From Prop. 71 to CAR-T and beyond: Enabling another 15 years of patient-centric innovation
By Amy DuRoss
CEO and Co-Founder, Vineti
Co-Founder and Executive Director, California Stem Cell Research and Cures Act
On a recent summer weekend, dedicated political and scientific leaders gathered in the Sierras to discuss paths to progress for our country. Amid the talk of major upcoming elections, addressing climate change, burgeoning trade wars, and growing educational gaps, another topic clearly stood out -- regenerative medicine. As highlights from more than 70 exciting new stem cell research studies were shared, I was reminded of another election cycle 15 years ago, and how far we’ve come.
In 2004, California voters passed the $3 billion California Stem Cell Research and Cures Act (Proposition 71) to help create a secure foundation for regenerative medicine in the United States at a time when federal funding support severely declined. No one could have predicted the myriad scientific and medical innovations that have arisen since, or the way our healthcare systems are pivoting to meet them. From an ongoing body of work in stem cell science to approved cell and gene therapeutics for late-stage cancer and rare genetic disorders, regenerative medicine is thriving today.
More than $37 billion dollars has been invested in the field since 2015 alone, according to the Alliance for Regenerative Medicine (ARM). There are more than 1,060 clinical trials in regenerative medicine underway worldwide, and almost 100 drug products have received some form of expedited approval designation. And in the meantime, a new digital infrastructure is being laid to deliver these new treatments to patients world-wide, safely and efficiently.
When we envisioned Proposition 71, we were most focused on stem cell research. But the field of regenerative medicine has since expanded. The original definition -- restoring or reestablishing normal physiological function by regenerating or replacing human cells, tissues, or organs -- has been broadened by new discoveries in science. With the advent of genomic engineering, the term has also come to mean re-engineering cells to circumvent biological mechanisms that make diseased cells look normal. Two approved cell therapies for blood cancer have recently brought this new capability into public view, by offering remarkable mechanisms to re-engineer the body’s own immune cells and turn them into powerful cancer killers.
Here’s a short timeline of some of the major developments in regenerative medicine:
- 1968 - First recorded bone marrow transplant 
- 1978 - Discovery of stem cells in human cord blood 
- 1981 - First in vitro stem cell line developed from mice 
- 1998 - Isolation of human embryonic stem cells 
- 2004 - California Proposition 71 stem cell research initiative
- 2009 - First clinical trial with human embryonic stem cells (hESC)
- 2010 - First autologous cellular therapy for cancer, sipuleucel-T (PROVENGE) approved by the U.S Food and Drug Administration (FDA)
- 2012 - Nobel prize awarded to Dr. Shinya Yamanaka and Sir John Gurdon - discovery of reprogrammability of mature cells to pluripotency
- 2015 - CRISPR/cas9 gene editing in hESCs 
- 2017 - first CAR-T cell therapies for cancer, tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (YESCARTA), approved by the FDA
Today, the innovations are coming at a pace so rapid that new headlines pop up almost daily. Gene therapies for inherited disorders such as childhood blindness, thalassemia, and spinal muscular atrophy have been approved by regulators. Vector-mediated gene therapies, delivered into cells by mechanisms such as viruses, have become so numerous that discussions of viral vector shortages and how to address them have become commonplace. The approved CAR-T approaches for blood cancers, based on re-engineering of immune cells known as chimeric antigen receptor T-cells, are being optimized to shorten manufacturing times and reduce side effects. Researchers are investigating how best to address solid tumors, utilizing other immune system-based mechanisms such as TIL (tumor infiltrating lymphocytes) and NK (natural killer) cells. Personalized cancer vaccines -- based on patient data and/or cells -- are also demonstrating promise against some solid malignancies. Multiple lines of inquiry are studying the potential therapeutic benefits of gene editing -- using technologies such as ZFNs (zinc finger nucleases), TALENs (transcription activator-like effector nucleases), and CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats) -- while regenerative medicine leaders work to keep use of gene editing technology safe and ethical. And combination therapies, either among regenerative approaches or between advanced and traditional therapies, are actively under investigation.
In the meantime, an entire infrastructure is being laid to support a new medical landscape that is truly regenerative and patient-specific. New digital technologies are enabling the safe, efficient delivery of personalized therapeutics, making sure that the right drug product reaches the right patient and enabling worldwide scale. In the first such requirement of its kind, regulators are now mandating that these enabling technologies are in place as part of approval review, ensuring a new digital safety net for patients in the regenerative medicine age. FDA leaders, who have demonstrated true leadership in this area, have stated they expect to receive about 200 cell and gene therapy IND (investigational new drug) applications per year, and are planning on approximately 10 to 20 annual approvals by 2025. Major medical associations have taken notice of the field’s growth, with the American Society of Clinical Oncology named CAR-T cell immunotherapy its Advance Of The Year in 2018. And payers and lawmakers have taken notice, with the U.S. Centers for Medicare & Medicaid Services (CMS) finalizing the decision to cover CAR-T cell therapy this year.
Amid so much astounding progress, so much more work remains to be done. In a regenerative medicine world where the patient truly is the product -- where patients are an essential cornerstone of the cure -- here are four key advances that will help us reach as many patients as possible as quickly as possible.
- Standards. Without standardization, we cannot industrialize or scale regenerative medicine. Each patient has her own unique biology, and each therapeutic approach brings innovations and nuances. But underlying these essential differences are critical harmonizing drivers, such as digital infrastructure, industry guidelines, and regulations, that will make these therapies more predictable, repeatable, and scalable. The Standards Coordinating Body, an independent non-profit organization doing FDA-funded work in this area, can be looked to as a source of information, community discussion, and progress.
- Integration. For the regenerative medicine ecosystem to flourish, it must truly operate as an ecosystem. In a patient-centric value chain, all parts must be connected to provide timely, reliable, cost-effective care. We all must work together to enable progress, and we must connect our systems to operate this ecosystem on behalf of as many patients as possible.
- Outreach. Other industries offer valuable best practices to draw from. Digital innovation in other industries, for example, offers critical lessons on simplicity and usability that are already helping make cell and gene therapy operations and delivery simpler and more reliable for healthcare providers. As our field matures, we should actively collaborate with other industries that have already mastered scale.
- Funding. At the federal level, recently budget increases for the National Institutes of Health (NIH) , National Cancer Institute (NCI) , and FDA  all point to a promising trend that should be extended at the state and local levels. In California, the California Institute for Regenerative Medicine (CIRM) has given out almost $3 billion in research grants as part of its voter-approved mandate, is considering next steps to continue its pioneering work. As a variety of public and private funding options are being considered, it is essential to remember that CIRM’s leadership role warrants further support to help enable ongoing innovation.
Fifteen years ago, I joined with colleagues to help plug an important funding gap for stem cell research. It is with deepest gratitude to those teammates and voters in 2004 that I look at the remarkable progress all around us now and envision where regenerative medicine will advance in the next 15 years. As was the case in 2004, not all of tomorrow’s advances can be predicted today. But I am more confident than ever that, by working together and committing true support to this field in a clear and focused way, we can create a broad personalized ecosystem. Today, in cancer and rare disease care centers, some patients truly are already the cure, receiving regenerative therapies that are transforming their lives. Let’s work together in earnest -- committing our innovations, effort, and resources -- to extend that opportunity to all patients in need.
Amy DuRoss is the CEO and Co-Founder of Vineti, a digital technology company that provides a software platform for advanced therapies. Before co-founding Vineti, Amy focused on healthcare new business creation for GE Ventures/ healthymagination. Prior to GE, Amy was Chief Business Officer at Navigenics, a genomics company sold to Life Technologies in 2012. She was co-founder and Executive Director of Proposition 71, California’s $3B stem cell research initiative passed in 2004, as well as Chief of Staff at the resulting state grant oversight agency.
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