By Bruce Levine, Ph.D.
In the 1966 science fiction film Fantastic Voyage, a submarine and crew are miniaturized and injected into the body of a scientist to remove an inoperable blood clot in his brain. We now no longer need to miniaturize ourselves; we can use cells as medicines to treat diseases including cancer. In 2017, we saw the first gene therapy approved by the FDA. This “drug” is an engineered Immune cell, a chimeric antigen receptor (CAR) T lymphocyte, genetically modified and trained to seek out cancer cells and kill them. We also saw the FDA approval of the first stand-alone gene therapy, which treats and inherited form of blindness. In 2020, we will see clinical evidence of exquisite regulating mechanisms designed in to cells, and the use of cells to deliver drugs themselves in a controlled and directed fashion.
Skeptics will say that the manufacture and delivery of cells to treat disease is too expensive to be worthwhile, especially when the disease fighting cells must be derived from each patient themselves. They will say it takes too long to generate customized medicines while very ill patients are waiting for therapy. Yet, multiple scientific advancements have coalesced to the point where we are in the midst of a scientific revolution, in the words of philosopher Thomas Kuhn, a paradigm shift that will change how we think of medicines.
Off-the-shelf drugs, such as checkpoint antibodies for the immunotherapy of cancer are the fruit of Nobel prize-winning research and now in use around the world for several types of cancer. Bi-specific antibodies are tandem antibody drug conjugates that bring T lymphocytes in close proximity to cancer cells to kill them. However, these engineered recombinant antibodies themselves are expensive, do not induce clinical responses in a significant percentage of patients, and do not permeate to all sites of cancer, such as the brain. New off-the-shelf drugs for cancer are often given indefinitely, as long as patients continue to respond. Drugs such as insulin continue to rise in price and must be taken for a lifetime. In other words, the longer patients respond, the more financial toxicity accumulates.
Technology now exists to engineer cells to produce these medicines in a programmed fashion and for long duration. Yangbing Zhao and Carl June at the University of Pennsylvania reported in 2016 the ability to engineer T cells to produce bispecific antibodies in mice. Marcela Maus at the Massachusetts General Hospital recently showed in a mouse model of brain cancer that CAR T cells (themselves trained to find and kill cancer) can simultaneously deliver a bispecific antibody. Renier Brentjens at Sloan Kettering has shown in mouse models of blood cancers and solid tumors that CAR T cells can be programmed to produce checkpoint antibodies once triggered by a tumor antigen recognized by the CAR molecule. Other investigators have shown in pre-clinical studies that immune cells can deliver chemical messengers that direct immune cells and have anti-cancer activity, and that oncolytic viruses encoding a bispecific antibody can be effectively combined with CAR T cells targeting a second tumor antigen. These types of studies point to a trend that will continue to develop in 2020, which is chimeras and combinations of technologies to enhance potency and targeting.
A second trend to watch is the development of control switches for the genetically reprogrammed operating system of engineered cells. Controlling the production of antibodies and drugs in cells is possible through tunable receptors — receptors that can be turned on and off with the delivery of a small molecule, Boolean combinations of and/or/not receptors, or modular targeting receptors.
The utility and safety of various gene editing platforms in the clinic will be a third trend to watch. Gene editing can knock out checkpoint receptors on immune cells that tumors use to turn off immunity. At the University of Pennsylvania, a clinical trial has tested multiplex knockout of three genes to generate more potent anti-cancer T cells. This sort of multiplexing, genetic delivery of receptors and function enhancing or modifying molecules will be reaching many more patients and indications in 2020 and will continue to accelerate in applications in the coming years. We will also see the emergence of more clinical data of cells from healthy donors modified and retargeted to treat disease. Donated cells are now being modified in such a way that they may be less visible to the immune system. Whether donated cells are as potent and durable as self-donated autologous cells is yet to be seen.
Delivering cargo to cells is a fourth trend to watch. We currently are using viral vectors as Trojan Horses to deliver genetic materials to cells. However, viral vector manufacturing is relatively slow and expensive. There is a theoretical risk of genotoxicity, more so in stem cells. The good news is progress in vector manufacturing is being made and costs are (slowly) coming down. However, there are still long queue times for contract manufacturing of clinical grade vector. Electroporation has been a mainstay of inducing permeabilization in cell membranes to deliver genetic material or other cargo. We now see the development or perhaps kinder and gentler ways of permeabilizing cells through mechanical and chemical disruption through squeezing, transient volume exchange, and soluporation.
Cell and gene therapies, whether autologous or allogeneic, or off-the-shelf, are often personalized. In some indications such as gene replacement and CAR T cells in pediatric acute lymphoid leukemia, the response rates are much higher than any other available treatment regimen. In other diseases, cell and gene therapy clinical responses are positive in a subset of patients. In 2020, a fifth trend to watch is the incorporation of biomarker profiles and artificial intelligence to cell and gene clinical development. Powerful new technologies will aid in correlative studies analysis, product and process development, and will be considered for determining which patients may be more likely to benefit from advanced therapies.
A sixth trend is a continuing trend that will plaque the field for some time. There is a critical shortage of talent at all levels; from technicians and development scientists, manufacturing and analytics staff, to clinical expertise in the management of cell and gene patients. There is a huge need for more cell and gene specific education programs as scientific and clinical development has outpaced the training of new professionals to meet the demand.
The implications of emerging cellular and gene technologies and the requirements for adoption goes beyond the science. A seventh trend to watch is how will regulations and policies be revised and adapted to allow the advancement of cells and engineered cells producing medicines? For a limited series of infusions with durable or lifetime benefit, payment and reimbursement is evolving, especially in multi-payer countries such as the United States. How do we ensure access for all patients who could benefits from cell and gene therapies? An important issue is protecting patients and families from unregulated and unethical interventions. The proliferation of so-called “stem cell” clinics and speculative cell banking shows that profiteering and piggybacking on new technologies are a continuing risk to ethical scientifically validated development. To permit advances and protect patients from physical and financial harm, public engagement by cell and gene therapy professionals is critical so that sound policies and regulations may be developed.
As what was once science fiction is now science fact; to realize the full potential of cells as medicines we must adapt for the benefit of patients.
Bruce Levine is the Barbara and Edward Netter Professor in Cancer Gene Therapy at the University of Pennsylvania and President-Elect of the International Society for Cell and Gene Therapy. He can be reached on Twitter @BLLPHD.