The next breakthrough: using Cell Therapies to treat solid tumors
Cori Gorman, Ph.D., is Senior Director, Biopharmaceutical CMC and Regulatory Affairs at Biopharma Excellence, a PharmaLex company.
Back in the early and mid 1990s, when gene therapy was sweeping though biotech and pharma companies, the term gene therapy encompassed both correction of genetic defects outside the body, or ex vivo (now called cell therapy), and modification of cells — in vivo.
Since then, cell therapy has advanced both in the clinic and in drug approvals faster than gene therapy. Early efforts using donor-provided peripheral blood cells were used to treat leukemia relapse after bone marrow transplantation in combination with interleukin 2.
By early 2000 this work led to the use of allogeneic stem cell transplantation as well as efforts to develop the first chimeric receptors containing portions of an antibody and T cell receptor (TCR). These receptors bind to specific antigens in abnormal cells, causing the T cell to attack these cells and fight diseases such as cancer.
Another type of cellular therapy to have gained prominence is CAR T cell therapies. T cells from the patient and adding chimeric antigen receptors (CAR), which recognize and bind to antigens on the surface of cancer cells. The therapies then kill any cancer cells they find.
This first CAR T treatment was autologous, using the patient’s own cells to treat them. The initial treatments focused mainly on blood-borne diseases, with the FDA approving the first CAR T cell therapy in 2017 — tisagenlecleucel (Kymriah) for B-cell acute lymphoblastic leukemia (ALL). Since then, the FDA has approved another five CAR T cell therapies, all for blood cancers.
CAR T therapy has expanded greatly throughout 2022, with at least 94 companies working within this space. However, CAR T therapies have not had the same success with solid tumors as has been seen with liquid tumors. This is due to the fact that other cells surround these tumors, and this tumor microenvironment of an extracellular matrix and assorted signaling molecules serves as a barrier to active T cells getting to the tumor.
Current research is focused on two approaches to treat solid tumors with cell therapies: 1) understand what is limiting the CAR T access; 2) use cells other than T cells. A review of 50 companies conducting ongoing clinical trials  targeting solid tumors shows there are over 30 different targets being tested. Some of the innovative companies that have taken on the challenge of CAR T therapy in solid tumors include: Arcellx, Cell Therapies, Bellicum Pharmaceuticals, CARsgen Therapeutics, CytoMed Therapeutics, PersonGen BioTherapeutics (Suzhou), and Verismo Therapeutics. Arcellx is of interest as they plan to use their technology to treat both cancer and autoimmune diseases. To accomplish this task they have developed a somewhat unique approach with the design of a novel D-Domain, which is a small stable synthetic binding molecule with a hydrophobic core. This structure, when used in a CAR, has the potential to improve target specificity and increased binding affinity. Though their clinical work has been focused on liquid tumor they have ongoing efforts to treat two solid tumors: hepatocellular carcinoma (HCC) and small cell lung cancer (SCLC).
The potential for cell therapies to target solid tumors has moved a step closer with some breakthrough findings using cell types other than T cells, such as Natural Killer (NK) cells, Macrophages, Gamma-Delta (γδ) T Cells, and Invariant Natural Tiller T cells (iNKT).
The work with NK cells, using CAR-NK, is perhaps the most advanced research targeting solid tumors. NK cells are part of the body’s natural immune system and are known for their effectiveness in killing virally infected cells as well as tumor cells This presents a huge leap forward in what has proven to be a scientific barrier. One of the earliest to adopt this approach was Dragonfly, which has focused its cell therapy platform on NK cells and cytokines – both part of the immune system – to target diseased cells. Like most companies in this space, Dragonfly has only been around for a few years.
Other companies focused on CAR-NK cell therapy to treat solid tumors include FATE therapeutics, Alloplex Biotherapeutics, ImmunityBio, and Acepodia Biotech. Each has adopted a different approach. The hope is that these companies will take cell therapy into an exciting new era, bringing hope to more patients.
One company developing macrophage cell therapy is Carisma Therapeutics. This company uses macrophages, which are actively recruited to solid tumors. The focus is on engineering strategies to target these cells to the specific tumors via CAR-Macrophages. Novartis recently began working with Carisma Therapeutics targeting HER2+ cancers. Other companies using macrophage cell therapies include Inceptor Bio, which is developing CAR platforms using T cells, NK cell and Macrophages.
CytoMed Therapeutics, Alloplex Biotherapeutics and Adicet Bio are all using Gamma-Delta T cells to target solid tumors. These cells have been shown to have anti-cancer activity, tissue tropism, and multivalent response against a broad spectrum of the tumors. Gilead company Kite and early stage biotech company Appia Bio are working together to test CAR-iNKT cell therapy with the hope of using the technology in solid tumors. Elsewhere, SUDA Pharmaceuticals is working with Imperial College London to develop CAR-iNKT cells. In addition, Arovellla Therapeutics and Mink Therapeutics are both making progress toward testing CAR-iNKT cells in the clinic.
The next frontier is to make all these novel cell therapies into “off the shelf drugs”. This would allow the successful treatments to be available to a larger portion of cancer patients.
 https://bioinformant.com/car-t-companies-the-meteoric-rise-of-cellular-immunotherapies/#introductio; https://www.cancer.gov/publications/dictionaries/cancer-terms/def/t-cell-receptor
 To learn more about Gamma-Delta cells and iNKT cells see these links: Cells. 2020 May; 9(5): 1305.Int. J. Mol. Sci. 2022, 23, 7547.
 British Society for Immunology, Natural Killer Cells, https://www.immunology.org/public-information/bitesized-immunology/cells/natural-killer-cells
 Read more about CAR-Macrophages at: Nat Rev Immunol 20, 273 (2020) and Nat Biotechnol. 38, 947 (2020)