Cell therapy pioneer predicts ‘bright’ future for field
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Moffitt Cancer Center in Tampa has been one of the early leaders in cellular therapies for cancer treatment.
Consequently, it came as no surprise the institution appointed Patrick Hwu, MD, as its new CEO.
Hwu — an expert in cancer immunology and melanoma treatment — was part of a pioneering team at NCI that conducted some of the earliest research on adoptive cell therapies for cancer, and he has been a champion of the modality since then.
Hwu later served as head of the division of cancer medicine at The University of Texas MD Anderson Cancer Center before his appointment at Moffitt, which took effect in November.
Hwu called Moffitt Cancer Center “a special place” that has allowed him to continue pursuing clinical research and see patients while performing his administrative duties.
Healio spoke with Hwu about the development of cell therapies, the current state of the science, and the work underway at Moffitt that may help advance the field.
Healio: How has your role at Moffitt complemented your previous research?
Hwu: The topic of cell therapy is close to my heart. I worked at NCI, where we did some of the first studies with CAR-T in the early 1990s. Moffitt is a leader in cell therapies. We have an entire ward at our center dedicated to clinical trials with cell therapies, and we helped get CAR-T products across the finish line with the FDA. Moffitt is committed to cell therapies through our robust research program.
Healio: CD19-directed CARs have induced impressive responses. Where does the field go from here?
Hwu: There is huge potential for this technology. T cells recognize tumors by recognizing specific antigens in what we call the [major histocompatibility complex (MHC)]. Once the T cells recognize a target, they release enzymes that poke holes in the cancer and cause apoptosis.
Recent developments in CAR T-cell therapy are just the tip of the iceberg in terms of cell therapy’s potential. For example, in lymphoma, we are using CD19-directed CAR-T against previously hard-to-treat subtypes, including double-hit lymphoma. This type of lymphoma has two critical mutations, which makes it aggressive. We are seeing good responses with CD19 CAR-T among patients with this disease.
There are many cancer types for which immunotherapies — including immune checkpoint blockade — will not work. However, nearly all cancer types have targets that can make them susceptible to being recognized and killed by a T cell. That is why I am so excited about T-cell therapy. The key is to take these T cells and grow out the lines or put receptors on them that allow them to kill specific tumors. If we do this, we can get many of these tumors to regress and, ultimately, decrease the cancer death rate worldwide.
Healio: In addition to your cell therapy research, you still treat patients with melanoma. Are you investigating cell therapies for melanoma?
Hwu: Our lab is working with tumor-infiltrating lymphocytes (TILs). We also are working with CRISPR technology to eliminate genes that might suppress immune cells, such as the transforming growth factor (TGF)-beta receptor genes that inhibit immune cells as soon as they get into the tumor microenvironment. I am very excited about our use of CRISPR. We can knock out almost any gene with this technology, and I think we will be able to apply this clinically for cell therapy. Using this cutting-edge technology for cell therapy hopefully will help the therapies become more effective and allow us to scale better so we need fewer cells for each infusion, allowing the therapies to be more efficient economically.
Healio: What do you think about the future of TILs for melanoma?
Hwu: It is an exciting development. When I was at MD Anderson, I was part of a clinical trial that used a TIL modified to be resistant to the negative effects of TGF-beta by putting in the dominant negative receptor. Results from that work have not yet been published.
Despite the great advances in melanoma — including targeted therapy with BRAF inhibitors and immunotherapy with immune checkpoint inhibitors — half of patients will have disease that is resistant to these cutting-edge treatments. There is a huge need for improved therapies in melanoma, and I believe TILs will help fill some of that need.
TILs still require further optimization. Our lab at Moffitt is working on improving TIL therapy for melanoma, as well as for several other common cancers. We want to improve therapies for melanoma, but we also want to take what we have learned and develop cell therapies for extremely resistant and hard-to-treat diseases, such as triple-negative breast cancer, pancreatic cancer and glioblastoma.
Healio: You have been involved in adoptive cell therapy since its earliest days. Are you pleased with the pace of development?
Hwu: As long as patients with cancer are dying, the speed of new therapy development is never fast enough. Further, the development of cellular therapies has taken a long time. CAR T-cell therapy was first applied to cancer in 1993 and was part of a paper in Journal of Experimental Medicine that I co-authored with Steven A. Rosenberg, MD, PhD, at NCI and Zelig Eshhar, PhD, of the Weizmann Institute of Science in Israel. It took nearly 30 years after that to get FDA approval for the first CAR T-cell therapy. That is way too long.
We need to make these approvals much faster. This likely will occur simply because we know so much more than when we started working with this approach. At that time, we could barely get the genes into lymphocytes and — once we got the genes into lymphocytes — we observed little transcription. We have spent much of the past few decades optimizing this process, making it much more straightforward to get additional treatments to the FDA for review. Because the technology is so much better, hopefully we can produce therapies on a scale that will allow us to effectively treat many kinds of cancers.
Healio: The most recent CAR-T approved by the FDA is indicated for multiple myeloma. What impact will this have on clinical care?
Hwu: The data look very promising in myeloma. At the same time, we have to understand how we can achieve longer responses that are even more durable using CAR T-cell therapy. Active research in real time will be needed to determine what causes resistance. We need to answer questions about why certain patients do not respond to CAR-T and, for those who do have an initial response, why they sometimes stop responding to therapy. For example, with CD19-directed CAR-T in lymphoma, data have suggested downregulation of CD19 by cancer cells or deactivation of the body’s immune cells as two possible reasons for resistance. We need to figure out why these things occur so we can reverse or mitigate the process with other therapeutics — either in combination with existing CAR-Ts or with further development of more potent CAR T cells.
Healio: Do CAR-T and other cellular therapies offer the possibility of durable cures for certain types of cancer?
Hwu: Absolutely. In fact, I know cell therapy can achieve this because I have treated patients with very resistant disease who are doing great years after therapy. They are essentially cured. With CD19-directed CAR-T, there are patients who have had very long durable responses. They, too, are essentially cured. However, we also had patients with treatment-resistant disease progress after receiving CAR-T. The key is to understand why certain patients do not respond and why some patients who do don’t achieve more durable responses. If we can understand the science behind this process, we can figure out how to get around the resistance and allow all patients to achieve longer, more durable responses. In the end, that is all that any patient with cancer wants. They want to see their kids get married and know their grandchildren, and we need to offer that opportunity. It is possible with cell therapy because T cells can live in the body for decades. They can be persistent for a very long time. Because of that, we can get durable responses. We must increase the number of patients who achieve the durable responses that every patient wants.
Healio: Do you think the success of CAR-T for blood cancers can be translated into solid tumors?
Hwu: Absolutely. We have seen some great responses in melanoma with TIL therapy, and we have seen responses in sarcoma using a novel gene-modified T-cell therapy with an engineered T-cell receptor designed to target tumors that express the ESO-1 protein. We know it can work, and I have great hope for that. With CAR-T, we need to find the right antigen that is on the cancer cell but not found on essential organs, such as the liver, the lungs or the heart. The key is picking the right antigens, and there is a lot of technology available that can help us achieve that specificity.
Healio: Do you think CAR-T use will be limited to patients with high-risk, relapsed or refractory disease, or do you foresee it moving into earlier lines of therapy?
Hwu: In its current form, CAR-T is limited because of the high cost, adverse events, and the fact that only a limited number of centers can afford to provide the therapy or have experience dealing with treatment-related toxicities. Additionally, not all patients can afford CAR T-cell therapy.
In time, a broader array of health care professionals will be more skilled at providing these therapies, but this is how any new technology starts out. The first computers were very expensive and lacked substantial computing power by today’s standards. Cell therapy will follow the same path. As the technology improves, it will scale down to many fewer cells for each therapy, and those cells will be more highly targeted to kill cancer cells with less toxicity. In the future, we will administer this as an outpatient therapy. It will be much more effective, much less toxic and much easier for practitioners to deliver.
We need breakthroughs that help us understand how to grow the cells in an optimal way and which antigens to target. I am confident we can move the field forward to influence almost any kind of cancer in a positive way and successfully provide that therapy in a scalable manner. It is an exciting future, and that is why we are ‘tripling down’ on this at Moffitt. We are really going in big on cell therapy because we see its future being so bright.
References
D'Angelo SP, et al. Abstract 11504. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
Hwu P, et al. J Exp Med. 1993;doi:10.1084/jem.178.1.361.
For more information:
Patrick Hwu, MD, can be reached at Moffitt Cancer Center, 12902 Magnolia Drive, CSB-8 CEO, Tampa, FL 33612; email: patrick.hwu@moffitt.org.
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