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More than twenty years ago, Levine, with Carl H. June, first began collaborations with a small biotech company, Cell Genesys, on a technique to genetically alter T cells to create synthetic immune cells, known as chimeric antigen receptor T (or CAR T) cells.
“During my postdoctoral fellowship with Carl June, I had developed the magnetic bead technology to grow T cells, and Cell Genesys contacted us about research they were doing on chimeric antigen receptor T cells. That was the beginning of that relationship,” said Levine. This technology is now the primary method used by investigators to grow activated T cells.
“In the very early CAR T cell trials by several groups, there were some lab indicators that the cells persisted, that they were there, but clinical responses were minimal at best,” said Levine. “We used microbead technology to more efficiently grow T cells and later, a disabled form of the HIV virus to deliver the CAR gene to T cells. Expression of the CAR on the surface of T cells redirects and trains them to target the CD19 protein on malignant B cells and kills those cells,” explained Levine.
“We have had other industry partners in the time since the early collaboration with Cell Genesys in the 1990s,” said Levine. “Carl June and I were still at Naval Medical Research Institute at that time. When we moved to the University of Pennsylvania in 1999, inquiries followed from other companies about technology they wanted to get into clinical trials, including Sangamo BioSciences, to create HIV resistant cells using zinc finger nucleases in the first gene editing clinical trial in humans. We have worked with other companies including VIRxSYS, Adaptimmune, and Takara taking the technology they had developed into clinical trials, serving as R&D in clinical trial development and execution.”
At critical junctures in the Penn team’s research, they ran out of funding. Research is expensive. Cell and gene therapy clinical trial research even more so. “Over the last 27 years that we have been working in the field, adoptive immunotherapies have had a lot of peaks and valleys,” said Levine. “In the 1990s and early 2000s, it was seen as something boutique of ‘isn’t that quaint,’ and ‘interesting, but it’s never going to work.’ This idea of redirecting T cells or immune cells was groundbreaking. NIH grant reviewers saw it as a totally different paradigm than they were used to, and many comments were not kind.
“Then in 2004, we applied for a grant from the Alliance for Cancer Gene Therapy (ACGT). This foundation was started by Edward and Barbara Netter, who endowed my Chair at the University of Pennsylvania,” said Levine. “Edward, who passed away eight years ago from pancreatic cancer, was a graduate of Penn. They started the foundation in 2001 because their daughter-in-law, Kimberly Lawrence-Netter, was diagnosed with breast cancer and passed away from it. Edward was a polymath, interested in everything. After his daughter-in-law passed away, he heard about a seminar organized by Savio Woo, PhD, at Mount Sinai School of Medicine on gene therapy. It was then that Mr. Netter determined he would direct their Foundation’s efforts to gene therapy.”
In a 2010 trial in patients with advanced blood cancers who were infused with their own CAR T cells, pounds of leukemia then melted away over several weeks, according to Levine. “We were out of money, we had striking results and we were asking ourselves ‘What do we do? If we publish we can get more grants.’” At that point in 2011, with no funding left to continue the research, June and Levine and their Penn team published their results, sparking a media sensation as to the potential of CAR T cell therapies.
Without the renewed interest of and resulting involvement by partners, progress on these groundbreaking discoveries may have never seen the light of day, so to speak. Partnerships have played an important role in progressing this research and have boosted the progress of Levine’s recent work.
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When they published in 2011, they had no idea of the press coverage it would generate, appearing in over 800 media outlets, resulting in 3,000–4,000 inquiries from people interested in the clinical trials. Penn had to build a website (that is still in use) to take the inquiries. The 2011 publications led to interest from industry in licensing the technology.
“Ten to 12 companies of various sizes, all the way up to Novartis, contacted us wanting to license and develop the technology,” said Levine. “We then signed with Novartis in 2012. The partnership between the University of Pennsylvania and Novartis allowed the development of clinical trials of CAR T cells in leukemia and other blood cancers in adults, and in children as well. The ripple effect of the Penn–Novartis alliance was a ‘licensing and investment frenzy’ across the US and now around the world among various biotech, research universities and hospitals.”
Jump ahead to 2017 and the first FDA approved gene therapy became Kymriah® (Novartis) for acute lymphoid leukemia (ALL) in children and young adults up to the age of 25, followed several weeks later by Yescarta® (Kite Pharma) for relapsed or refractory Diffuse Large B Cell Lymphoma (DLBCL). Kymriah® was approved by the FDA for DLBCL in May 2018. Global approvals have since ensued for Kymriah® in Europe, Canada, Switzerland, Japan, and Australia, and for Yescarta® in Europe and Canada.
To put the Novartis collaboration in perspective, everyone in the field thought at the time that big pharma would never be interested in cell and gene therapies; it broke their business model from multi, continuous dosing to a one time or couple time infusion where immune cells are detected years after infusion. The collaboration spurred attention in the field as to what other groups were doing, followed by the work at Juno, Kite Pharma and other companies picking up steam. Said Levine, at last count there were more than a hundred companies in the field of engineering immune cells to redirect against cancer, including T cells and NK cells, and big time acquisitions of Kite by Gilead and Juno by Celgene, and now Celgene by Bristol-Myers Squibb.
The role of partnerships in the development of cell and gene therapies and cures came up frequently for Levine.
“Over the past 20 years and even more recently, in the last five to ten years, there has been an evolution in how translational research and research in general works,” said Levine. “Declining NIH funding, and signs of future cuts means academic investigators must rely more on philanthropy and industrial partnerships to conduct research, especially for translational and clinical research. As we have seen at Penn, the balance between academic-initiated hypothesis research that is NIH grant funded and industrial targeted research; academia and industry need to learn to speak one another’s language to collaborate.”
Collaboration necessitates the need for creation of industry-wide standards for the commercialization of cell and gene therapies.
“Not only is it a new field but it’s a new field in complex biology,” said Levine. “Consider the traditional development of drugs and characterization of drugs, where small molecules are characterized at will and made in big batches and delivered to patients. In cell therapy, you have a very complex entity. How do you characterize that in terms of potency and stability? That cell, especially autologous cells, varies greatly. How can you have a standard for that cell when they vary in so many parameters in different patients? Development of standards is important and difficult.
“We have had conversations on this with the Alliance for Regenerative Medicine (ARM), American Society of Gene & Cell Therapy (ASGCT), the International Society for Cell & Gene Therapy (ISCT), and the National Institute of Standards and Technology (NIST). One way to start is to look at instrumentation and determine reference standards, methods for counting, and methods for analysis. It’s very complex.
“The cell I develop is not likely to be the same as the cell another investigator develops if any of the many elements of sourcing and manufacture are even slightly different,” Levine said.
For cell and gene researchers, there is substantial benefit in collaborating early, but how can they attract the attention and support of partners at an early, high-risk stage?
“That’s a really good question,” said Levine. “I wish we knew all the answers. It’s simply a different audience. For an NIH review, there’s a defined format and investigators are well versed in how to put their proposal together.” Even so, many times researchers don’t know who the panel reviewing is or how well their proposals will be received. There have been new developments in philanthropic research funding in the last 10 to 15 years, as well. “Philanthropies are now asking for return on their investment with regard to rights on their IP,” said Levine. “This throws another wrinkle into the midst. If a company wants to license, they have to consider that throwback to the licensing stake.”
So, how should cell and gene companies pitch? “You start with ‘how is your research getting out there?’ and ‘is it being published?’” said Levine. “You have to determine if the backbone behind the IP and knowhow is attractive to licensing, and then get assistance in packaging your pitch to outside companies.”
Another critical but basic parameter is whether or not the research has been published. As evidenced from previous trends, there is a bandwagon effect when a concept or certain terminology gains popularity. Just look at the hype in recent years that culminated around stem cells, then nanotech, to name a couple. A partnership proposal can benefit from using popular or trending terminology, not in a sensational way, but in an intelligent way.
“The problem with a hot term is it can be hijacked. For example, so called stem cell clinics that skirt FDA oversight in pitching to patients and charging them for every indication under the sun where there commonly isn’t a scientific rationale,” said Levine. “You want to get attention for what you’re doing but researchers and partners need to do due diligence on each other.”
Back in 2010, Levine, June and the Penn team conducted initial trials of CAR T cells that targeted CD19 in three patients with advanced cases of chronic lymphocytic leukemia (CLL). Levine admitted that having partners at that very early stage would have benefited his work.
“We had some funding through the Alliance for Cancer Gene Therapy and the Leukemia & Lymphoma Society that took us to a certain point at a certain speed. We hoped, and it turned out to be the case, that we had something extraordinarily promising,” said Levine. “Had we had more funding earlier it would have developed more rapidly. We are grateful to Novartis for developing CAR T cells with us, and what turned out to be the first FDA approved gene therapy,” he said.
“It’s a totally different landscape now compared to the early days.” Levine, Carl June, Yangbing Zhao, Anne Chew, Jim Riley, and Bruce Blazar co-founded the startup Tmunity, spun out of the University of Pennsylvania.Tmunity is a clinical stage T cell engineering company with over a dozen targets in various stages of development, led by CEO Usman “Oz” Azam. “What is really exciting to me,” Levine said, “is that we have great science coming out of Penn feeding directly into Tmunity where we have our own GMP facility that is focused on next generation process development, analytics, and we hope to see manufacturing for multicenter trials by 2020.”
Cell and gene researchers are increasingly working with patients and patient advocacy organizations to reach a global community to advance their research and open doors at the drug policy level.
“The involvement of patient families and related groups is extraordinary,” said Levine.
Levine related a story of the first child treated with CAR T, Emily Whitehead, which was reported in the New York Times and other popular news, as well as being the subject of a 2012 documentary, “Fire with Fire,” filmed by Ross Kauffman, an Oscar-winning director. Whitehead became a celebrity patient, appearing on Stand Up 2 Cancer and featured at the April 2016 opening of Napster and Facebook billionaire Sean Parker’s Parker Institute for Cancer Immunotherapy, as well as meeting President Obama and Vice President Biden, among others.
“When the New York Times (NYT) story first appeared in 2012, the staff at the NYT said to the Whitehead family ‘Beware of the tsunami.’ The Whiteheads were very quickly contacted by media outlets and other patients around the world,” said Levine. Shortly thereafter, they founded a philanthropic foundation, the Emily Whitehead Foundation – Activate the Cure, which has funded the work of June and Levine at Penn and collaborators at the Children’s Hospital of Philadelphia in CAR T cells.
“This is an example of a girl who had failed all available therapies, who did not have long to live, whose parents enrolled her in a trial, she became a complete responder, and they are all now paying it forward in so many tangible ways in support of other patients. They are heroes,” said Levine.
Many patients desire to meet scientists who develop their cells and conversely, the scientists get to know their patients. Levine and his group frequently work with patient groups, foundations and advocacy organizations such as ARM. One of Levine’s former patients is on the Leukemia & Lymphoma Society board advocating for future therapies.
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Advocacy has a strong impact on top level decision makers, such as the NIH-backed Cancer Moonshotprogram which involves external experts from industry and advocacy. “When President Obama announced Cancer Moonshot, our labs were the first stop Vice President Biden made after the announcement,” said Levine.
Having perspective on the field, speaking with industry and government leaders, and seeing an opportunity to serve at a global level, Levine ran for the office of President Elect of the International Society for Cell and Gene Therapy, in which he currently serves and will assume the President’s office 2020–2022.
ISCT is a global society of clinicians, regulators, technologists, and industry partners with a shared vision to translate cellular therapy into safe and effective therapies to improve patients’ lives. ISCT offers a unique collaboration between academia, regulatory bodies, and industry partners in cell therapy translation. It operates with the conviction that, to grow the field and accelerate development of these new therapies, all involved must share knowledge, and educate, train, and mentor the next generation.
The idea is that this is no longer a small percolating field; it’s now evolved to the point where we have new considerations for therapies that are going to be approved and commercialized. It is real.
“There has been a cascade effect and the number of companies that have started in the field has increased exponentially these last few years,” said Levine. “It is important to have a forum where experts in the field can hear new science and new technologies from new companies. Producing CAR T cells require a complex and multi-step process, and all along the way you have ancillary reagents, technology, logistics, and so many pieces that go into it. The ability to partner is important to advance the field and promote understanding that this is a unique technology. Partnering is essential and required, it’s not optional.”
“I’ve been involved with ISCT and ARM for a number of years, as we work toward scale out of CAR T cell manufacturing,” said Levine. “I am making an effort to free up more of my time to be locally, nationally and globally engaged in advancement of cell and gene therapies. For me, personally, the timing is right, and with the approvals received by Novartis and Kite, the emergence of other companies, and our founding of Tmunity, there will be even more awareness of this field, and we are looking to professional, policy, and advocacy organizations to raise awareness in Washington and globally for these new therapies with regard to policies and regulation.”
At the end of the day, Levine attributes his inspiration to the people who will benefit from future therapies and cures. “It’s the patients. No question about it,” said Levine. “As a PhD, the ability to do work that is not only interesting but has application to new therapies, that is the ultimate reward; to be able to meet patients who have been impacted by this work. Just to have the opportunity to have been mentored by Carl June and now to be part of a large team starting in research all the way to translation to clinical labs, to see that large team of dozens of experts coming together to get therapies to the clinic and to see the patients has been very rewarding. I think we all feel very fortunate to be in this space at this time, and we owe a great debt of gratitude to the patients whose families enroll in these trials without whom we would not be able to develop new future therapies.”
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