Breakthroughs in next-generation cell therapies have continued to progress rapidly over the past several years. Currently, more than 1,000 cell and gene therapies are in clinical studies. These therapies have the potential to transform the lives of people living with cancer and other diseases.
The ONE Forum® 2020 highlighted new cell and gene therapy research and innovation, particularly its positive impact on hematopoietic stem cell transplantation (HSCT). The virtual event – hosted by our parent company the National Marrow Donor Program® (NMDP)/Be The Match® – brought together leading industry professionals from the field.
Here, we recap three of the sessions highlighting advances in cell therapy as well as regulatory hot topics.
Keynote discussion highlights promising advances in cancer treatment
In this keynote session, leading cell therapy researcher Carl June, MD, of the University of Pennsylvania joined Jeffrey Miller, MD, of the University of Minnesota, and Allison Matthews of the Mayo Clinic to share recent advances in both cell therapy treatment and patient support.
Carl June, MD, University of Pennsylvania
Dr. June collaborated on the development of Novartis’s Kymriah, one of the first commercially approved cell therapies. It has now been a decade since chimeric antigen receptor T cells (CAR-T cells) have been used to treat leukemia. During the session, Dr. June shared that a follow-up with one of the first patients treated revealed that CAR-T cells can continue to persist even 10 years after treatment.
Additional research published in Nature Medicine in 2018 indicates that the minimal effective dose of CAR-T cells may be very low. In one patient, a single CAR-T cell was responsible for eradication of cancer.
During the session, Dr. June shared an overview of recent advances in CAR-T therapy for treating hematologic malignancies. He explained that while side effects of CAR-T therapy – particularly the neurologic toxicity that can result from therapies that target the CD19 antigen – are still a concern, CAR-T research is a highly promising long-term treatment avenue for hematologic cancer.
Jeffrey Miller, MD, University of Minnesota
Dr. Miller is the Deputy Director of the Masonic Cancer Center at the University of Minnesota. He shared a research update on the use of natural killer (NK) cells in treating cancer. Like CAR-T treatment, NK cell therapy has exploded in recent years and is highly promising for the future of cancer treatment.
Dr. Miller explained how the University of Minnesota’s Trispecific Killer Cell Engager (TriKE) model successfully induces NK cell proliferation, leading to tumor eradication. Specifically, harnessing the cytokine interleukin-15 (IL-15) enhances the ability of NK cells to knock out cancer cells.
The results are very exciting. But, as Dr. Miller explained, the process of adoptive transfer is complex and expensive. Through a collaboration with Fate Therapeutics, Dr. Miller and his colleagues are exploring the use of induced pluripotent stem cells (iPSCs) to manufacture NK cells, rather than transferring cells from an allogeneic donor.
The initial research, published in November 2020 in Science Translational Medicine, show that iPSC-derived NK cells promote successful T cell recruitment both in vitro and in vivo. When used in combination with anti-PD1 therapies, they lead to tumor elimination in animal models.
Allison Matthews, Mayo Clinic
Matthews brought a different perspective to the conversation – that of the patient-facing service provider. Matthews explained that after spending time with many patients who receive cell therapy treatment and their caregivers, her team has learned that creating a strong understanding of every step of the therapeutic process is essential to successful treatment.
She emphasized the importance of a coordinated treatment experience, including warm handoffs from one team member to another. She also highlighted how explanatory materials, such as videos and workbooks, can help support patients and caregivers through what is a challenging and complex journey.
Matthews’ research is of equal importance to the scientific advances shared by Dr. June and Dr. Miller. Comprehensive patient service decreases patient anxiety and helps make successful cell therapy treatment possible.
The presentations from all three panelists showed that the work to continually advance cell therapy is necessarily holistic. It requires engagement and innovative thinking from all sides. As long as that holistic work continues, it’s clear that scientific innovation in cell therapy – and its promise for the millions of people living with cancer – will only continue to advance.
The impact of new cell and gene therapies on treatment options for HSCT patients
Since its onset about three decades ago, the cell therapy industry has evolved at a rapid rate. Especially in the last several years, therapies have become both more accessible and more commercially viable. Gene therapy also continues to advance rapidly as collective knowledge of safe and effective techniques grows.
In this session, the panelists explained the opportunities that emerging trends in cell and gene therapy offer for hematopoietic stem cell transplant patients. They also discussed how recent developments spark promise for the future of cancer treatment options.
Richard Jones, MD, Johns Hopkins University
As the technology for delivering cell and gene therapy treatments has evolved, receiving treatment has also become a more comfortable experience for the patient. Richard Jones, MD, Professor of Oncology and Medicine at Johns Hopkins University, explained that two decades ago, HSCT was “a fairly toxic procedure.”
“It really didn’t serve the majority of people who needed the procedure,” he said. He explained that donors were difficult to come by. In addition, older patients – who are often those diagnosed with blood cancer – weren’t candidates for HSCT. Since then, things have changed. Due to advances that allow for the use of haploidentical and mismatched allogeneic donors, “Everyone has a donor now, and the approach has become much kinder and gentler,” he said.
Dr. Jones pointed out that donor accessibility has also grown exponentially. Thanks to the consistent advances in the transplant field, HSCT continues to be used widely as an approach for both allogeneic and autologous cell therapy. Dr. Jones said new cell and gene therapies are evolving “not as a competition to transplant, but as cooperative and synergistic.”
Joseph McGuirk, DO, University of Kansas
Joseph McGuirk, DO, is a Professor of Hematology-Oncology at the University of Kansas. He believes that T-cell receptor and CAR-T cell therapy constructs, as well as advances in transplant technology such as alternative donor transplants and reduced intensity conditioning regimens, are continual improvements to historical HSCT.
“A lot of the science, a lot of the biology in those stories started with stem cell transplantation,” he said. He added, “We envision a future whereby we eventually get away entirely from non-specific, maximally intense radiation and chemotherapy, and move to a future where we could modulate the immune system of the recipient,” thereby allowing for reconstitution of the immune system and mediating of anti-tumor effects.
With the technology currently available and the continued contributions of skilled researchers, Dr. McGuirk expects that oncology therapy is trending toward highly specific treatments that combine the use of all available technologies. He sees advances in HSCT as a platform for more novel therapeutic strategies, including the use of immune modulators in combination with cell therapies.
Leonard Sender, MD, NantKwest
Leonard Sender, MD, Senior Vice President of Medical Affairs at NantKwest, further emphasized that one of the key hurdles of treating cancer is solving the challenges of the immune system.
“If you were asked to play Beethoven’s fifth symphony, you wouldn’t want to do it just with a violin, you’d want to have the whole orchestra. We need to think about the immune system and how we approach it as an orchestration of different components,” which are brought together to modulate immune effects. Researchers need to leverage advances in cellular therapies to develop therapies that avoid toxicity and negative long-term health effects, he said.
The panelists also stressed the importance of collaboration, both between research fields and between the industry and academic research communities. All of them are hopeful that with continued dedication of and cooperation from everyone involved, the future of cancer treatment will be one of high accessibility, comfort and accuracy.
“I’ve been at this for 30 years now, and I’m more excited and stimulated today than I was even 30 years ago about the prospects for our patients and their families,” said Dr. McGuirk. “It’s really a very promising future.”
Ethics and safety: Regulatory hot topics in cell therapy
As the field of cell therapy has rapidly grown, existing regulatory environments have sometimes been slow to keep up. Ongoing discussion within the industry has focused on understanding these regulatory mismatches and working with all parties to advance regulations that prioritize patient safety while encouraging therapeutic innovation.
Regulatory experts at the NMDP/Be The Match described the two regulatory categories of cell and gene therapies and detailed two important subjects which are garnering much scrutiny and discussion in the cell therapy industry at present:
- The ethics of donor compensation
- The regulatory impacts of COVID-19 on donations
The regulatory requirement landscape for cell therapy products is complex. Human cells, tissues, and cellular and tissue-based products (HCT/Ps) are regulated by two disparate sections of the Public Health Service Act (PHSA): sections 351 and 361.
This distinction has important ramifications for the regulatory oversight of any given therapy. Those that fall under 351 must seek full FDA review and approval through the Biologics License Application (BLA) procedure before they can be marketed. Those that fall under 361 are not required to obtain premarket approval from FDA. The two central qualities that distinguish a 361 therapy are: 1) that it be minimally manipulated, and 2) that it is intended for homologous (or autologous) use only.
Lori Hanley, NMDP/Be The Match
Lori Hanley is a Senior Regulatory Compliance Specialist at the NMDP/Be The Match. She explained that these distinctions leave significant gray areas for many of today’s cell and gene therapy developers.
“This is complicated. And within the industry, where a product lies within definition of minimal manipulation and homologous use is best defined with guidance that the FDA has provided,” she said. Ongoing industry discussion has focused on clarifying what these categories mean in practice.
Another area of industry focus has been the subject of donor compensation. The National Organ Transplant Act of 1984 outlawed compensation for organ donors in the U.S. However, no similar restriction was ever enacted for the donation of blood stem cells or bone marrow, explained Jared Schuster, Regulatory Affairs Associate at NMDP/Be The Match.
Today, the compensation decision is largely left to the discretion of individual transplant centers. However, some in the industry have expressed concern that paying donors could encourage them to incompletely disclose their medical history, leading to potential safety issues for patients who receive the resulting therapy. Other countries, namely Japan and Canada, have clear regulations requiring that cell therapy products are only sourced from uncompensated donors.
Finally, a growing area of regulatory interest just this year has been whether apheresis centers should be required to screen donors for COVID-19. FDA guidelines require the screening for certain emerging infectious diseases in cell and tissue products, including West Nile virus and Zika virus, both of which are transmissible through tissue.
There is little evidence to date that COVID-19 is transmissible through tissue. Consequently, it is not required that donors be screened for the virus. However, some in the cell therapy industry have advocated for this to change, citing the safety benefits to apheresis center staff, as well as the possibility that future research could reveal insights about COVID-19 that might change how banked cells are used.
In general, the FDA provides a somewhat malleable framework for regulations to keep donors and donations safe and effective, allowing the guidelines to evolve to address the ever-changing needs of our society.
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