Cell therapy is a transformative, rapidly expanding field presently revolutionizing the treatment of life-threatening diseases. Diseases amenable to cell therapy include those with no currently available effective treatment, those that are resistant to or fail to improve with conventional therapies, or diseases where current therapeutic strategies require long-term administration of drugs with deleterious side effects and invasive procedures. While they hold significant promise, biotechnology and biopharmaceutical companies face several challenges that require innovative technological solutions to facilitate an efficient, collaborative, and agile data-driven approach to developing and delivering cell therapies. Currently, cell therapies are primarily being developed for cancers (e.g., B cell lymphoma and leukemia); however, this treatment can be applied to a broad range of other debilitating diseases, such as neurodegenerative diseases (e.g., Alzheimer’s) or cardiovascular diseases. This article will describe some approaches to oncological cell therapy as well as efforts to deliver these treatments in other therapeutic areas.
Broadly, cell therapy is the administration of live cells into a patient to treat disease by acting as ‘living drugs. It may be used to eliminate cancer cells, or in the case where tissue function is impaired, regenerate, or direct development of tissue. Therapeutic cells can originate from the patient themselves (autologous cells) or a donor (allogeneic cells) and are generally classified by their potential to differentiate into desired cell types. Pluripotent cells can transform into any cell type, multipotent cells are progenitors with a limited lineage potential, and fully differentiated or primary cells are fixed. A variety of cell types can be used as therapeutic products and the optimal cell type is typically dependent on the therapeutic application.
Cell therapy may not only involve the harvesting and reintroduction of the desired cell types to a patient, but also require some form of genetic engineering of isolated cells or selection of stem and progenitor cells to induce or generate the correct cellular phenotype. Typical desired phenotypes include the ability to target specific protein biomarkers for the killing of cancer cells or expansion of a particular cellular lineage. In this way, technologies developed for cell therapies often overlap with those developed for gene therapy, which involves the introduction, removal, or change of genetic content to increase or decrease production of a key protein or to produce modified or novel proteins (e.g., using CRISPR methods to generate chimeric proteins).
Cancer is the predominant disease in cell therapy clinical trials, with about one third of all active projects1 focused on this area. This is due to the pressing need to develop improved treatment for patients suffering from cancers that have been historically difficult to treat, such as solid tumors or lymphomas, which exhibit refractory or chronic relapsing behavior where traditional therapies do not offer any long-lasting remission. Such patients urgently require efficacious, fast-acting, and precise treatment options that are tailored to their unique clinical presentations and other factors affecting pathophysiology (e.g., genotypes). In oncology, there is also a possibility for broad applications across numerous indications and the potential for a strong return on investment relative to treatment for rare conditions.2
Cell therapy technologies have the potential to offer such a targeted treatment with high degrees of personalization. Cancer cell therapy focuses on eliminating cancer cells by blocking tumor vascularization and boosting the immune response to tumor antigens. Adoptive cell therapy (ACT)—also known as cellular immunotherapy—uses differentiated, and often genetically modified, adoptive immune cells to eliminate cancer by enhancing their cancer-fighting abilities. These exist in the form of four therapy types: Tumor-Infiltrating Lymphocyte (TIL), engineered T Cell Receptor (TCR), Chimeric Antigen Receptor (CAR) T cell, and Natural Killer (NK) cell therapies.3 As outlined below, each cell therapy approach carries with it certain advantages for application in the treatment of various cancer types, but also specific challenges.
TIL Cell Therapy
Tumors are often infiltrated by tumor-specific T cells, but these cells may fail to control tumor growth. T cells must first become activated before they can effectively kill cancer cells, and then they must be able to maintain that activity for a sufficiently long period of time to sustain an effective anti-tumor response. TIL therapies involve harvesting naturally occurring tumor-infiltrating T cells from the immunosuppressive tumor microenvironment (TME), activating, and expanding them in vitro using IL-2, and subsequently infusing them back into the same patient. This cell therapy has been successful in controlling melanomas and multiple studies indicate that tumor regression following TIL transfer is mediated by T cells targeting tumor-specific antigens, also known as neoantigens.4 TILs are a heterogeneous population, and therefore enrichment of the final product in neoantigen-reactive T cells may enhance clinical efficacy. However, the widespread use of TIL therapy is still challenging and hindered by the logistics of obtaining tumor biopsies for cell extractions. Consequently, the newer therapeutic techniques outlined below, which entail the use of genetically manipulated cells, have gathered favor.
TCR Cell Therapy
Engineered TCR-based ACT therapies isolate peripheral blood T lymphocytes, identify the patient-specific neoantigen repertoire, and genetically engineer the extracted cells to express TCR proteins from TCR gene sequences cloned from TILs capable of targeting neoepitopes with high avidity.5 Some success has been shown in melanoma, sarcoma, and myeloma studies. Despite these successes, methods to generate good manufacturing practice (GMP)-grade, neoantigen-specific, personalized autologous T cells are costly, labor-intensive, and time-consuming. Moreover, such therapies are dependent on co-stimulation and presentation of the targeted neoepitope via the MHC-I complexes on those target cells, which are often downregulated in cancer cells.6
CAR-T Cell Therapy
The limitations of target cell presentation of antigens through MHC-I complexes that plague TIL and engineered TCR therapeutics can be overcome with the use of CAR-T cells. To develop this therapy, peripheral T lymphocytes are extracted and genetically modified in vitro to express CAR molecules able to specifically recognize and bind natively expressed surface antigens not requiring MHC-I presentation on cancer cells. While this narrows the range of potential antigenic targets, the independence and engineered specificity of those cells provide greater productization opportunities with high degrees of customization. CAR-T cell therapy has demonstrated high response rates in patients with chronic lymphocytic anemia as well as B cell lymphoma.7 Out of all adoptive cell therapies, CAR-T cells are the only ones to have received regulatory approval with four products already on the market. These include Kymriah (Novartis) used to treat leukemia, Yescarta (Gilead/Kite Pharma) for lymphoma, Tercatus (Kite Pharma) for the treatment of relapsed or refractory lymphoma, and Breyanzi (Juno Therapeutics, BMS).
Moreover, adult stem cell progenitors of T cells from a single donor could potentially be utilized to generate off-the-shelf cellular products for use in multiple patients. There are, nevertheless, drawbacks to this form of therapy. For example, clinical trials show that CAR-T cells can engraft in the peripheral blood, traffic to tumors, and respond to target antigens but fail to expand, persist, and mediate tumoral expansion or induce regression.8,9 Complex solid tumor microenvironments (TMEs) entail immunosuppressive cells (e.g., regulatory T cells) and molecules (e.g., PD-L1, IL-10, TGF-β), hypoxia, necrosis, and nutrient shortages, all of which must be overcome for CAR-T cells to effectively persist and create circumstances of susceptibility to inhibition and cellular exhaustion. Technologies that provide an in-depth understanding of the heterogeneity of such complex systems will be key to overcoming these challenges to develop successful CAR-T cell therapies.
NK Cell Therapy
NK cells are different from T cell-based therapies in that they express a repertoire of inhibitory and activating surface receptors that are germline-encoded, and therefore they do not require recombination and clonal selection. This enables them to recognize and rapidly act—by releasing cytotoxic granules to directly lyse malignant tumor cells—without prior sensitization. NK cells are not only stronger candidates for allogeneic product development (a more in-depth discussion of this topic will be presented in a future article) but may also be genetically engineered for precision targeting (i.e., CAR-NK cells). As with all ACTs, there are many challenges to overcome in NK cell therapy, such as the difficulty to meet clinical-grade ex vivo expansion, limited in vivo persistence, limited infiltration into solid tumors, and tumor editing to evade NK cell activity.10
In fact, all ACT approaches carry the risks of low cellular expansion, cellular dysfunction, loss of function due to tumor heterogeneity, and antigen loss (the time from cell extraction to reinduction must be narrow to ensure capture of an effective window for treatment), and toxicity. Yet, the promise of these therapies to combat elusive cancers is extremely alluring and has already shown some promise in the market.
Other cells of the innate immune system are also found in the TME, which modulate the adaptive immune response to destroy cancer cells.11 These innate immune system cells—including dendritic cells and macrophages—are being further explored for their therapeutic potential as they reveal promising effects, especially for solid tumors against which T cell therapy has limited efficacy.12
Delivering Cell Therapies to Other Therapeutic Areas
While the use of immune cell (and gene) therapy technologies has found a niche in the realm of oncology, the initial advances in the field came through using undifferentiated or in vitro differentiated stem cells for the treatment of degenerative and systemic diseases. Studies in these fields have advanced to the use of engineered pluripotent cells that show promise as off-the-shelf products. In addition to neurological and neuromuscular diseases such as Alzheimer’s, Parkinson’s, and Muscular Dystrophy, the use of various multi- or pluripotent stem cells has also been shown experimentally to aid in combatting loss of function from physical injuries or heritable autoimmune diseases. Current approved stem-cell therapies include use of mesenchymal stem cells (MSCs), hematopoietic stem cells (HSCs), or induced pluripotent stem cells (iPSCs).
MSCs are multipotent cells derived from sources such as umbilical cord blood, amniotic fluid, or bone marrow. MSC therapies have been applied as treatment for a broad variety of diseases, including cardiovascular diseases, degenerative disorders, and inflammatory bowel diseases. MSCs from cord blood could be used to treat Type 2 diabetes and slow the loss of pancreatic insulin production13, or to selectively migrate to areas of brain injury and repair damaged brain tissue, as observed in cerebral palsy.14 Cord blood stem cells are strong candidates for such regenerative therapies due to their autologous nature, which reduces the risk of exhibiting graft versus host disease after reinduction of a patient’s own stem cells.
HSCs are multipotent stem cells able to self-renew and differentiate into mature blood cells that form the myeloid and lymphoid cell lineages. They are generally bone marrow derived, but many successful products have also utilized cord blood sources due to their tolerance for HLA type mismatches between donors and patients and the avoidance of graft versus host disease. HSC products have already been approved for the treatment of blood disorders through transplantation to reconstitute the hematopoietic and immunologic systems.15
iPSCs are adult cells derived from skin or blood tissue that have been reprogrammed back into an embryonic-like pluripotent state. This, in turn, generates a self-renewing cell source that can be directed in vitro into any type of human cell needed for therapeutic purposes. For example, to treat hematopoietic disorders, musculoskeletal injuries, spinal cord injury, and liver damage by the generation of specific cells.16 Together, stem cell types provide immense opportunities for cell therapies to be applied in previously untreatable conditions.
Prospects, Promises, and Risks of Cell Therapy
The application and development of cell therapy technologies carry immense potential, but also a lot of risk. These risks lie not only in patient safety but for pharmaceutical companies, also in return on investment following a very nuanced, complex, and costly development process that can vary widely from one company to another. Mitigating risks and maximizing efficacy are critical to the success of any new therapeutic product, however cell and gene therapies carry with them the added cost of personalized development. This added product development cost, especially that of autologous cell therapies, demands continuous examination of processes to maximize efficiency. Given the staggering speed at which these technologies change, it was evident at the last ASGCT meeting that companies operating in this field require flexible partnerships with collaborators, CROs, and vendors. Valuable qualities of these organizations include a comprehensive knowledge base and the agility to evolve in concert with the changing needs of partner companies. Over 3000 clinical trials are currently underway for cell and gene therapies1 and adapting organizational infrastructure to monitor the tremendous amounts of scientific and clinical information and enable real-time decision making is essential.
Cell therapies could provide effective treatment solutions for a number of diseases, but it is only through gaining a clear understanding of the science behind each new methodology that we can fully determine the breadth of what each therapy can offer a patient and how to ensure the best healthcare outcome possible. This understanding is also required to continue making technological advances in cell therapy that will enable its application in the treatment of a wider variety of diseases beyond cancer. When developing these therapies, it is important to understand the background and characteristics that differ from patient to patient (and donor to donor) to match the right therapy to the right patient in a precise manner.
Maximum precision can only be achieved from these therapies using a technological solution that assesses outcomes by correlating product efficacy, patients stratified by suitability for a product, and markers of treatment success. Genedata Profiler® is an innovative software solution that allows users to overcome the complex challenges faced during the development and administration of cell therapy products. It facilitates the efficient integration of voluminous real-time data to track efficacy, maintenance of desired cellular phenotypes, and population expansion. The capability to harmonize layered multi-modal data while enabling patient stratification is crucial in the development of cell therapies. It allows acceleration of key decisions in the development of new methods and products, whilst increasing manufacturing process efficiency and reducing cost and treatment delivery time. Genedata is committed to supporting companies framing the future of cell and gene therapy by improving the efficiency of processes and thereby ensuring the best care for patients before, during, and following treatment.