Transforming Healthcare: What’s on the Horizon for Cell Therapies?

Cell therapy is a promising, rapidly advancing field with the potential to transform treatments across many diseases. It is primarily used to treat cancer but is expanding into incurable diseases such as autoimmune disease and heart fibrosis.

“Cell therapies have enormous potential to treat patients with a disease or injury that requires replacement or repair,” explained Dr. April Pyle, professor and vice chair of microbiology, immunology and molecular genetics at the University of California, Los Angeles’ (UCLA's) Broad Stem Cell Research Center. “They can be used to directly deliver new cells to patients in need of cells in a particular tissue or organ system.”

“These cells could be isolated from a matched donor (allogeneic), or isolated from a patient, then processed in the lab and reinfused to the same patient (autologous)," added Dr. Ahmed Gad, a postdoctoral associate in pediatric hematology, oncology and cell and gene therapy at Baylor College of Medicine.

This broad definition means blood transfusions and bone marrow transplants are considered types of cell therapy, but more recently, the term is used to refer to the transfer of a particular cell population, including stem cells and immune cells.  

Cell-based therapies, such as stem cell-based therapies and CAR T-cell therapies, are transforming healthcare, but what does the future hold for them and how can we overcome the barriers to their expansion?

Immune cell therapies

Immune cell therapies isolate and process a particular immune cell population and use it for therapeutic intervention. The first to receive US Food and Drug Administration (FDA) approval was sipuleucel-T, a dendritic cell (DC) therapy for men with advanced prostate cancer that had not responded to hormone therapy.

Gad describes sipuleucel-T as “kind of a hack to the system” with DCs acting as “professional antigen-presenting cells” that detect foreign antigens originating from pathogens, mutated proteins or foreign tissues. DCs travel to an injured site, ingest proteins, digest them into small peptides (epitopes) and present them on their surface with human leukocytic antigen (HLA), before moving to the lymph nodes where T cells and B cells reside.

During treatment, a patient’s DCs are isolated and incubated in the lab with synthetic prostate cancer proteins. This is then reinfused into the patient to activate T cells – what Gad calls "professional assassins" – that seek out and destroy cancerous cells displaying HLA and foreign antigens specific to the prostate cancer proteins.

The FDA has since approved multiple T-cell therapy products, including those with transgenic T-cell receptors (tgTCRs) or chimeric antigen receptors (CARs).

CAR T-cell therapy and cancer

Gad’s lab focuses on CAR T-cell therapy (Figure 1), “a form of engineered T-cell therapy that brings the best of two worlds together”. Used mainly in oncology, patient-derived T cells are “engineered to express a synthetic surface receptor that has the antigen binding domain of an antibody fused to the TCR signaling machinery; this fusion is what gives it the name ‘chimeric’,” he explained.

Figure 1: In CAR T-cell therapy, T cells are isolated from the blood and genetically modified to express cancer-targeting CARs. Engineered cells are then expanded and administered back to the patient. Credit: Technology Networks.

Antibodies have “the superb ability to identify proteins in their intact form with no need for digestion and presentation on HLA,” Gad continued. When a CAR's antibody-derived antigen-binding domain identifies a tumor cell's surface antigen, it forms an immune synapse – an interaction site between the CAR T cell and the tumor cell. This triggers downstream signaling, recruiting co-activatory, co-inhibitory and adhesion molecules to the immune synapse. These interactions lead CAR T cells to recruit lethal mechanisms to the immune synapse to kill the cancer cell.

Gad said CAR T-cell therapy is “compatible with any patient's cancer and can be easily engineered against any tumor-associated surface protein.” His lab pioneers the development of HER2 CAR T-cell therapy for treating brain and bone/sarcoma cancers.

To better understand the determinants of CAR T-cell success on the microscopic level, Gad’s research focuses on the CAR immune synapse (CARIS), the “battlefront between a CAR T cell and a cancer cell”, and the events taking place there. This offers a better insight into the tactics used by both the CAR T cells and tumor cells during their fight and can drive the engineering of CAR T cells with better therapeutic capacities. In their recent research paper, Gad and colleagues found that the two most common designs of CAR T cell – CD28 signaling and 41BB signaling CAR T cells – use two different killing strategies.

“CD28 CAR T cells are serial killers,” Gad explained. “They have the ability to kill a cancer cell fast and move to kill others.” They succeed because they have brief synapse interactions, “in which they can converge toxic granules ‘grenades’ toward the synapse and release them onto the tumor cell. These grenades make pores in the cell membrane of the tumor cell through which toxic proteins get in to kill it.”

The second design, 41BB CAR T cells, Gad describes as ‘cooperative killers’: “When they see the tumor, they expand into more CAR T cells. Multiple CAR T cells then bind to a single cancer cell. They have a more protracted interaction that rely on a more chronic killing machinery, which is the chronic interaction between Fas ligands on CAR-T with Fas receptors on the surface of tumor cells.”

On the molecular level, Gad found that CAR T cells use special membrane microdomains called lipid rafts to recruit functional receptors to the CARIS. These rigid islands that float on the surface of the fluid cell membrane provide structural and functional support at the immune synapse.

Gad’s research found that the dynamics of CAR interaction with lipid rafts influence the cancer-killing behavior of CAR T cells. “For example, the brief cellular interactions that CD28 CAR T cells have with cancer cells are a reflection of the brief molecular interactions between CD28 CAR molecules and CAR T cell membrane lipid rafts,” Gad explained.

“In the same sense, 41BB CAR T-cell protracted CARIS correlates with protracted interactions between 41BB CAR molecules and CAR T cell membrane lipid rafts. This knowledge can guide us to control the dynamics of CAR recruitment to the CARIS, and accordingly, the killing strategy used by CAR T cells.”

Stem cell-based therapies

Stem cells are unique in that they can differentiate into the cell type of interest, meaning they are of great use in cell therapies.

“There are two different types of stem cells: multipotent, which can give rise to cells from a particular tissue (i.e., blood stem cells); or pluripotent, which can give rise to all three major lineages of the body (i.e., mesoderm, ectoderm and endoderm),” explained Pyle.

“Pluripotent stem cells are powerful in that they can generate most if not all cell types in a dish and can even be generated from each patient to enable personalized medicine approaches to treat disease,” Pyle said.

Stem cell therapy, or regenerative medicine, uses stem cells or their derivatives to promote the repair response of diseased, dysfunctional or injured tissue. Stem cells are cultivated in the laboratory and manipulated to develop into specific types of cells, which can then be infused into a patient.

Pyle studies human pluripotent stem cells (hPSCs) and their ability to differentiate into one of the mesoderm lineages called skeletal muscle.

“Skeletal muscle is endowed with a stem cell called a muscle stem cell that can regenerate after injury, but is defective in aging, muscle loss and in various genetic diseases,” said Pyle. “We have shown that hPSC-derived skeletal muscle cells can repopulate regions of muscle with the potential to restore function in patients with muscle disease.”

Pyle and her colleagues have created a first-of-its-kind roadmap of the development of human skeletal muscle. They identified various cell types, but focused on muscle progenitor cells, which form muscles before birth, and muscle stem cells, which aid muscle formation after birth and regeneration from injury throughout life.

The researchers charted how the cells' gene networks changed as cells mature, locating the precise networks present in muscle progenitor and stem cells across development. Their work is essential to developing methods to create such cells in a dish to treat muscle disorders like muscular dystrophies and sarcopenia, the age-related loss of muscle mass and strength

The future of cell therapy

Pyle says the potential for stem cell-based cell therapy is enormous. “Not only can we generate most specialized cell types from pluripotent stem cells now in the lab, but many in the field have also begun to translate these to patients in need, including for diabetes and heart disease, among many others.”

“The future of stem cells is bright and offers groundbreaking therapies for many developmental and adult disorders and diseases,” said Pyle.

Gad is just as enthusiastic about the future of CAR T-cell therapies. Most targeted biological therapies and CAR T-cell therapies are in the field of oncology, “as they can laser-target tumor cells with much less side effects compared to chemo- and radiotherapy,” Gad said. While many CAR T-cell therapies target solid tumors in the clinical pipeline, “the complexity of the disease renders these therapeutic modalities less successful compared to those against hematological malignancies.”

Gad foresees CAR T-cell therapy moving “toward more sophisticated designs that address the resistance mechanisms used by cancer to evade immune response.” He also believes CAR T-cell therapy could target with high precision other incurable diseases such as autoimmune disease and heart fibrosis. “Accordingly, CAR T-cell therapy can transform the healthcare system, given that the system can adapt to their [patients] very different needs.”

But there are barriers to overcome, which Gad believes are likely to be industrial rather than scientific. Personalized therapies like CAR T-cell therapy and tgTCR are manufactured from the blood of each single patient and processed separately, then delivered to the hospital where the patient is being treated. “This makes the production much slower, requires more sophisticated shipping and introduces more variables to the process,” Gad said.

Some companies have developed point-of-care manufacturing where benchtop machines manufacture CAR T-cell therapy at the hospital, “reducing the vein-to-vein time, by limiting the wait time that comes with production in large-scale industrial facilities, shipping and delivery,” explained Gad.

Another option is for “off-the-shelf" CAR T-cell therapy, to try to delete immune recognition genes from CAR T cells and make them compatible with all patients rather than a single patient, to avoid rejection by the patient's immune system. “This would make larger-scale production more feasible. Together with more training for healthcare personnel, cell therapies can be more affordable and accessible,” Gad said.

Pyle believes that, depending on the type of therapy needed, the ability to expand cells to the levels needed for clinical avenues can be challenging. “However, many scientists, including those at UCLA, have been working on approaches to improve both scalability and safety in clinical good manufacturing settings. With training, hard work and dedicated teams working on these projects, I am certain we will be able to overcome these barriers.”