Brentjens Discusses Key Questions in CAR T-Cell Therapies

Renier J. Brentjens, MD

Could you briefly describe your own research interest in CD19-targeted therapies?

How is CD19 being targeted for cancer therapy and, in your opinion, what is the most successful approach to date?

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.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.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.

Why does CD19 make such an attractive target?

Why has CAR T-cell therapy focused on CD19 thus far?

What are the most significant limitations to CD19-targeted therapy?

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.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.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.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.

What are the challenges to commercializing CD19 CAR T-cell therapy?

The next generation of CAR T cells we call “armored CARs.” These are T cells that have additional genetic modifications—for example, the ability to secrete their own cytokines, or to express certain ligands that allow them to interact with the tumor or the tumor microenvironment—in such a way that has the potential not only to make them more potent, but also to potentially engage the patient’s own endogenous immune system to be more reactive to the tumor. So the T cell becomes an entity that can travel to the tumor and deliver a payload within the tumor environment to enhance antitumor efficacy.I think commercialization is already well in progress with a variety of different well-funded companies now in the space. I think that getting the cost of production down, which I think is readily possible, is going to be the big barrier to how marketable this technology is. From a very pragmatic standpoint, we have to start somewhere, and as soon as the first big company, like Novartis, buys into this, others will follow. The pharmaceutical industry will find a way to make this a profitable endeavor as long as the clinical outcome data remain as positive as it has been to date. This is a paradigm-shifting technology, and if it’s really as effective as it has proven to date, the pharmaceutical industry will accommodate itself to making it available to the broader public.

One issue is administration of this type of technology into patients. It does require some extra training, but I think that community doctors can readily adjust to this shifting paradigm, which increases the market and the availability of this technology in places other than academic centers. So I do foresee a time when this becomes part of the routine in treating certain types of cancers, hopefully more than just ALL.