD19-positive tumors, I still think further modifications have to be made to make the cells more potent to eradicate certain types of B-cell cancers.